key: cord-0984450-fkfuivj3
authors: Acosta, Patricio L.; Byrne, Alana B.; Hijano, Diego R.; Talarico, Laura B.
title: Human Type I Interferon Antiviral Effects in Respiratory and Reemerging Viral Infections
date: 2020-05-08
journal: J Immunol Res
DOI: 10.1155/2020/1372494
sha: 4aac338565fbaf6a69ca06d73972a63ea1119313
doc_id: 984450
cord_uid: fkfuivj3

Type I interferons (IFN-I) are a group of related proteins that help regulate the activity of the immune system and play a key role in host defense against viral infections. Upon infection, the IFN-I are rapidly secreted and induce a wide range of effects that not only act upon innate immune cells but also modulate the adaptive immune system. While IFN-I and many IFN stimulated genes are well-known for their protective antiviral role, recent studies have associated them with potential pathogenic functions. In this review, we summarize the current knowledge regarding the complex effects of human IFN-I responses in respiratory as well as reemerging flavivirus infections of public health significance and the molecular mechanisms by which viral proteins antagonize the establishment of an antiviral host defense. Antiviral effects and immune modulation of IFN-stimulated genes is discussed in resisting and controlling pathogens. Understanding the mechanisms of these processes will be crucial in determining how viral replication can be effectively controlled and in developing safe and effective vaccines and novel therapeutic strategies.

Type I interferons (IFN-I) are members from a large family of signaling proteins known for their potent antiviral activity. IFN-I were discovered in 1957 by Lindenmann and Isaacs and received their names based on the ability to interfere with influenza virus replication in chick cell culture [1] [2] [3] . In recent years, the knowledge about the mechanism of IFN-I production has quickly expanded.

IFN-I are produced by most cell types, the best known members of this group are IFN-α and IFN-β, and it also includes IFN-ο, IFN-δ, IFN-κ, IFN-ε, IFN-τ, and IFN-ω [4, 5] , which directly mediate a potent antiviral response. IFN-α includes 13 partially homologous members, encoded by chromosome 9, while IFN-β is composed by a single member and the gene is located on chromosome 12 [4] .

IFN-I production occurs primarily when pattern recognition receptors (PRRs) present on the cell surface or in the cytosolic compartment of virtually all cell types are stimu-lated by pathogen-associated molecular patterns (PAMPs) [6] [7] [8] . The most widely studied PRRs are Toll-like receptors (TLRs). Ten different TLRs have been identified in humans, all of which detect PAMPs either on the cell surface or the lumen of intracellular vesicles, such as endosomes or lysosomes, and are involved in the recognition of a particular type of PAMP [6] . TLRs recognize different pathogen components, including double-stranded RNA (dsRNA) (TLR-3), single-stranded RNA (ssRNA) (TLR-7), or CpG DNA [6, 9, 10] . Other PPRs include retinoic acid-inducible gene-I-(RIG-I-) like receptors (RLRs) and nucleotide-binding oligomerization domain-(NOD-) like receptors (NLRs).

The recognition of TLR ligands leads to the recruitment of adaptor molecules that contain Toll interleukin-1 receptors (TIR) such as TIR-domain-containing adapter (TRIF), TRIF-related adaptor molecule (TRAM), Myeloid differentiation primary response gene 88 (MyD88), or TIR-domaincontaining adaptor protein (TIRAP), leading the activation of molecular cascades that finally promote the activation of nuclear transcription factors such as nuclear factor κB (NF-κB), IFN regulatory factor 3 (IRF-3), and 7 (IRF-7) [11, 12] , which leads to the induction of genes encoding IFN-I (Figure 1(a) ).

Both IFN-α and IFN-β use the same receptor, IFN-α/β receptor (IFNAR), which is expressed on a vast variety of cell types [5] (Figure 1(b) ). This receptor is associated with Janus kinase 1 (JAK1) and Tyrosine kinase 2 (TYK2). IFN-α/IFN-β binding to IFNAR activates JAK1 and TYK2, which subsequently phosphorylate the transcription factor signal transducer and activator of transcription 1 (STAT1) and STAT2 [13] , among other less characterized transcription factors such as STAT3, STAT4, and STAT5. Once phosphorylated, these factors associate with IRF-9 to form the IFN-stimulated gene factor 3 complex (ISGF3). In the nucleus, this complex binds specific DNA sequences containing IFN-stimulated response elements (ISRE) that promote the transcription of hundreds of IFN-stimulated genes (ISGs) including IRF-1, IRF-7, IRF-8, and IRF-9, whose function is to inhibit viral replication and induce an antiviral response in the area of the infected cell [13] [14] [15] . Some ISGs have been widely studied; the best known members include IFN dsRNAdependent protein kinase R (PKR), 2′-5′oligoadenilate synthetase (OAS), IFN-inducible transmembrane proteins (IFITM), dsRNA-specific adenosine deaminase (ADAR), and Myxovirus resistance protein A (MxA) and B (MxB) [16, 17] .

The viral infectious cycle involves several steps, and ISGs target different stages of the viral cycle. For example, PKR, which was among the first ISG described, is a PRR that recognizes dsRNA, inducing IFN production and further ISG production [18] . PKR inactivates eIF-2α, leading to a global translation blockage of both viral and cellular mRNA [19] . OAS is also activated by cytoplasmic dsRNA and is subsequently involved in the degradation of RNA (through RNAse L), contributing to the inhibition of protein synthesis and therefore viral replication [20] . In the case of IFITM, the four members (IFITM-1, IFITM-2, IFITM-3, and IFITM-5) are present in endosomes and lysosomes and have a critical role in the inhibition of viruses that require vesicles for effective infection [21] . ADAR is a nucleic acid editing enzyme that disrupts base pairing. ADAR catalyzes the deamination of adenosine (A) to produce inosine (I) in dsRNA, inducing the replacement of the AU base pair by IU, which produces dsRNA destabilization [22] . On the other hand, MxA and MxB play a critical role during viral entry; while MxA acts in the early stages of infection once the virus has traversed the plasmatic membrane, MxB acts at the nuclear stage, inhibiting nuclear entrance [23, 24] .

Dendritic cells (DCs) play a key role in the production of IFN-I. Although both myeloid DC (mDC) and plasmacytoid DC (pDC) produce IFN, the latter express specialized TLR-7 and TLR-9 and has a high constitutive expression of IRF-7 that allow them to respond to viruses with rapid and extremely robust IFN-α production [25] [26] [27] . Upon activation and production of IFN, pDCs mature into antigen-presenting cells (APC) serving as a key link between the innate and adaptive immune responses [28] . In addition, DCs produce IL-12, which drives naïve T cells into Th1-type responses, as well as IFN-α, which increases the frequency of IFN-γ producing CD4 + T cells [29] . Moreover, IFN-I also boost natural killer (NK) and CD8 + T cell responses, promoting both survival and clonal expansion of the latter [30] [31] [32] . IFN-α and IFN-β lead to an immediate innate antiviral response and stimulate the adaptive immune system, affecting myeloid cells, NK cells, T cells, and B cells to mount an adequate Th1-biased immune response [16, 33] .

Since its discovery, IFN's role as an important player of the immune system against viral infections has become evident. Although IFN is known for its innate beneficial response, recent studies have also linked these immune mediators to pathogenesis.

This review summarizes the current knowledge of the roles of IFN-I in respiratory virus and reemerging flavivirus infections (Table 1 ) and on the strategies that different viruses adapt to subvert IFN-I responses, mainly focusing on studies in human cells and subjects.

2.1. Human Respiratory Viruses. Respiratory viruses including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (hMPV), parainfluenza virus (PIV), human rhinovirus (HRV), and human coronavirus (HCoV) are a major cause of respiratory disease and mortality in humans [34] [35] [36] . The disease can range in severity from mild or asymptomatic upper airway infections to severe wheezing, bronchiolitis, pneumonia, or death. Numerous factors can increase the risk of severe disease, including neurological conditions, chronic lung and/or heart disease, metabolic disorders, or a weakened immune system [37] . However, the majority of severe cases occur in previously healthy persons [34, 35] .

When a cell is infected, the viral sensing activates pathways that trigger host immune responses. The viral presence is detected by several distinct PRRs including TLR-2, 3, 4, 6, 7, and 8, RLRs including RIG-I and MDA5 pathways among others [38] [39] [40] . These signaling pathways converge on IRF-3/IRF-7 and NF-κB that promote the induction of IFN-I that inhibit viral replication and contribute to the initiation of more specific adaptive immune responses [40] . IFN-α and IFN-β bind to receptor complexes, which activate STAT1 and STAT2 phosphorylation. IRF-9 binds to STAT1/STAT2 heterodimers forming the ISGF3 complex, which translocates to the nucleus to induce transcription of ISGs and to mount an antiviral state within the cell [39, 41] .

Respiratory viruses, like other pathogens, target core molecules of the immune cascade to evade the host response. Like other different viruses, one major strategy used by respiratory viruses is to modulate, evade, or inhibit the IFN response that allows viral replication and transmission [41] [42] [43] .

2.1.1. Influenza Virus. Influenza virus is a negative-sense, ssRNA virus that belongs to the Orthomyxoviridae family. This pathogen is a leading cause of respiratory illness in humans and causes annual epidemics and pandemics of differing severity [44] . The human subpopulations most vulnerable to influenza virus infections are children, pregnant women, and persons over 65 years old. [77, 190, [193] [194] [195] [196] Human (in vivo) Pathogenic Higher levels of IFN-β in severe vs. nonsevere dengue children [197] Human (in vivo) Pathogenic Higher levels of IFN-β in primary DHF patients compared to those with primary DF [198] ZIKV Human (in vivo) Protective SNP at TLR-3 that decreased IFN-I response has been associated with microcephaly in newborns [232] Human (in vitro) Protective

Replication of Asian ZIKV strain Brazil 2015 (associated with neurodevelopmental disorders) was less sensitive to IFN-I, compared to other ZIKV strains [233] WNV Human (in vitro) Protective PI3K that induces IFN-I controls WNV infection [238] Human (in vitro) Protective Early activation of RLR or IFN-I signaling could block WNV infection [239] Human (in vivo) Inconclusive IFN-α treatment was well tolerated and might have potential beneficial effects, due to treatment or chance [293] [294] [295] [296] YFV Human (in vitro) Protective/pathogenic ISGs shown to inhibit or enhance viral replication [258] JEV Human (in vitro) Protective IFN-α at higher concentrations showed more efficacy in combating the replication of JEV [297] Human (in vivo) Inconclusive No benefits from IFN-α2a treatment against children with JEV infection [298] SLEV Human (in vivo) Protective IFN-α2b therapy for meningoencephalitis suggested a beneficial effect on the early neurologic course of the disease and clinical improvement [299, 300] 4

Influenza virus is primarily recognized by two different types of PRRs: RLRs and TLRs. Regarding the RLR family, RIG-I, LGP2, and MDA5 sense viral RNA during viral replication in the cytoplasm [45] [46] [47] . Once activated, RIG-I and MDA5 interact with the mitochondrial antiviral-signaling protein (MAVS), leading the activation of NF-κB and IRF-3 to stimulate IFN production ( Figure 2 ). On the other hand,

LGP2 has been related to the regulation of RIG and MDA5 activation [48] . Two different TLRs are activated by influenza virus, TLR-3 and TLR-7. The stimulation of TLR-3 in DCs and macrophages signal through TRIF, activating IRF-3/ NF-κB, leading to IFN-β secretion. On the other hand, TLR-7 in DCs activates MyD88, which activates IRF-7 and produces the secretion of both IFN-α and IFN-β [49, 50] .

Influenza virus NS1 suppresses IFN synthesis through several different mechanisms [51] [52] [53] [54] (Figure 3 ). First, it limits the pretranscriptional induction of IFN by forming a complex with RIG-I and limiting its signaling [55, 56] . Second, it directly limits the extent of the antiviral state by inhibiting PKR by sequestering dsRNA and by forming a complex with PKR avoiding its activation [57, 58] . Third, it inhibits mRNA maturation by interfering with the effector domain of the 3 ′ -end processing [59] . Finally, NS1 activates phosphatidyl-inositol-3 kinases (PI3K) which can delay apoptosis of infected cells [60] .

The evidence supporting the role of IFN-I during influenza infection in human populations is limited. Much of the available information focused on animal studies that have yielded mixed results. While some studies have found a protective role of IFN-I, others found no effect or even a pathogenic role [61] [62] [63] [64] . Originally, Hall et al. detected that increased IFN production in nasal washes in children infected with influenza virus was associated with decreased shedding of virus [65] . Subsequent studies identified the high levels of IFN-I in breastfeeding children infected with influenza virus, providing support to the hypothesis that breastfeeding protects against respiratory viral infection [66, 67] . Additionally, a study of elderly subjects demonstrated that IFN-α production is decreased during influenza virus infection and suggested that this impairment can produce multiple defects in their innate and adaptive immune responses that could lead to increased severity [68] . Likewise, other studies have shown that pregnant women have an attenuated IFN-α response to influenza virus [69] .

As mentioned previously, IFITM are a family of interferon-induced antiviral restriction factors with constitutive expressions in different cell types that are known to be induced by IFN-I. Recent evidence has shown that ISG IFITM3 is a potent antiviral factor in restricting influenza virus infection and a decrease in its expression results in a higher risk of hospitalization [70, 71] .

. RSV is a common virus that belongs to the Paramyxoviridae family. RSV is a negative-sense ssRNA virus that causes a wide range of symptoms and the severity can vary from mild to lethal disease [59] . RSV is especially severe in infants, the elderly, and immunocompromised individuals [72, 73] . Despite years of research, RSV is the only major etiological agent of acute lower respiratory tract infection (ALRI) for which no vaccine or specific treatments are available.

Several PRRs are involved in RSV recognition, including TLRs (TLR-2, TLR-3, TLR-4, and TLR-7), RLRs (RIG-I and MDA5), and NLRs (NOD-2). IFN-I production during RSV infection is activated by different mechanisms (Figure 4 ). TLR-3 detects dsRNA during viral replication 5 Journal of Immunology Research and signals through TRIF, which activates IFN-α production through NF-κB and IRF-3 pathway [74] . Other important PRRs for IFN-I production are RIG-I and MDA5 which subsequently link MAVS. This recruits TRAF2/6 and TRAF3 which leads to the activation of IRF-7 and IRF-3 through NF-κB [75] . Together, these IRFs stimulate ISRE sequences that promote IFN-I production [76, 77] . NLRs also play a role in activating the IFN-I pathway. NOD-2 can recognize RSV ssRNA, thus, mediating IRF-3 and NF-κB activation pathways and leading to the IFN-β production [78] . Although RSV can lead to IFN-I production through multiple pathways, it has been established that this virus in particular is a poor stimulator of IFN-I. Unlike other respiratory viruses, studies have shown a limited role for IFNs in response to RSV infection [65, 79, 80] . Thereby, NS1 and NS2 (2 proteins encoded by RSV) appear to interact (and interfere) with multiple molecules of the IFN pathway (RIG-I, TRAF3, and IRF-3), which then interfere with IFN synthesis [81] [82] [83] [84] (Figure 3 ). Studies of RSV NS1 and NS2 proteins have demonstrated that they are crucial for virus replication in vitro, however, through IFN-I antagonism, they contribute to adequate RSV replication in vivo (and in vitro) [85] . Using interference RNA that allowed the inhibition of NS1, the expression of IFN-α and IFN-β was augmented and this increase was associated with a reduction in viral titer [86] . On the other hand, NS2 has been shown to be the main IFN-I antagonist related to the STAT-2 pathway [82, 87] , thus, inhibiting IFN-α and IFN-β responses through JAK/STAT signaling [82, 88] .

One interesting study by Marr et al. showed that RSVinduced IFN-α expression by primary pDCs exposed to RSV is strongly correlated with age, observing higher IFN-α expression in healthy adults, followed by preschool children and little to no expression in healthy full-term infants [89] . This analysis of developmental innate immunity associated with poor IFN-I production during the first year of life suggests a role for IFN-I in RSV pathogenesis. Deficits in MAVS or RIG-I signaling events could explain this deficit. Furthermore, infants with severe bronchiolitis have less IFN-I levels when compared to those with moderate disease [90] . Taken together, these results suggest a critical role for IFN-I in RSV infection.

. hMPV is a member of the Paramyxoviridae family, genus Metapneumovirus [91] . Isolated in 2001 [91] , hMPV is a nonsegmented negative-strand RNA virus [92] and has been associated with the upper and lower respiratory tract infections with symptoms ranging from colds to pneumonia. hMPV particularly affects children, the elderly, and immunocompromised individuals [93] . Worldwide, hMPV is recognized as the second most common cause of bronchiolitis and pneumonia in children under 5 years old [94] . Despite the fact that hMPV is a clinically relevant pathogen, no vaccine is currently available.

Similar to RSV, two major pathways for the secretion of IFN-I during hMPV infection have been described. Each pathway involves different types of PRRs, one utilizes RLRs and the other TLRs. The former is primarily activated by RIG-I and MDA5, whereas the latter involves TLR-3 and TLR-7. RIG-I-and MDA5-mediated signal transduction begins when viral RNA is sensed in the cytosol. This recognition leads to the activation of IRF-3 and IRF-7 through the MAVS pathway [75, 95, 96] . TLR-3 activates the IFN pathway through IRF-3 and TLR-7 via IRF-7.

It is worth noting that the vast majority of cells express IRF-7 only after the activation of IRF-3 (which is expressed constitutively and is activated essentially by the RIG-I/MAVS pathway) or in response to IFNs. Importantly, TLR-7 is the main PRR that participates in sensing hMPV by pDCs, whereas MDA5-MAVS is the major pathway mediating hMPV sensing in conventional DCs [75] .

Similar to other respiratory viruses, evidence suggests that hMPV has mechanisms for evading IFN-I production through interference in TLR-and RLR-dependent surveillance pathways. Early studies published by Dinwiddie et al. showed that hMPV can inhibit the IFN-α pathway in A549 cells. Therefore, this virus abolished the IFN-α pathway and downstream ISG signaling through mechanisms that regulate STAT1 activation [97] . One study supporting this information found that hMPV suppressed IFN-I responses through mechanisms involving the regulation of STAT1, STAT2, JAK1, TYK2, and the surface expression of IFNAR1 [98] . hMPV proteins impair the activation of PPRs through several different mechanisms. hMPV M2-2 protein interferes with MyD88 adaptor, a critical component for the activation of proinflammatory genes. This protein also interacts with MAVS, altering the production of IFN-β and also prevents IRF-3 phosphorylation [99] . In addition, hMPV G protein alters the recognition by RIG-I thereby influencing the secretion of IFNs, and the small hydrophobic protein can inhibit NF-κB, which is an important component in the IFN pathway [100] . Finally, the hMPV phosphoprotein B1 interferes with RIG-I recognition [75] .

Studies describing the role of IFN-I in hMPV infections in humans are very limited. One study has shown that IFN-β was induced after hMPV infection in children [101] . In addition, a deleterious effect of IFN-I was reported in a murine model, in which IFN-I contributed to disease pathogenesis due to increased inflammatory lung disease during infection [102] .

PIVs are a group of nonenveloped, negative-sense, ssRNA viruses that belong to the Paramyxoviridae family. First isolated in the 1950s, PIVs are composed of five different (antigenic and genetic) types, PIV-1, PIV-2, PIV-3, and PIV-4 with two subtypes PIV-4a and PIV-4b [59, 103] . The virus was named Parainfluenza because it produces influenza-like disease and has a lipid envelope and hemagglutination and neuraminidase activities [59] . Worldwide, PIVs are important causes of upper and lower respiratory tract illnesses. Although PIV infections are generally self-limiting, some patients require hospitalization and the disease may lead to mortality, especially in children under the age of five years [104] , the elderly, and the immunocompromised individuals.

All PIVs encode 6 universal proteins, N, P, M, F, HM, and L, and at least one additional protein from the P gene (C, V, D, W, and I), which is not essential for viral replication [59] .

The innate immune response to PIV is not well-characterized, and little is known about the signaling pathways. Unlike other respiratory viruses, TLR signaling is not described but is thought to play a role in the IFN pathway activation during PIV infection. Regarding RLRs, a study showed that RIG-I is involved in IFN-I induction via IRF-3 after PIV-3 infection [105] . In addition, MDA5 has also been found to be activated by degraded products of RNase L from PIV [106] .

This group of viruses is known to encode proteins that block innate immune responses to viral infections, allowing PIV replication. As mentioned above, pathogen RNA synthesis provides strong stimuli to mount an IFN immune response. PIV-1 and PIV-3 encode C proteins, while PIV-2 encodes a V protein. Both proteins, C and V, are involved in the blockade of IFN-I induction by preventing PKR activation [107] [108] [109] [110] . The viral strategy in the case of PIV-1 and PIV-3 is to avoid the IFN production. PIV-1 does not inhibit the IFN pathway, given that the synthesis of the viral RNA can activate IFN production. Rather, the viral C protein modulates its RNA production, preventing MDA5 activation [109, 111] . This protein also interferes with STAT1, avoiding signaling through this pathway and thus IFN production [112] . The V protein of PIV-2 interferes with the IFN production in different ways. One of the mechanisms is the inhibition of MDA5 activation [113] . In addition, the highly conserved V protein Cys-rich domain has been shown to be both necessary and sufficient to limit the activation of the IFN-β promoter [114] . Finally, the V protein interferes with the IFN pathway by abolishing STAT2 signaling [115] . Interestingly, there is evidence that shows that this protein also regulates viral RNA production (as PIV C protein) [116] .

Overall, little is known about IFN-I response after the PIV infection in human population studies. An early work detected IFN-I in patients with primary PIV infection [65] .

In vitro experiments have shown that PIV-2 induced IFN-α by day 2 postinfection, PIV-3 by day 3, and that PIV-1 did not produce this molecule. IFN-β production was shown to be poor in all serotypes [117] .

HRV is a small, nonenveloped, positive-sense, ssRNA virus that belongs to the Picornaviridae family. The family is divided into three species: rhinovirus A, B, and C [59] . HRV is a ubiquitous seasonal microorganism and is the most frequent cause of common cold (causing more than 50% of upper respiratory tract infections in humans worldwide). Given that the viral genetic diversity is huge (>160 serotypes), recurrent infections with this virus are frequent. Although HRV infections are not life-threatening, they can be also detected in the lower airways where they can cause severe exacerbations in patients with asthma and chronic obstructive pulmonary disease [118, 119] .

Different PRRs are involved in HRV recognition, belonging to two different families of receptors: TLRs (TLR-2, 3, 7, and 8) and RLRs (RIG-I and MDA5). TLR-2 on the cell surface recognizes the virus capsid, even without viral replication. In addition, TLR-3, TLR-7, and TLR-8 localized in intracellular compartments are stimulated once the viral particle is internalized and the dsRNA/ssRNA is sensed [120] . The TLR stimulation leads to the activation of downstream signaling molecules that activate IRF-3, IRF-7, and NF-κB, triggering IFN-I secretion. The evidence regarding TLR-3 is somewhat unclear; while one study described an important role for this receptor in the host response against the HRV infection [121] , others found no function for this PRR [120] . The HRV genome is also recognized by RIG-I and MDA5 (both localized in the cytosol) which can recognize ssRNA and dsRNA, respectively. The RLR stimulation leads to the activation of MAVS and the consequent activation of NF-κB and IRF, triggering the production of IFN-I in the airway cells [120, 122, 123] . Responses mediated by IFN-I in vivo are critical for the antiviral effects that limit HRV through the activation of NK cells [124] .

Similar to other respiratory viruses, HRV seems to suppress IFN synthesis using multiple strategies. Even though IFN evasion mechanisms have been well-studied in other enteroviruses, the information for HRV is scarce. A study showed that the MAVS adaptor is cleaved by 2A and 3C proteases of HRV to stop IFN-I signal transduction [125] . Furthermore, the 3C proteases have been implicated in the cleavage of RIG-I altering IFN-I production [126] . Regarding TLRs, despite their crucial role in viral sensing, there is no evidence of TLR signaling evasion by HRV.

Different studies have attributed susceptibility to HRV infection to impaired IFN-I production that leads to a higher viral load [127, 128] . Abnormal HRV-induced IFN in asthmatic patients was shown in peripheral blood mononuclear cells (PBMCs) for IFN-α and in primary human bronchial epithelial cells for IFN-β [129] . In addition, in vitro studies on epithelial cells showed that exogenous IFN-I led to reduced viral load [130] . Furthermore, this has been confirmed in epithelial cells from asthmatic patients, suggesting a role for IFN-I in limiting induced viral exacerbations [131] . However, other groups have found no differences between viral loads in asthmatic and control subjects during HRV infections [132] . Further investigation regarding the role of IFN-I during HRV infections needs to be completed.

2.1.6. Human Coronavirus (HCoV). The family Coronaviridae contains two subfamilies, the Coronavirinae and the Torovirinae. They are a large group of positive-sense ssRNA genome viruses that can infect mammals and birds, causing a wide variety of diseases which can lead to frequent mutations and infections of new species. They have been divided into four genera, two of which, alphacoronavirus and betacoronavirus contain viruses infecting humans [133] . To date, four HCoVs (HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1) circulate globally in the human population and contribute to approximately one-third of common cold infections in humans [134] . HCoVs had been regarded as mildly pathogenic until the early 2000s. At that time, a new disease appeared in China, severe acute respiratory syndrome (SARS), which was quickly attributed to a new HCoV, the SARS-CoV. Following that outbreak, a related but different HCoV producing severe respiratory disease emerged, the Middle East respiratory syndrome coronavirus (MERS-CoV) [135] . Recently, a novel coronavirus (2019-nCoV) has emerged. The 2019-nCoV is causing an outbreak of unusual viral pneumonia in patients. It initially began in Wuhan, China and has spread to many countries worldwide [136] .

Similar to previously described respiratory viruses, HCoVs are detected by TLR-3, TLR-7, RIG-I, and MDA5 [137] . TLR-3 activated by dsRNA stimulates TRIF that activates AP-1, NF-κB, IRF-3, and IRF-7 leading to the IFN 8

Journal of Immunology Research production [138] . TLR-7 senses the ssRNA, leading to the activation of IRF-7 that also stimulates IFN secretion. RIG-I and MDA5 sense viral molecules in the cytoplasm, and their activation stimulates MAVS that induces the activation of IRF-3 and NF-κB to finally induce the IFN production [139] . Like other viruses, HCoVs use multiple mechanisms to evade IFN-I immune response. Evidence shows that different viral structures can inhibit or modulate the IFN production or activity. Thereby, NS protein-16 codified by SARS-CoV and HCoV-229E induces the methylation of viral mRNA cap structures that inhibit recognition by MDA5 [140, 141] . The papain-like protease (PLPRO) domain of NS protein-3 of SARS-CoV and HCoV-NL63 inhibits the activation of IRF-3 [142, 143] . Moreover, it was demonstrated that PLPRO encoded by MERS-CoV suppresses the induction of IFN-β through its deubiquitinating activity [144] . Protein M of SARS-CoV inhibits IFN-I production by impeding the formation of the TRAF3-TANK-TBK1/IKKϵ Complex [145] . ORF9b protein of SARS-CoV was shown to stimulate the degradation of MAVS and TRAF6, inhibiting the IFN-I pathway [146] .

The IFN response seems to be contributing simultaneously to the protection against viruses and to the pathology induced by the same viral infections. Human pDCs demonstrate a robust IFN-I production after MERS-CoV infection, especially IFN-α, and this response is greater than that elicited by SARS-CoV [147] . High IFN-α and IFN-γ have been associated with early SARS-CoV sequelae suggesting that unregulated IFN responses during acute-phase SARS-CoV may be deleterious for this infection [148] .

Flaviviruses. The interplay of climatic and environmental changes as well as the growth of the human population and increased urbanization has triggered the reemergence and rapid spread of arthropod-borne viruses significant to public health. Yellow fever virus (YFV), dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV) are mosquito-borne flaviviruses that have reemerged in both hemispheres during recent decades. Other flaviviruses have emerged in specific regions of the world, including the Japanese Encephalitis virus (JEV) and Saint Louis encephalitis virus (SLEV), among others [149] .

DENV, ZIKV, WNV, YFV, JEV, and SLEV belong to the flavivirus genus of the Flaviviridae family, which comprises a diverse group of enveloped, positive-sense, ssRNA viruses transmitted by blood-feeding mosquitoes, causing disease in humans [150] . The flavivirus RNA genome (11 kb), which encodes a single open reading frame flanked by highly structured 5 ′ and 3 ′ untranslated regions (UTRs), is transcribed as a single polyprotein that is proteolytically processed by host and viral proteases to yield three structural proteins (C, prM, and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5), the latter of which regulate viral translation, transcription, and replication as well as attenuate host antiviral responses [150] .

In human cells, the host responds to flavivirus infection by recognizing viral nucleic acids through several distinct PRRs including RLRs, TLR-3, 7, and 8, NLRs, and the cyclic GMP-AMP synthase/stimulator of IFN genes-(cGAS-STING-) dependent sensing pathway [151, 152] (Figure 5 ). Among RLRs, RIG-I and MDA5 are involved in the detection of cytoplasmic dsRNA produced during viral replication [153] . The TLRs of importance during flavivirus infections are TLR-7 and TLR-8, which detect ssRNA as well as TLR-3, which identifies dsRNA produced during viral replication [152, 153] . Recently, it has been reported that DENV infection activates TLR-9 signaling, which is known to recognize bacterial or viral DNA, by inducing mitochondrial DNA (mtDNA) release in human DCs [154] . The cGAS-STING pathway, which is known to sense DNA viruses, has also been recently involved in restricting flavivirus infections [151] . It has been reported that during DENV infection, mtDNA is spilled into the cytoplasm and this subsequently activates the cGAS/STING signaling pathway to stimulate the production of IFN-I [155] . pDCs are a predominant source of IFN-I during viral infection and TLR7 signaling in pDCs has been reported to promote the contact of these cells with infected cells in a specialized platform that enables viral RNA transfer and antiviral responses [156] . The binding of viral ssRNA and/or dsRNA to PRRs activates downstream signaling cascades, such as the activation of transcription factors IRF-3 and IRF-7 and NF-κB, that result in the induction of IFN-α and -β. Subsequent secretion of IFN-I and binding to IFNAR activates JAK/STAT dependent-and independent-signaling cascades that result in the transcription of hundreds of ISGs, which encode proteins that inhibit flavivirus replication and spread [151, 153, 157] .

To facilitate propagation, flaviviruses, like other viruses, have evolved specific strategies involving one or more viral nonstructural proteins to either prevent IFN induction or to inhibit IFN signaling. The inhibition of IFN-I induction is achieved by either sequestration or modification of viral RNA and inhibition of PRRs [151] . In addition, several flavivirus nonstructural proteins such as NS2A, NS2B-NS3, NS4B, and NS5 have been shown to interfere with IFN signaling pathways through different mechanisms depending on the virus [152, 158, 159] (Figure 6 ). Recently, subgenomic flavivirus RNA (sfRNA), a nongene product encoded in 3 ′ UTR generated by incomplete degradation of viral RNA by a cellular 5 ′ -3 ′ exoribonuclease, has been proposed to play a modulatory role in the host antiviral response in mammalian cells by antagonizing IFN-I, as well as displaying viral interference in insect cells [24, [160] [161] [162] .

The protective role of IFN-I against flaviviruses has been extensively demonstrated in mice since IFN-I signalingdeficient mice are highly susceptible to infection by DENV, ZIKV, and WNV [163] [164] [165] [166] . The reported effects of IFN-I in flavivirus infections in human cells and subjects are discussed in the following sections.

. DENV is an acute febrile disease caused by four distinct antigenically related DENV serotypes (DENV-1, -2, -3, and -4) that are transmitted to humans by the bite of Aedes spp. mosquitoes, mainly Aedes aegypti [167] . DENV infects an estimated 390 million people every year of which 96 million have apparent DENV infections, with different levels of disease severity [168] . The clinical manifestations of dengue can range from mild febrile 9 Journal of Immunology Research illness with myalgia and rash (formerly known as dengue fever (DF)) to severe forms of disease, characterized by plasma leakage and hemorrhage (dengue hemorrhagic fever (DHF)) leading to potentially life-threatening hypovolemic shock [169] . At present, several DENV vaccines are under development, including one that has been registered in Journal of Immunology Research several countries with high endemicity due to the limited efficacy in naïve individuals and against all four DENV serotypes [170] . DENV has been reported to trigger a robust IFN-I response, which has been shown to be important in controlling DENV infection [171] . IFN-I has been reported to inhibit DENV infection in a variety of human cells, including hepatoma, fibroblasts, and myeloid cells [172, 173] . RIG-I and MDA5 sensing of DENV has been critical in the immune response [39] , as knockdown of RIG-I and MDA5 in Huh7 cells resulted in increased DENV replication [174] . In addition to TLR-3, 7, and 8 [151] , DENV has been reported to activate and upregulate the expression of TLR-2 and 6 in human PBMCs [175] . NLRs have also been shown to be activated in DENV and WNV infections leading to the formation of the inflammasome complex with subsequent production of inflammatory cytokines of the IL-1β family [176] . DENV sensing by PRRs results in the secretion of IFN-I which triggers the JAK/STAT pathway leading to the production of ISGs with diverse antiviral properties [151] .

DENV nonstructural proteins have been involved in the downregulation of the IFN pathway in humans, targeting important signaling molecules downstream of PRRs, resulting in the inhibition of IFN-regulated gene expression [177] . NS4B in combination with NS2A and NS4A have been reported to block IFN-I signaling by decreasing STAT1 phosphorylation in human A549 cells [178] . Furthermore, the DENV NS2B-NS3 protease complex has been involved in the cleavage of the human adaptor molecule STING or MITA, inhibiting IFN-I production [179, 180] . Interestingly, DENV cleaves STING in humans but not in nonhuman primates that may serve as its sustaining reservoir in nature [181] . In addition, the DENV NS2B-NS3 protease interacts with the cellular IκB kinase, an important kinase involved in the IFN-I induction, disrupting RIG-I signaling and inhibiting the IFN production [182] . The DENV polymerase NS5 has also been reported as a potent and specific IFN-I antagonist, due to its binding to human STAT2 for ubiquitin-mediated proteasomal degradation [183, 184] . The ability of DENV NS5 to bind and degrade human but not mouse STAT2 may be the major reason behind DENV's efficient replication in human but not in wild-type mouse cells [185] . Recently, increased virulence of different type 1 DENV isolates has been associated with a higher capacity of NS proteins to suppress IFN signaling [186] . Likewise, sfRNA of DENV strains that are associated with greater epidemic potential prevents the ubiquitination-dependent activation of RIG-I by binding to the ubiquitin ligase tripartite motif protein 25 (TRIM25), subverting the RIG-I pathway, and consequently impairing IFN-I induction [162] .

The viral control and immune regulation exerted by IFN-I in dengue patients and human cells infected with DENV have been studied in several reports [172, 173, [187] [188] [189] . Even though a strong IFN-I response has been described in dengue patients, the association of this response with disease severity is controversial [188, [190] [191] [192] . While some studies reported similar serum levels of IFN-α or IFN-β in DF and DHF in Thai and Mexican patients [188, 191] , several other reports from Brazil, Mexico, Colombia, Taiwan, India, and Thailand showed higher levels of IFN-α in patients with milder dengue disease [77, 190, [193] [194] [195] [196] , suggesting that a robust production of IFN-α may be correlated with a better clinical condition with respect to dengue infection and disease progression. Conversely, a recent study from Paraguay reported higher levels of IFN-β in severe vs. nonsevere dengue children [197] . Similarly, a study from Northeast Brazil described higher levels of IFN-β in primary DHF patients compared to those with primary DF [198] . Considering the preexisting immunity of patients to DENV, several reports described higher levels of IFN-α in patients undergoing primary infection compared to those with secondary DENV infections [77, 190, 192, 195] , while other studies observed a similar expression of IFN-α levels in both types of infections [197, 198] . Furthermore, different serum levels of IFN-α and IFN-β have been reported in DENV-infected patients [192] , probably due to the differential kinetics of IFN-I induction during DENV infection of human cells [199, 200] .

. ZIKV is a newly emerging flavivirus transmitted to humans by Aedes spp. mosquitoes, including Aedes aegypti [201] . Since the first human ZIKV infection was reported in Uganda in 1964 [202] , human ZIKV infections had remained sporadic and limited to small-scale epidemics in Africa and Southeast Asia for decades [203, 204] , until 2007, when a large outbreak of Zika fever was reported on Yap Island (Micronesia) [205] . Over the next seven years, outbreaks were reported in other Pacific Islands [206] . In 2015, the largest outbreak of ZIKV ever reported began in Brazil, with a rapid expansion of the virus in South and Central America [207] [208] [209] . Typically, ZIKV infections can be asymptomatic or manifested as a self-limiting febrile illness characterized by rash, headache, conjunctivitis, arthralgia, and myalgia [204] [205] [206] [207] 209] . However, recent outbreaks in the South Pacific and Latin America reported severe neurological complications, including Guillain-Barré syndrome (GBS) in adults and microcephaly in newborns [210] [211] [212] . ZIKV has been shown to cross the placental barrier, disrupting brain development [213] . Recently, ZIKV spread by sexual contact has also been documented [214] . At present, there is an urgent need for vaccines and therapeutics to combat ZIKV.

The induction of antiviral immune responses after ZIKV infection of human cells has been reported in several studies [215] [216] [217] [218] [219] . The innate immune response after ZIKV infection of skin cells and endometrial stromal cells was characterized by a strongly enhanced IFN-β gene expression and the induction of ISGs, including OAS, ISG15, and MX1 [215, 216] . Moreover, the transcription of PRRs such as TLR-3, RIG-I, and MDA5 has been reported to be induced upon ZIKV infection of human skin cells [215] . Similar to DENV, NLR (inflammasome) activation has also been reported in ZIKV infection of monocytes [220] . Elevated secretion of IFN-β was also reported in human lung epithelial cells, which may delay the apoptosis exerted by ZIKV infection [217] . Schwann cells (SC), which play a central role in peripheral nerve disease and can be the target for damage in GBS, were susceptible to infection with ZIKV and YFV, but not DENV, and ZIKV infection of SC induced expression of IL-6, IFN-β, IFN-λ, IFIT-1, TNF-α and IL-23A mRNAs, and negative regulators of IFN signaling [218] . Furthermore, ZIKV infection of human DCs produced a strong induction of the RLR signaling pathway at the RNA transcription level, but ZIKV was able to block IFN-I signaling by targeting STAT1 and STAT2 phosphorylation [219] .

The mechanisms by which ZIKV antagonizes IFN-I induction and signaling in human cells, which might contribute to the broad cellular tropism and persistence of ZIKV, have been reported in recent studies [159, [221] [222] [223] . ZIKV NS1 has been reported to interact with RIG-I and downregulate the antiviral signaling pathway [224] . In addition, Donald et al. reported that sfRNA in ZIKV acts as the antagonist of RIG-I-dependent IFN production [161] . Furthermore, ZIKV NS4A impairs RLR-MAVS interaction and subsequent induction of antiviral immune responses by binding to the caspase activation and recruitment domain (CARD) of MAVS and thus blocking its accessibility by RLRs [225, 226] . ZIKV NS3 has been shown to antagonize antiviral gene induction by RIG-I and MDA-5 by binding to and sequestering the scaffold proteins 14-3-3ε/η [227] . ZIKV NS1, NS2A, NS2B, and NS4B have been shown to interact directly with TANK-binding kinase 1 (TBK1), required for the phosphorylation of IRF-3 [159, 228] . In addition, the NS2B-NS3 protease complex of ZIKV has been reported to impair the JAK/STAT signaling pathway by promoting the degradation of JAK1 and to block RLR-triggered apoptotic cell death. Furthermore, the cooperation between NS1, NS4B, and NS2B-NS3 further attenuates antiviral immunity, by impairing IFN-induced degradation of NS2B-NS3 [159] . Similar to DENV, ZIKV NS5 has been reported as a potent antagonist of IFN-I responses by targeting human but not mouse STAT2 for ubiquitin-mediated proteasomal degradation [183, 185, 221, 222] . However, unlike DENV, ZIKV NS5 did not require the E3 ubiquitin ligase UBR4 interaction, exhibiting a virus-specific mechanism [222] . In addition, ZIKV NS1 and NS5 interact with NLRP3 and promote assembly of the NLRP3 inflammasome complex resulting in IL-1β production and stimulated ZIKV replication [229] [230] [231] .

Recently, ZIKV microcephaly in newborns has been associated with rs3775291 single nucleotide polymorphisms (SNP) at TLR-3 reducing the activation of NF-κB and thus decreasing IFN-I responses in mothers infected by ZIKV during pregnancy [232] . Furthermore, comparative analysis of African and Asian lineage-derived ZIKV strains revealed pronounced differences in the activation of innate immune signaling and inhibition of viral replication which may be related to differential pathogenesis [233] . Compared to the replication of other ZIKV strains, the replication of Asian ZIKV strain Brazil Fortaleza 2015, which was associated with neurodevelopmental disorders, was less sensitive to the antiviral actions of IFN-I, while infection with this strain induced weaker and delayed innate immune responses in vitro.

. WNV is a mosquito-borne flavivirus of international health concern. WNV is maintained in a natural cycle involving primarily Culex spp. mosquitoes and avian hosts, but it also infects humans, horses, and other animals [234] . WNV is endemic in parts of Asia, Africa, and Europe, and it was first introduced to North America in 1999 [235] . Since then, the virus has spread rapidly throughout the United States and has been associated with over 21,000 encephalitis/meningitis cases and 1,800 deaths [236] . However, no effective prophylactic or therapeutic measures are currently available [234] . Infection with WNV in humans remains asymptomatic and/or subclinical in most cases and causes symptoms in 20-30% of WNV-infected individuals. The clinical manifestations range from a mild flu-like illness to more severe neuroinvasive disease, associated with significant morbidity and mortality [234, 237] .

The protective role of IFN-I after WNV infection has been extensively demonstrated in mice by the marked increase in mortality in infected IFN-α/β receptor-deficient mice [166] . The studies of IFN-I protection after WNV infection are more limited in human cells. Recently, the PI3K, which play an important role in the induction of IFN-I antiviral responses, have been shown to control West Nile virus infection in human and mouse cells [238] . The presence of PI3K inhibitors blocked the translocation of IRF-7 from the cytosol to the nuclei, reduced IFN-I mRNA and protein expression, and decreased the secretion of IFN-I. Recently, in human monocyte-derived DCs early activation of RLR or IFN-I signaling could block WNV infection [239] . Furthermore, in human glioblastoma cells, WNV replication was regulated by early IFN-β induction, while in human neuroblastoma cells, a delayed IFN-β response, due to the concealing of viral dsRNA in intracellular membranes, resulted in efficient WNV replication [240] . In addition, differences in replication and induction of IFN-I responses between attenuated and virulent WNV strains in human monocytederived DCs accounted for the differing virulence in humans [241] .

WNV NS4B and NS5 have been reported as important IFN-I antagonists [178, 242] . Similar to DENV, NS4B inhibited the JAK/STAT signaling pathway by decreasing STAT1 phosphorylation [178] . The NS5 of WNV strain NY99 blocked IFN-I responses by inhibition of STAT1 phosphorylation [242] . The helicase domain of WNV NS3 has been reported to inhibit IFN-I signaling and differences in virulence between the NY99 and NSW2011 strains of WNV have been attributed to differential inhibition of the helicase domain of NS3 [243] . Furthermore, WNV NS1 has been demonstrated to antagonize IFN-β production by suppressing RLR activation [244] .

The human studies evaluating the IFN-I response to WNV infection and its relationship with disease severity are scarce [245] . Recently, a study with WNV-infected blood donors revealed that symptom development was positively correlated with early, potent IFN-α production [246] . However, this robust IFN-I response was associated with an inability to maintain continuing immunity during WNV infection, suggesting that an increased initial inflammation may negatively impact the adaptive-T cell responses.

. YFV, the causative agent of yellow fever, is endemic in the tropical regions of Africa and the Americas and is transmitted to humans and 12

Journal of Immunology Research nonhuman primates by Aedes spp. mosquitoes, including Aedes aegypti [150] . Despite the presence of an effective vaccine YF17D [247] , YFV infection has remained a public health concern in restricted parts of the world, with an incidence of 200,000 cases per year, leading to about 30,000 deaths [150] . In humans, YFV infection produces variable clinical manifestations, ranging from asymptomatic infection to mild febrile illness and to a possibly fatal disease characterized by severe hepatitis, renal failure, hemorrhage, and shock [248] . IFN-I induction has been shown in YF17D-vaccinated human subjects [249, 250] and combined IFN-I and -III are crucial for controlling YFV infection in mice [251] .

Recently, it has been reported that cells infected with YFV stimulated pDCs to produce IFN-I in a TLR7-and cell contact-dependent manner. Cells producing immature particles as well as capsid-free viral RNA participated in pDC stimulation [252] .

NS4B and NS5 of YFV have been reported as IFN-I antagonists. YFV NS4B interacts with STING, blocking IFN-I stimulation [253] . Moreover, YFV NS5 inhibits IFN-I signaling via binding and inhibition of STAT2 following IFN-I-induced phosphorylation of STAT1 and requires K6 ubiquitination [254] . This IFN-induced ubiquitination of YFV NS5 is absent in murine cells resulting in a lack of binding of YFV NS5 and human STAT2 in murine cells, highlighting the importance of YFV ubiquitination in determining the host cell range for YFV [255, 256] .

Gene expression microarray analysis in PBMCs from YF17D-vaccinated humans revealed an immune profile related to antiviral IFN-I responses [249] , suggesting that IFN-I may play a role in effective protection in vaccinated subjects. Moreover, human DCs infected with vaccine virus YF17D and a chimeric YF17D/DENV2 produced higher levels of IFN-α than those infected with DENV-2 [193] , also indicating an induction of IFN-I production by YF17D vaccine virus. Recently, it has been reported that an inherited IFNAR1 deficiency resulted in life-threatening complications of vaccination with the YF vaccine in a previously healthy individual [257] .

The dual role of IFNs in protection against and pathogenesis of viral infections was suggested using a gene overexpression screening approach in human cells [258] . In this study, several ISGs (ADAR, FAM46C, LY6E, and MCOLN2) were identified as inhibitors of YFV, WNV, HCV, HIV, chikungunya virus (CHIKV), and Venezuelan equine encephalitis virus (VEEV) replication. Conversely, several ISGs were found to enhance the replication of YFV, WNV, CHIKV, and VEEV, highlighting the complexity of the IFN-I system.

. JEV is a mosquitoborne flavivirus causing severe neurologic disease, characterized by flaccid paralysis, meningitis, and encephalitis [150] . JEV is transmitted to humans by Culex spp. mosquitoes and is maintained in a zoonotic cycle involving pigs as the major reservoir and water birds as carriers [259] . JEV infections primarily occur in Asia, where 35,000-50,000 cases and 10,000-15,000 deaths are reported annually [150] .

JEV infection of human microglial cells has been shown to induce an innate immune response characterized by the production of IFN-β via IRF-3 activation and phosphorylation. The overexpression of the ubiquitin ligase TRIM21, which interacts with IRF-3 negatively, regulated this innate immune response by targeting IRF-3-mediated IFN-β production [260] . Recently, neuronal transcriptomic responses to JEV infection showed the upregulation of RIG-I and MDA5, suggesting that neuronal cells play a significant role in immunity against JEV [261] .

The antagonist activity of JEV NS5 in IFN-I responses has been reported. The JEV NS5 has been shown to block IFN-I signaling by reducing the phosphorylation of TYK2 and STAT1 and subsequently inhibiting STAT1 nuclear localization [262, 263] . Furthermore, JEV NS5 inhibited the nuclear translocation of IRF-3 and NF-κB by binding to nuclear transport proteins KPNA3 and KPNA4, impairing the production of IFN-β [264] .

The IFN-I response during JEV infection in humans has not been fully characterized. A study of proinflammatory profile in humans with JE revealed that nonsurviving patients with JE showed higher levels of IFN-α in cerebrospinal fluid than those from survivors during the first days of illness, suggesting that it may be associated with higher viral load [265] .

. SLEV is a mosquito-borne flavivirus transmitted to humans by Culex spp. mosquitoes, first discovered in 1933 when a large epidemic of encephalitis occurred in St. Louis, Missouri [150] . SLEV distribution ranges from Canada to Argentina and across North America [266] . SLEV produces a mild febrile disease in children and young adults and severe neurologic manifestations that are more frequently observed in elderly and immunocompromised patients.

Information about IFN-I induction and signaling as well as IFN-I evasion by viral proteins after SLEV infection in human cells is currently very limited. Former studies have shown a variable effect of human IFN in primary human fetal glial cell cultures [267] . Similar to DENV, ZIKV, and WNV, the protective role of IFN-I against SLEV has been demonstrated in mice since IFN signaling-deficient mice are more susceptible to infection by SLEV than in immunocompetent mice [268] . Specifically, the protective effects of IFN-α have been shown in mice by reducing mortality from SLEV delivered by the aerosol and subcutaneous routes [269] .

IFNs are increasingly recognized as therapeutic agents. Three different types of human IFN (α, β, and γ) are widely used for the treatment of various diseases due to their immunomodulating, antiviral, and antiproliferative properties [270, 271] . However, the optimal dose and duration of IFNs as therapeutic agents have not been established [272] . This is important since IFNs administered in pharmacological doses produce considerable toxicity that is dose-related and that may require cessation of therapy. Common side effects due to IFN-α include flu-like symptoms (fatigue, fever, myalgias, and headaches), pulmonary toxicity, gastrointestinal symptoms, 13 Journal of Immunology Research neurotoxicity, and depression [273] [274] [275] . Lethal toxicity associated with IFN-α regimen is rare and severe toxicity due to IFN-α is manageable if recognized expeditiously [276, 277] .

The role of endogenous and/or exogenous IFN in the viral infections discussed in this review has been partially explored in human cell lines, animal models, and clinical studies. Depending on the virus, the model used, and the time of infection, IFNs can be either beneficial or deleterious (Table 1) .

Regarding influenza disease, a pathogenic role for endogenous IFN-I has been suggested in children with influenza infection, in whom clinical disease severity was associated with an increased level of IFN-α [278] . In agreement with this, another study associated severity with epithelial cell damage mediated by TNF-α related apoptosis-inducing ligand (TRAIL) [279] whose expression can be induced by IFN-α and IFN-β [280] . Moreover, recent evidence showed that the upregulation of TRAIL expression by monocytes and death receptor 5 (DR5) expression by epithelial cells contributed to the pathogenic mechanism induced by IFNα/β, where enhanced production of this molecule can contribute to immunopathology in severe infections [64] .

Concerning RSV infections, intranasal administration of recombinant IFN to infants with RSV infection has shown to be safe and to decrease the duration of symptoms without affecting the time of viral shedding [281] [282] [283] .

During the 1980s, different studies showed that the use of high doses of intranasal IFN-α were useful in the prevention of HRV infection [284] [285] [286] . However, it was also found that the use of this molecule (in high doses) was associated with the occurrence of undesirable effects, as described above. Although low-dose treatment has proven to be better tolerated, it has been ineffective as postexposure prophylaxis [287] . Further investigation regarding the role of IFN-I during HRV infections needs to be completed.

Dual effects of IFN-I have been observed in HCoV infections, as mentioned previously. A series of case studies describing moderate and severe MERS-CoV infections in adults found that moderate cases had no IFN-α response, while severe cases had variable levels of IFN-α [288] . However, other studies have shown that MERS-CoV and SARS-CoV patients improved with IFN-α therapy [289, 290] .

Regarding DENV infections, the studies evaluating the association of IFN-I response with disease severity in humans have yielded mixed results [188, [190] [191] [192] , as described previously. Recent studies in dengue patients in South America have suggested that high levels of IFN-β might accompany a worsened progression of the disease [197, 198] . In addition, monocytes of individuals with past severe dengue (SD) exhibited a significant upregulation of IFNB-1, RIG-I, and NLRP3 genes compared to those with past non-SD that was accompanied with higher viral loads, suggesting that initial innate immune responses may influence disease outcome [291] .

With regard to ZIKV, IFN-I treatment has not been described in ZIKV patients. A recent murine model of ZIKV infection using dexamethasone-immunosuppressed mice showed that IFN-I treatment improved clinical outcomes, reducing viral load and inflammation in different visceral organs including testicles, suggesting the consideration for evaluating the effects of recombinant IFN treatment in patients at high risk for ZIKV-associated complications [292] .

Concerning WNV-infected patients, the use of IFN-α is limited to case reports of meningoencephalitis, where different outcomes have been described [293] [294] [295] [296] . IFN-α treatment was well tolerated and might have potential beneficial effects. However, the dynamic course of WNV neuroinvasive disease prevented the determination of whether the beneficial effects were due to the experimental therapy or to chance. Further randomized, double-blinded, placebo-controlled clinical trials are needed to define the role of IFN-α treatment in WNV-infected patients.

The antiviral effects of IFN-α against JEV have been originally described in cell cultures [297] . In humans, IFN-α2a treatment against JE was also evaluated in a randomized double-blind placebo-controlled trial in Vietnamese children with JEV infection [298] . Intramuscular IFN-α administration did not show beneficial effects on hospital death or severe sequelae at discharge, suggesting that higher doses, alternative administration routes, or combination with other antiviral drugs might be needed.

Similar to WNV and JEV, the use of IFN-α was evaluated in human subjects with SLEV severe neurologic disease. A nonrandomized, unblinded, interventional pilot study evaluated IFN-α2b therapy for meningoencephalitis produced by SLEV and suggested a beneficial effect on the early neurologic course of the disease, indicating that two weeks of treatment were well tolerated [299] . A subsequent study in solid organ transplant recipients with SLEV meningoencephalitis showed that even with delayed administration, the combination treatment with IFN-α2b and intravenous immunoglobulin G was associated with a potential clinical improvement [300] . These studies support the conduction of a subsequent randomized, double-blinded, placebo-controlled trial of IFN-α2a therapy for SLEV meningoencephalitis.

Upon recognition of viral infection, the cell, through PRRs, mediates the production of IFN-I leading to the transcription of hundreds of ISGs by the JAK/STAT pathway [301] . ISGs are the effectors of cell-autonomous antiviral defense and have been shown to be very effective at resisting and controlling pathogens. ISGs are induced to vastly different levels during viral infection or IFN treatment, and expression levels are often dependent on time, dose, and cell type. They act at different stages of the viral life cycle, from entry, replication, assembly, and release, providing adequate cellular immunity against both RNA and DNA viruses [302] . Microarray studies have identified between 50-1000 ISGs, with 200-500 genes typical of many cell types. Representative and wellstudied ISG members with specific or broad antiviral activities include IRF1, IRF3, IRF7, IRF9, IFITM3, ISG15, and OASL. The products of these ISGs exert numerous antiviral 14 Journal of Immunology Research effector functions, many of which are still not fully described. However, as the mechanisms of more IFN effectors are uncovered, it is likely that their modes of action will collectively span the majority of virus life cycle stages [303] . In addition to having potent antiviral activity, ISGs also augment the innate immune response to viral infection, thereby strengthening this response [304] . This has driven special attention in the attempt to advance novel therapeutics to control viral infection and their pathogenesis. Currently, there are vaccines for influenza virus, YFV and JEV; however, neither effective vaccines nor specific therapies are available for RSV, hMPV, PIV, HRV, HCoV, DENV, ZIKV, WNV, or SLEV. Although several vaccines are under diverse phases of development for these viruses, there is a need for alternative antiviral therapeutic approaches. Several ISGs have been described in the setting of respiratory viruses ( Table 2) . Recent work has shown that the egress of the influenza virus is also targeted by an ISG. Viperin interacts with the cellular enzyme farnesyl diphosphate-synthase to perturb lipid rafts, resulting in inhibition of influenza and rhinovirus release [305, 306] . In addition, ZAP, which can be upregulated independently from IFN production, limits influenza virus replication via the enhancement of RIG-I [307] . TRIM56 is another ISG with broad antiviral activity. Although its upregulation is dependent on IFN-I, it abrogates influenza virus A and B and HCoV infection through STING and TLR-3/TRIF [308, 309] . TRIM21 has shown activity against rhinovirus by intercepting incoming antibody-opsonized virions during cellular infection, mediating efficient postentry neutralization [310] . A new human IFN-induced gene that we have termed ISG20 codes for a 3 ′ to 5 ′ exonuclease with specificity for single-stranded RNA and, to a lesser extent, for DNA. ISG20-overexpressing HeLa cells showed resistance to infections by the influenza virus. The mechanism has been shown to be related to the impairment of the polymerase activity, inhibiting both the replication and transcription [311, 312] . Finally, TDRD7 (tudor domain containing 7) has shown activity against several 15 Journal of Immunology Research paramyxoviruses, such as HPIV3 and RSV by interfering with the activation of AMP-dependent kinase (AMPK). The activation of AMPK is required for efficient replication. TDRD7 interferes with the activation of AMPK, limiting viral replication [313] .

Several ISGs have been reported to inhibit flavivirus infection through different mechanisms ( Table 2 ). The expression of IFN-I inducible ISGs such as IFITM2/3, viperin, ISG15, ISG20, OAS, BST2, RyDEN, TRIM69, and IFI6 has been shown to block DENV infection [314] [315] [316] [317] [318] [319] [320] at multiple steps of the viral cycle. IFITM2 and IFITM3 disrupted the early steps (entry and/or uncoating) of DENV and WNV infection [314, 316] . In contrast, three IFN-induced cellular enzymes, viperin, ISG20, and dsRNAactivated protein kinase, inhibited the steps of the DENV and WNV cycle in viral proteins and/or RNA biosynthesis [314] . DENV infection-induced viperin which has antiviral properties residing in the C-terminal region of the protein that acts to restrict early DENV RNA production/accumulation, potentially via the interaction of viperin with DENV NS3 and replication complexes [315] . The expression of the Repressor of yield of DENV (RyDEN) conferred resistance to all serotypes of DENV in human cells. RyDEN is likely to interfere with the translation of DENV via interaction with viral RNA and cellular mRNA-binding proteins, resulting in the inhibition of virus replication in infected cells [317] . OAS and its downstream effector RNase L have been reported to block DENV replication and likely contributed to host defense against DENV infection playing a role in determining the outcomes of DENV disease severity [318] . ZIKV has been reported to induce the expression of ISG15 in primary human corneal epithelial cells, and the silencing of ISG15 increased ZIKV infectivity [321] . ISG15 has also inhibited the replication of several flaviviruses, including DENV, WNV, and JEV [322] [323] [324] . IFN-α-inducible protein 6 (IFI6), an endoplasmic reticulum-(ER-) localized integral membrane effector, prophylactically protected uninfected cells by preventing the formation of virus-induced ER membrane invaginations that house flavivirus (YFV, WNV, and DENV) replication machinery [320] . TRIM69 interacts with DENV NS3 directly and mediates its ubiquitination and degradation, thus, interrupting DENV replication [319] . Recently, Schlafen 11, an ISG that controls the synthesis of proteins by regulating tRNA abundance, has been reported to restrict WNV, DENV, and ZIKV replication by impairing viral infectivity [325] .

After 60 years of research, the protective role of IFN-I has been demonstrated from cell culture to animal models and in human subjects. More recently, pathogenic effects of IFN-I have been described during viral infections highlighting the vast and intricate interactions of IFN-I in the immune response. Further insights into the effector mechanisms of individual ISGs in the complex signaling networks in human viral diseases are needed in order to design more specific and effective therapeutic strategies.

The authors declare that there is no conflict of interest regarding the publication of this paper.

PLA, ABB, DRH, and LBT contributed to the literature search and paper preparation. Journal of Immunology Research

Virus interference. I. The interferon

Fifty years of interferon research: aiming at a moving target

Virus interference. II. Some properties of interferon

Interferons, interferon-like cytokines, and their receptors

Type I interferons (alpha/beta) in immunity and autoimmunity

Toll-like receptors and their crosstalk with other innate receptors in infection and immunity

Interferon induction and function at the mucosal surface

Plasticity and virus specificity of the airway epithelial cell immune response during respiratory virus infection

Toll-like receptor control of the adaptive immune responses

Inferences, questions and possibilities in toll-like receptor signalling

The NF-B pathway

Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors

Induction and regulation of IFNs during viral infections

The interferon-α/β system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors

Regulation of type I interferon responses

Antiviral actions of interferons

Intrinsic antiviral immunity

The role of protein kinase R in the interferon response

Molecular mechanisms of translational control

Viral encounters with 2',5'-oligoadenylate synthetase and RNase L during the interferon antiviral response

Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus

Numerous transitions in human parainfluenza virus 3 RNA recovered from persistently infected cells

Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity

Japanese encephalitis virus non-coding RNA inhibits activation of interferon by blocking nuclear translocation of interferon regulatory factor 3

IRF family proteins and type I interferon induction in dendritic cells

Human plasmacytoid dendritic cell accumulation amplifies their type 1 interferon production

The nature of the principal type 1 interferon-producing cells in human blood

The role of type I interferon production by dendritic cells in host defense

Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells

Type I interferons keep activated T cells alive

Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation

Direct action of type I IFN on NK cells is required for their activation in response to vaccinia viral infection in vivo

Links between innate and adaptive immunity via type I interferon

Disease burden of the most commonly detected respiratory viruses in hospitalized patients calculated using the disability adjusted life year (DALY) model

Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology

Burden, etiology, and risk factors of respiratory virus infections among symptomatic preterm infants in the tropics: a retrospective single-center cohort study

Etiology and clinical outcomes of acute respiratory virus infection in hospitalized adults

TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization

Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity

Intracellular toll-like receptors

Differential type I interferon induction by respiratory syncytial virus and influenza a virus in vivo

Human metapneumovirus: mechanisms and molecular targets used by the virus to avoid the immune system

Induction and evasion of type I interferon responses by influenza viruses

Influenza virus RNA polymerase: insights into the mechanisms of viral RNA synthesis

The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses

Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses

Lengthdependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5

LGP2 plays a critical role in sensitizing mda-5 to activation by doublestranded RNA

Cutting edge: influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells

Recognition of single-stranded RNA viruses by toll-like receptor 7

The multifunctional NS1 protein of influenza A viruses

Inefficient control of host gene expression by the 2009 pandemic H1N1 influenza A virus NS1 protein

Modulation of innate immune responses by the influenza A NS1 and PA-X proteins

Functions of the influenza A virus NS1 protein in antiviral defense

Permissive secondary mutations enable the evolution of influenza oseltamivir resistance

RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates

Influenza virus NS1 protein counteracts PKR-mediated inhibition of replication

Influenza A virus virulence depends on two amino acids in the N-terminal domain of its NS1 protein to facilitate inhibition of the RNA-dependent protein kinase PKR

A new player in a deadly game: influenza viruses and the PI3K/Akt signalling pathway

Protective role of beta interferon in host defense against influenza A virus

Early control of H5N1 influenza virus replication by the type I interferon response in mice

The role of alpha/beta and gamma interferons in development of immunity to influenza A virus in mice

Pathogenic potential of interferon αβ in acute influenza infection

Interferon production in children with respiratory syncytial, influenza, and parainfluenza virus infections

Breastfeeding is associated with the production of type I interferon in infants infected with influenza virus

Differential gender response to respiratory infections and to the protective effect of breast milk in preterm infants

Influenza-induced production of interferon-alpha is defective in geriatric individuals

Pregnant women have attenuated innate interferon responses to 2009 pandemic influenza A virus subtype H1N1

IFITM3 restricts the morbidity and mortality associated with influenza

Hepatitis B virus spliced variants are associated with an impaired response to interferon therapy

The burden of respiratory syncytial virus infection in young children

Respiratory syncytial virus infection in elderly and high-risk adults

Predominance of Th2 cytokines, CXC chemokines and innate immunity mediators at the mucosal level during severe respiratory syncytial virus infection in children

Cell type-specific recognition of human metapneumoviruses (HMPVs) by retinoic acid-inducible gene I (RIG-I) and TLR7 and viral interference of RIG-I ligand recognition by HMPV-B1 phosphoprotein

Orchestrating the interferon antiviral response through the mitochondrial antiviral signaling (MAVS) adapter

Different clinical and laboratory manifestations 18 Journal of Immunology Research between dengue haemorrhagic fever and dengue fever with bleeding tendency

Activation of innate immune antiviral responses by Nod2

The limited role of the human interferon system response to respiratory syncytial virus challenge: analysis and comparison to influenza virus challenge

Interferon in nasal secretions from infants with viral respiratory tract infections

Respiratory syncytial virus NS1 protein degrades STAT2 by using the Elongin-Cullin E3 ligase

Respiratory syncytial virus nonstructural protein 2 specifically inhibits type I interferon signal transduction

A novel mechanism for the inhibition of interferon regulatory factor-3-dependent gene expression by human respiratory syncytial virus NS1 protein

Human respiratory syncytial virus nonstructural protein NS2 antagonizes the activation of beta interferon transcription by interacting with RIG-I

Recombinant respiratory syncytial viruses with deletions in the NS1, NS2, SH, and M2-2 genes are attenuated in vitro and in vivo

Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene

Specific inhibition of type I interferon signal transduction by respiratory syncytial virus

Respiratory syncytial virus nonstructural proteins NS1 and NS2 mediate inhibition of Stat2 expression and alpha/beta interferon responsiveness

Attenuation of respiratory syncytial virus-induced and RIG-I-dependent type I IFN responses in human neonates and very young children

Reduced nasal viral load and IFN responses in infants with respiratory syncytial virus bronchiolitis and respiratory failure

A newly discovered human pneumovirus isolated from young children with respiratory tract disease

Human metapneumoviruswhat we know now

Ten years of human metapneumovirus research

Epidemiology of human metapneumovirus

Role of retinoic acid inducible gene-I in human metapneumovirus-induced cellular signalling

Human metapneumovirus inhibits IFN-β signaling by downregulating Jak1 and Tyk2 cellular levels

Human metapneumovirus inhibits IFN-α signaling through inhibition of STAT1 phosphorylation

Human metapneumovirus M2-2 protein inhibits innate cellular signaling by targeting MAVS

Functional motifs responsible for human metapneumovirus M2-2-mediated innate immune evasion

Human metapneumovirus small hydrophobic protein inhibits NF-kappaB transcriptional activity

Cytokine profiles in human metapneumovirus infected children: identification of genes involved in the antiviral response and pathogenesis

Role of type I interferon signaling in human metapneumovirus pathogenesis and control of viral replication

Isolation and characterization of monoclonal antibodies to human parainfluenza virus type 4 and their use in revealing antigenic relation between subtypes 4A and 413

Parainfluenza virus infection of young children: estimates of the population-based burden of hospitalization

Retinoic acid inducible gene I activates innate antiviral response against human parainfluenza virus type 3

Activation of IFN-β expression by a viral mRNA through RNase L and MDA5

Human parainfluenza virus type 2 V protein inhibits interferon 19 Journal of Immunology Research production and signaling and is required for replication in non-human primates

The C proteins of human parainfluenza virus type 1 (HPIV1) control the transcription of a broad array of cellular genes that would otherwise respond to HPIV1 infection

The C proteins of human parainfluenza virus type 1 limit double-stranded RNA accumulation that would otherwise trigger activation of MDA5 and protein kinase R

Attenuating mutations in the P/C gene of human parainfluenza virus type 1 (HPIV1) vaccine candidates abrogate the inhibition of both induction and signaling of type I interferon (IFN) by wild-type HPIV1

The human parainfluenza virus type 3 (HPIV 3) C protein inhibits viral transcription

The C proteins of human parainfluenza virus type 1 block IFN signaling by binding and retaining Stat1 in perinuclear aggregates at the late endosome

mda-5, but not RIG-I, is a common target for paramyxovirus V proteins

The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter

Degradation of STAT1 and STAT2 by the V proteins of simian virus 5 and human parainfluenza virus type 2, respectively: consequences for virus replication in the presence of alpha/beta and gamma interferons

Hepatitis C virus and antiviral innate immunity: who wins at tug-of-war?

Human parainfluenza virus serotypes differ in their kinetics of replication and cytokine secretion in human tracheobronchial airway epithelium

The ABCs of rhinoviruses, wheezing, and asthma

Viral respiratory infections due to rhinoviruses: current knowledge, new developments

Human rhinovirus recognition in non-immune cells is mediated by toll-like receptors and MDA-5, which trigger a synergetic pro-inflammatory immune response

Toll-like receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells

MDA5 and TLR3 initiate pro-inflammatory signaling pathways leading to rhinovirus-induced airways inflammation and hyperresponsiveness

Co-ordinated role of TLR3, RIG-I and MDA5 in the innate response to rhinovirus in bronchial epithelium

Defining critical roles for NF-κB p65 and type I interferon in innate immunity to rhinovirus

Cleavage of IPS-1 in cells infected with human rhinovirus

RIG-I is cleaved during picornavirus infection

Impaired innate interferon induction in severe therapy resistant atopic asthmatic children

Rhinovirus stimulated IFN-α production: how important are plasmacytoid DCs, monocytes and endosomal pH?

Rhinovirus 16-induced IFN-α and IFN-β are deficient in bronchoalveolar lavage cells in asthmatic patients

Effect of exogenous interferons on rhinovirus replication and airway inflammatory responses

Exogenous IFN-β has antiviral and anti-inflammatory properties in primary bronchial epithelial cells from asthmatic subjects exposed to rhinovirus

Comparison of viral load in individuals with and without asthma during infections with rhinovirus

Human coronaviruses: what do they cause?

The molecular biology of coronaviruses

Severe acute respiratory syndrome coronavirus phylogeny: toward consensus

Emerging coronaviruses: genome structure, replication, and pathogenesis

Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion

Induction and function of type I and III interferon in response to viral infection

Type I interferons in infectious disease

Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses

Ribose 2'-_O_ -methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5

Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling

Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus

MERS-CoV papain-like protease has deISGylating and deubiquitinating activities

Severe acute respiratory syndrome coronavirus M protein inhibits type I interferon production by impeding the formation of TRAF3.TANK.TB-K1/IKKepsilon complex

SARS-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome

High secretion of interferons by human plasmacytoid dendritic cells upon recognition of Middle East respiratory syndrome coronavirus

Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome

Emerging arboviruses: why today?

Flaviviruses

Innate immune escape by dengue and West Nile viruses

Inhibition of type I interferon induction and signalling by mosquito-borne flaviviruses

Mechanisms of evasion of the type I interferon antiviral response by flaviviruses

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells

Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity

Plasmacytoid dendritic cells and infected cells form an interferogenic synapse required for antiviral responses

Dengue virus control of Type I IFN responses: a history of manipulation and control

The many faces of the flavivirus NS5 protein in antagonism of type I interferon signaling

Zika virus evades interferonmediated antiviral response through the co-operation of multiple nonstructural proteins in vitro

Noncoding flavivirus RNA displays RNA interference suppressor activity in insect and Mammalian cells

Full genome sequence and sfRNA interferon antagonist activity of Zika virus from Recife, Brazil

Dengue subgenomic RNA binds TRIM25 to inhibit interferon expression for epidemiological fitness

Characterization of a model of lethal dengue virus 2 infection in C57BL/6 mice deficient in the alpha/beta interferon receptor

Enhanced infection of liver sinusoidal endothelial cells in a mouse model of antibody-induced severe dengue disease

A mouse model of Zika virus pathogenesis

Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival

Dengue

The global distribution and burden of dengue

Dengue virus pathogenesis: an integrated view

Dengue infection

Immune response to dengue and Zika

Interferon inhibits dengue virus infection by preventing translation of viral RNA through a PKR-independent mechanism

Modulation of dengue virus infection in human cells by alpha, beta, and gamma interferons

RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection

Activation of TLR2 and TLR6 by dengue NS1 protein and its implications in the immunopathogenesis of dengue virus infection

West Nile virus infection and immunity

Evasion of the human innate immune system by dengue virus

Inhibition of interferon signaling by dengue virus

Dengue virus targets the adaptor protein MITA to subvert host innate immunity

DENV inhibits type I IFN production in infected cells by cleaving human STING

Dengue viruses cleave STING in humans but not in nonhuman primates, their presumed natural reservoir

Dengue virus subverts the interferon induction pathway via NS2B/3 protease-IκB kinase epsilon interaction

NS5 of dengue virus mediates STAT2 binding and degradation

Dengue virus NS5 inhibits interferon-α signaling by blocking signal transducer and activator of transcription 2 phosphorylation

Mouse STAT2 restricts early dengue virus replication

Virulence difference of five type I dengue viruses and the intrinsic molecular mechanism

Dengue virus inhibits the production of type I interferon in primary human dendritic cells

High levels of interferon alpha in the sera of children with dengue virus infection

Acute dengue virus 2 infection in Gabonese patients is associated with an early innate immune response, including strong interferon alpha production

A strong interferon response correlates with a milder dengue clinical condition

Serum levels of IFN-β are associated with days of evolution but not with severity of dengue

Both viremia and cytokine levels associate with the lack of severe disease in secondary dengue 1 infection among adult Chinese patients

Dengue-2 and yellow fever 17DD viruses infect human dendritic cells, resulting in an induction of activation markers, cytokines and chemokines and secretion of different TNF-α and IFN-α profiles

Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections

Immune response to dengue virus infection in pediatric patients in New Delhi, India-association of viremia, inflammatory mediators and monocytes with disease severity

Selective dysfunction of subsets of peripheral blood mononuclear cells during pediatric dengue and its relationship with clinical outcome

Characterization of type I interferon responses in dengue and severe dengue in children in Paraguay

Primary dengue haemorrhagic fever in patients from northeast of Brazil is associated with high levels of interferon-β during acute phase

Flavivirus induces interferon-beta gene expression through a pathway involving RIG-I-dependent IRF-3 and PI3K-dependent NF-kappaB activation

Production of interferon alpha by dengue virus-infected human monocytes

Oral susceptibility of Singapore Aedes (Stegomyia) aegypti (Linnaeus) to Zika virus

Zika virus infection in man

Genetic characterization of Zika virus strains: geographic expansion of the Asian lineage

Zika virus outside Africa

Zika virus outbreak on Yap Island, Federated States of Micronesia

Zika virus

First report of autochthonous transmission of Zika virus in Brazil

Zika virus genome from the Americas

Zika virus outbreak

Zika virus spreads across Americas as concerns mount over birth defects

Microcephaly and Zika virus infection

Zika virus and Guillain-Barré syndrome: another viral cause to add to the list

Notes from the field: evidence of Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses-Brazil

Evidence of sexual transmission of Zika virus

Biology of Zika virus infection in human skin cells

Human endometrial stromal cells are highly permissive to productive infection by Zika virus

The South Pacific epidemic strain of Zika virus replicates efficiently in human epithelial A549 cells leading to IFN-β production and apoptosis induction

Human Schwann cells are susceptible to infection with Zika and yellow fever viruses, but not dengue virus

Zika virus antagonizes type I interferon responses during infection of human dendritic cells

ZIKV infection regulates inflammasomes pathway for replication in monocytes

Zika virus inhibits type-I interferon production and downstream signaling

Zika virus targets human STAT2 to inhibit type I interferon signaling

Chikungunya virus and Zika virus, two different viruses examined with a common aim: role of pattern recognition receptors on the inflammatory response

Insights into ZIKV-mediated innate immune responses in human dermal fibroblasts and epidermal keratinocytes

Zika virus non-structural protein 4A blocks the RLR-MAVS signaling

Zika virus antagonizes interferon response in patients and disrupts RIG-I-MAVS interaction through its CARD-TM domains

Zika virus NS3 mimics a cellular 14-3-3-binding motif to antagonize RIG-I-and MDA5-mediated innate immunity

An evolutionary NS1 mutation enhances Zika virus evasion of host interferon induction

Zika virus induces inflammasome activation in the glial cell line U87-MG

Zika virus infection induces host inflammatory responses by facilitating NLRP3 inflammasome assembly and interleukin-1β secretion

Zika virus elicits inflammation to evade antiviral response by cleaving cGAS via NS1-caspase-1 axis

Association between Zika virus microcephaly in newborns with the rs3775291 variant in toll-like receptor 3 and rs1799964 variant at tumor necrosis factor-α gene

Comparative analysis of African and Asian lineage-derived Zika virus strains reveals differences in activation of and sensitivity to antiviral innate immunity

A review of the epidemiological and clinical aspects of West Nile virus

1999: results of a household-based seroepidemiological survey

West Nile virus: epidemiology and clinical features of an emerging epidemic in the United States

An essential role of PI3K in the control of West Nile virus infection

West Nile virus infection blocks inflammatory response and T cell costimulatory capacity of human monocyte-derived dendritic cells

Delayed IFN response differentiates replication of West Nile virus and Japanese encephalitis virus in human neuroblastoma and glioblastoma cells

Comparison of attenuated and virulent West Nile virus strains in human monocyte-derived dendritic cells as a model of initial human infection

The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling

Helicase domain of West Nile virus NS3 protein plays a role in inhibition of type I interferon signalling

West Nile virus NS1 antagonizes interferon beta production by targeting RIG-I and MDA5

Interferon and interferon-induced chemokine expression is associated with control of acute viremia in West Nile virus-infected blood donors

Differences in early cytokine production are associated with development of a greater number of symptoms following West Nile virus infection

Yellow fever: an update

Treatment of yellow fever

Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans

Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses

Type III interferon-mediated signaling is critical for controlling live attenuated yellow fever virus infection in vivo

Immature particles and capsid-free viral RNA produced by yellow fever virus-infected cells stimulate plasmacytoid dendritic cells to secrete interferons

STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

The interferon signaling antagonist function of yellow fever virus NS5 protein is activated by type I interferon

The role of NS5 protein in determination of host cell range for yellow fever virus

Host-specific NS5 ubiquitination determines yellow fever virus tropism

Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines

A diverse range of gene products are effectors of the type I interferon antiviral response

Japanese encephalitis virus: from genome to infectome

Regulatory role of TRIM21 in the type-I interferon pathway in Japanese encephalitis virus-infected human microglial cells

Neuronal transcriptomic responses to Japanese encephalitis virus infection with a special focus on chemokine CXCL11 and pattern recognition receptors RIG-1 and MDA5

Blocking of interferon-induced Jak-Stat signaling by Japanese encephalitis virus NS5 through a protein tyrosine phosphatase-mediated mechanism

Blocking of the alpha interferon-induced Jak-Stat signaling pathway by Japanese encephalitis virus infection

Japanese encephalitis virus NS5 inhibits type I interferon (IFN) production by blocking the nuclear translocation of IFN regulatory factor 3 and NF-κB

Proinflammatory cytokines and chemokines in humans with Japanese encephalitis

Epidemiology of St. Louis encephalitis virus

Sensitivities of neurotropic arboviruses to human interferon

Development of a model of Saint Louis encephalitis infection and disease in mice

Interferon-alpha protects mice against lethal infection with St Louis encephalitis virus delivered by the aerosol and subcutaneous routes

Evaluation of routes of administration of interferon in cancer: a review and a proposal

Adjuvant treatment of anogenital warts with systemic interferon: a systematic review and meta-analysis

The use of interferon in melanoma patients: a systematic review

Pulmonary arterial hypertension in patients treated with interferon

Understanding and managing toxicities of vascular endothelial growth factor (VEGF) inhibitors

Neurotoxicity of interferon-? in melanoma therapy

Tolerability of adjuvant high-dose interferon alfa-2b: 1 month versus 1 year-a Hellenic Cooperative Oncology Group study

Meta-analysis: mortality and serious adverse events of peginterferon plus ribavirin therapy for chronic hepatitis C

Mucosal immune responses predict clinical outcomes during influenza infection independently of age and viral load

Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand

Macrophageexpressed IFN-β contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia

Treatment of respiratory syncytial virus infection with recombinant interferon alfa-2a

Pilot study of recombinant interferon alpha-2a for treatment of infants with bronchiolitis induced by respiratory syncytial virus

Toxicity profile of interferon alfa-2b in children: a prospective evaluation

Intranasal interferon-alpha 2 for prevention of natural rhinovirus colds

Intranasal interferon 2 for prevention of rhinovirus infection and illness

Prevention of natural colds by contact prophylaxis with intranasal alpha 2-interferon

Ineffectiveness of postexposure prophylaxis of rhinovirus infection with low-dose intranasal alpha 2b interferon in families

Clinical progression and cytokine profiles of Middle East respiratory syndrome coronavirus infection

Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study

Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study

Altered monocyte response to the dengue virus in those with varying 25 Journal of Immunology Research severity of past dengue infection

Zika virus infection in dexamethasone-immunosuppressed mice demonstrating disseminated infection with multi-organ involvement including orchitis effectively treated by recombinant type I interferons

Use of interferonalpha in patients with West Nile encephalitis: report of 2 cases

The first reported case of West Nile encephalitis in Korea

Failure of interferon alpha-2b in a patient with West Nile virus meningoencephalitis and acute flaccid paralysis

Successful treatment of West Nile virus infection after approximately 3 weeks into the disease course

The effect of interferon on Japanese encephalitis virus in vitro

Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebocontrolled trial

Effect of interferon-alpha2b therapy on St. Louis viral meningoencephalitis: clinical and laboratory results of a pilot study

Neuroinvasive St. Louis encephalitis virus infection in solid organ transplant recipients

Interferon-stimulated genes and their antiviral effector functions

Interferon-stimulated genes: a complex web of host defenses

Transcriptional regulation of antiviral interferon-stimulated genes

Interferon-stimulated genes as enhancers of antiviral innate immune signaling

The interferoninducible protein viperin inhibits influenza virus release by perturbing lipid rafts

The role of viperin in the innate antiviral response

ZAP-mediated mRNA degradation

The C-terminal tail of TRIM56 dictates antiviral restriction of influenza A and B viruses by impeding viral RNA synthesis

Overlapping and distinct molecular determinants dictating the antiviral activities of TRIM56 against flaviviruses and coronavirus

TRIM21 promotes cGAS and RIG-I sensing of viral genomes during infection by antibody-opsonized virus

ISG20, a new interferon-induced RNase specific for single-stranded RNA, defines an alternative antiviral pathway against RNA genomic viruses

Influenza A virus-induced expression of ISG20 inhibits viral replication by interacting with nucleoprotein

A new mechanism of interferon's antiviral action: induction of autophagy, essential for paramyxovirus replication, is inhibited by the interferon stimulated gene

Identification of five interferon-induced cellular proteins that inhibit west nile virus and dengue virus infections

Viperin is induced following dengue virus type-2 (DENV-2) infection and has anti-viral actions requiring the C-terminal end of viperin

The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus

Characterization of RyDEN (C19orf66) as an interferon-stimulated cellular inhibitor against dengue virus replication

Distinct antiviral roles for human 2',5'-oligoadenylate synthetase family members against dengue virus infection

Interferon-stimulated TRIM69 interrupts dengue virus replication by ubiquitinating viral nonstructural protein 3

A CRISPR screen identifies IFI6 as an ER-resident interferon effector that blocks flavivirus replication

Interferonstimulated gene 15 (ISG15) restricts Zika virus replication 26 Journal of Immunology Research in primary human corneal epithelial cells

ISG15 facilitates cellular antiviral response to dengue and West Nile virus infection in vitro

The antiviral activities of ISG15

Interferon-mediated ISG15 conjugation restricts dengue virus 2 replication

Schlafen 11 restricts flavivirus replication

The authors apologize to colleagues whose work could not be cited due to space constraints. This work was supported by Agencia Nacional de Promoción Científica y Tecnológica (Grant PICT 2015 N°0076) and CONICET. PLA and LBT are career researchers from CONICET and ABB is a fellow from the same institution.