key: cord-0923198-hdjlnot1
authors: Kheshtchin, Nasim; Bakhshi, Parisa; Arab, Samaneh; Nourizadeh, Maryam
title: Immunoediting in SARS-CoV-2: Mutual Relationship between the Virus and the Host
date: 2022-01-10
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2022.108531
sha: 690a92c60663d855fdcdd1b20927523e78fa264a
doc_id: 923198
cord_uid: hdjlnot1

Immunoediting is a well-known concept that occurs in cancer through three steps of elimination, equilibrium, and escape (3Es), where the immune system first suppresses the growth of tumor cells and then promotes them towards the malignancy. This phenomenon has been conceptualized in some chronic viral infections such as HTLV-1 and HIV by obtaining the resistance to elimination and making a persistent form of infected cells especially in untreated patients. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a heterogeneous disease characterizing from mild/asymptomatic to severe/critical courses with some behavioral aspects in an immunoediting setting. In this context, a coordinated effort between of innate and adaptive immune system leads to detection and destruction of early infection followed by equilibrium between virus-specific responses and infected cells, which eventually end up with an uncontrolled inflammatory response in severe/critical patients. Although the SARS-CoV-2 applies several escape strategies such as mutations in viral epitopes, modulating the interferon response and inhibiting the MHC I molecules similar to the cancer cells, the 3Es hallmark may not occur in all clinical conditions. Here, we discuss how the lesson learnt from cancer immunoediting and accurate understanding of these pathophysiological mechanisms helps to develop more effective therapeutic strategies for COVID-19.

1. Immunoediting is a well-known concept that occurs in cancer through three steps of elimination, equilibrium, and escape (3Es) 2 . Immunoeditingn has been conceptualized in some chronic viral infections such as HTLV-1 and HIV due to their resistance to elimination and making a persistent form of infected cells 3. Coronavirus disease 2019 (COVID-19) is a heterogeneous disease characterizing from mild/asymptomatic to severe/critical courses with some behavioral aspects in an immunoediting setting. 4 . Elimination in SARS-CoV2 infected cells include the early detection and destruction through the accordance between innate and adaptive immune system 5. Equilibrium is defined as a balance between virus-specific responses and infected cells 6 . Escape is a terminal process with an uncontrolled inflammatory response in severe/critical patients.

Immunoediting is a well-known concept that occurs in cancer through three steps of elimination, equilibrium, and escape (3Es), where the immune system first suppresses the growth of tumor cells and then promotes them towards the malignancy. This phenomenon has been conceptualized in some chronic viral infections such as HTLV-1 and HIV by obtaining the resistance to elimination and making a persistent form of infected cells especially in untreated patients. Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a heterogeneous disease characterizing from mild/asymptomatic to severe/critical courses with some behavioral aspects in an immunoediting setting. In this context, a coordinated effort between of innate and adaptive immune system leads to detection and destruction of early infection followed by equilibrium between virus-specific responses and infected cells, which eventually end up with an uncontrolled inflammatory response in severe/critical patients. Although the SARS-CoV-2 applies several escape strategies such as mutations in viral epitopes, modulating the interferon response and inhibiting the MHC I molecules similar to the cancer cells, the 3Es More than 250 million people have been diagnosed with COVID-19 and over 5 million died by the end of November 2021 [3] .

Various studies have illustrated that the heterogeneity of COVID-19 and severity of disease are closely related to the virus itself, the hosts' immune system, and the environment as a whole. Two arms of the immune system, the innate immunity involving monocytes, granulocytes, natural killer (NK) cells, and dendritic cells (DCs), and the adaptive immunity composed of T and B lymphocytes provide defense mechanisms against SARS-CoV-2. An effective immune function is crucial for an individual to suppress the virus and enter the recovery phase, while several factors including age, gender, malnutrition, and underlying diseases can affect the quality of immune responses [1, 4] . In such immunocompromised individuals, the virus is not easily removed, and the disease will progress to a severer phase. Manifestations of severe COVID-19 include lymphopenia with decreased number of CD4 + and CD8 + T cells, increased ratio of circulating neutrophils to lymphocytes, uncontrolled activation of neutrophils and lymphocytes causing the massive release of a wide range of cytokines, a condition known as cytokine storm which is a major cause of death in COVID-19 [5, 6] . Therefore, increasing our knowledge on different aspects of cellular immune responses during the transition of patients from mild to a potentially fatal condition is highly required for improved diagnosis and applying the best therapeutic strategies.

Cancer immunoediting describes a dynamic process in which the immune system not only protects the body against tumor development but also shapes the immunogenicity of emerging tumors leaving behind subsets of tumor cells capable of escaping immune control. This occurs through three dynamic phases known as "3Es": elimination, equilibrium, and escape. The elimination indicates the process in which the elements of innate and adaptive immunity detect and destroy tumor cells, although some cells survive immune destruction and enter a dormancy phase or equilibrium. During the equilibrium phase, selection pressure of the immune responses results in the outgrowth of immunologically edited tumor cells. Then, edited tumor cells enter the escape phase where tumor cells uncontrollably progress, and become clinically detectable [7] . Recently, the capacity of the immunoediting has been suggested to occur in untreated viral infections in which immunosurveillance is a vital phase to control the early infection followed by an equilibrium between virus-specific CTL responses and infected cells that eventually leads to the escape of the virus from antiviral immune responses [8] . Untreated HIV infection with a non-malignant escape phase which parallels the escape phase in tumors, and HTLV-1 as an oncogenic virus with a coordinated interaction between the virus and the host-mediated immune responses are two examples of viral infections resembling the immunoediting process in cancer. Immunoediting of the virus, was firstly hypothesized by Brad Jones et al, as a hallmark of viral infections with a latent period wherein long-lived infected cells undergo extensive clonal expansion and persist in anatomical sites that are usually inaccessible for effector cells.

The concept of immunoediting in HIV-infected cells is based on the persistence of the cells expressing viral epitopes with escape mutations under the selective pressure of HIV-specific T cells and the available evidence on similarities between tumors and viral infections in terms of differential intrinsic susceptibilities to immunosurveillance [9, 10] . According to recent reports, a crossroad of COVID-19 and cancer has been demonstrated to some extent due to similar clinical relevance including the cytokine storm, crucial role of IFN-I, androgen-related severity of disease and aberrant regulation of immune checkpoint signaling. An immunoediting-like process has also been suggested in SARS-CoV-2 infection to help better understanding the virus behavior and to propose a treatment model [8] . Herein we discuss the fundamental knowledge of the phenomena and the possibility for SARS-CoV-2 to fit into immunoediting model through providing a detailed review of the literature and finding evidence for three distinct phases of immunoediting process in SARS-CoV-2 infection and suggest a non-cancerous escape phase for SARS-CoV-2 infected cells.

The idea that the immune system could control neoplastic disease was initially conceived by Ehrlich and approximately half a century later, in 1975, Burnet and Thomas proposed the cancer immunosurveillance hypothesis [11] . The immunosurveillance hypothesis was proved by various experimental studies and was mainly based on the function of the adaptive immune system. Substantial amounts of data refined the concept considering both arms of the innate and adaptive immune system in sculpting the immunogenic phenotype of tumors [7, 12] . In simplest form, tumors pass through each of three phases (3Es) of immunoediting sequentially, although transition or bidirectional manner is possible. External factors such as immune system aging and environmental stress might affect the process [12] .

The original concept of cancer immunosurveillance can be assumed equal to the elimination phase. Because of the stromal remodeling that occurs during tumor growth, the innate immune system becomes alert, and it is the first step of the antitumor immune response. Releasing chemokines at the site of tumor recruits more cells of the innate immune system which become activated following exposure to tumor antigens and cytokines, and finally help the adaptive immunity to completely eradicate the tumor cells. If the developing tumor is completely eliminated, the immunoediting process is finalized [7, 13] .

Equilibrium is probably the longest phase between 3Es and can be extended throughout many years. In the equilibrium phase, the elimination of cancer cells by the immune system continues along with the emergence of the immune resistant variants. During the equilibrium phase, genetic instability and heterogeneity are the main resistance forces of tumor cells against the immune system [14] .

Tumor cell variants that cannot be detected and eliminated in the two previous phases, progress into the escape phase. In the escape phase, tumor cells use various immune invasive strategies to evade the host's antitumor immune defenses towards an uncontrolled growth which makes them clinically detectable [7, 12, 15] .

During these three phases of immunoediting, immune selection pressure plays critical role in sculpting the tumor cells resulting in the selection of tumor cells with less-or non-immunogenic phenotypes. Several experimental findings indicate that lymphocytes such as CD8+T cells and cytokines like IFN-Y play a major role in elimination of the immunodominant cancer cells and push the cancer cells to evade by inducing the upregulation of immune checkpoint molecules like PD-1 to support T cell apoptosis or imposing the escape strategies to the cancer cells including the loss of MHC class I and II antigens and decreased expression of tumor antigens [16] . Moreover, a double edge sward role of IFN-γ has been shown for IFN-γ-dependent pro-and anti-tumorigenic effects [17] .

The concept of cancer immunoediting contains a complete integration between different functions of immune responses and tumor growth. Nevertheless, detailed identification of cellular and molecular mechanisms underlying the three phases of elimination, equilibrium and escape helps the scientists to develop the new therapeutic approaches especially in the escape phase as an important hallmark of cancer.

The concept of immunoediting is related to the gradual interaction between the immune system and a persistent factor like tumor cells or chronic infections. Most well-studied viruses develop chronic infections in a subset of patients [18] as evidenced in chronic Ebola infection being developed after acute infection [19] . The reservoirs of Ebola virus can be identified in tissues of infected individuals months or years after clearance of the virus from the blood. Viruses that cause chronic infections have developed a wide variety of strategies to ensure their long-term maintenance within the host's body. Viral integration, latency and persistent active replication are three mechanisms applied by different viruses to establish chronic infection in the host [20, 21] . Accordingly, a chronic viral infection comprises distinct stages which parallel three steps of immunoediting process in cancer. The primary or acute stage is characterized by efficient recognition and eradication of infected cells by host's CD8 + T cells and control of the viral replication (elimination phase). The chronic or latent phase implies a situation in which the virus remains in equilibrium with the host CTL responses for a long period of time (equilibrium phase) during which, the mechanisms of immune evasion are developed by the virus leading to a balance between viral replication and elimination of infected cells by the host immune responses. This process eventually is followed by a progressive latestage (escape phase) [9] .

Multiple studies have found evidence on persistence of coronavirus infections resulting in chronic diseases.

COVID-19 is a multisystem inflammatory syndrome with a very wide clinical spectrum [22] . While protective in the early phases of the disease, the immune responses contribute to disease severity and mortality via excessive proinflammatory cytokine release (cytokine storm) [22] . Although many SARS-CoV-2 infections resolve within 2-6 weeks, a growing number of investigations show that in some COVID-19 patients referred to as "long-haulers" unsuccessful clearance of the virus from the body leads to developing a prolonged illness known as "long COVID" [23] . Moreover, recent studies highlighted the possibility of viral latency in different tissues such as brain, testis, and gastrointestinal tract through detection of viral RNA and/or proteins [24] [25] [26] .

Single-stranded RNA viruses such as hepatitis C virus (HCV) develop mechanisms to establish persistent infections. Such mechanisms include protection of viral genome from being degraded by cellular ribonucleases or being recognized by innate immune receptors. Modifications at the 5′ and/or 3′ ends of the viral genomes is another strategy employed by RNA viruses to establish persistent infections [27, 28] . As discussed later, infection by SARS-CoV-2, as an RNA virus, is enabled by several strategies of immune evasion which strengthen the viral infection capacity and weaken the control of infection due to impaired innate immune mechanisms including interferon responses and induction of cytokine storm. These events may define a role for immunoediting in SARS-CoV-2 reservoir persistence.

Immunosurveillance is considered as a main potential feature of the immune system to detect and eradicate cancer cells and all other foreign invaders such as viruses, bacteria, and fungi. Antipathogenic effects of the immune system are initially begun through the generation of inflammatory mediators, recruitment of immune cells to the infection site, and induction of adaptive immune responses [29] . In the last two years since the pandemic began, numerous studies have been conducted on various mechanisms applied by the innate immune system to sense and defend against COVID-19 virus infection [6] .

It is well documented that activation of pattern recognition receptors (PRRs) including Toll-like receptors However, recent evidence shows a remarkable heterogeneity in IFN-I response between different cell types and different individuals concerning the amplitude and kinetics [6] . In vitro studies suggest an early transient wave of interferon-stimulated genes (ISG) upregulation in immune cells of COVID-19 patients, correlated with an early burst of IFN-α [35, 36] . Further studies showed that the early peak of IFNs is followed by a declined concentration of IFN-α and IFN-λ in mild-to-moderate COVID-19 [37] . However, in severe patients, the IFN levels continue to increase particularly during the second week of onset associated with elevated levels of inflammatory cytokines such as IL-1, IL-6, CXCL8, and TNF [37] . These findings are consistent with the observations in a murine model of SARS-CoV-2 infection which suggests a pathological rather than protective effect for IFNs-I in severe patients [38] . The complicated dynamics of IFN response in patients with COVID-19 demonstrate the coordinated interaction between antiviral immune responses and proinflammatory mechanisms in early stages of the disease and in mild to moderate patients [6] . Here, we theorize that virus-induced events early in infected individuals are a major driver of the first step in immunoediting. Viral protein expression in infected cells promotes the presentation of viral antigens which activates immunosurveillance mechanisms resulting in the elimination of the virus. The early IFN response and its subsequent decline in mild to moderate patients could reflect the events of this stage.

In addition to IFNs, inflammatory cytokines and chemokines such as IL-1ß, IL-18, IL-6, CCL2, and CCL7 prevent virus replication. Some investigators have found that SARS-CoV viroproteins such as envelope (E) and 3a stimulate the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome which in turn triggers caspase cascade and subsequent production of inflammatory cytokines (IL-1, IL-18, and IL- [45] . Although, neutrophil-driven inflammatory pathways sometimes can lead to immunopathologic damage in patients [46] . Pathogen-activated neutrophils are able to produce net-like structures known as NETs, composed of DNA-histone complexes associated with microbicidal peptides and oxidant enzymes. Several studies have speculated a central role for NETs formation in organ damage and death in COVID-19 patients [47] . NETosis is triggered by innate immune receptors following the recognition of microbial components and endogenous danger signals and must be strongly regulated to prevent tissue damage during acute or chronic inflammation and autoimmune disease [48, 49] .

Macrophages detect viral danger signals by PRRs, release several inflammatory molecules, and recruit different effector cells to emerge an effective response in viral infections [50] . As shown in previous reports, both monocyte-derived macrophages and tissue-resident alveolar macrophages in association with anti-SARS-CoV-2 antibodies play a crucial role in the elimination of infected pulmonary cells in COVID-19 patients [51] .

Dendritic cells as professional antigen-presenting cells (APCs) are central players in the initiation of adaptive responses, leading to elimination of viral infections [52] . Analysis of conventional dendritic cells (cDCs) in severe and mild COVID-19 patients illustrated decreased expression of co-stimulatory proteins, MHCII, and TAP molecules and increased levels of pro-inflammatory molecules including complement and coagulation factors in severely ill patients [53] . Moreover, plasmacytoid dendritic cells (pDCs) are known as IFN producers in the innate immune system. Increased activity of inflammatory and proapoptotic pathways have been shown in pDCs isolated from severe COVID-19 patients. In addition, a decrease in number and activity of pDCs was found in severe cases [54, 55] .

Eosinophils having potent pro-inflammatory functions are related to asthma and allergic diseases and involved in protection against parasites [56] . Furthermore, the protective effect of these cells has been demonstrated in some viral respiratory infections such as rhinovirus, respiratory syncytial virus (RSV), influenza, and para-influenza virus because eosinophils could restrict virus replication by the generation of nitric oxide (NO) via nitric oxide synthase 2 (NOS-2) [57] . Recent studies found lower eosinophil counts in peripheral blood of severe cases of COVID-19 infection, while increased eosinophil count is associated with a better prognosis. Therefore, eosinopenia may be applied as a prognostic factor for severe forms of COVID [58] . However, it is assumed that eosinopenia may be the result of the recruitment of the cells in the lung and intestinal epithelium as the main virus invasion locations [59, 60] . In the monkey model of MERS virus infection, a huge amount of eosinophils infiltrated in the alveolar cavity, bronchi, and necrotic bronchial epithelial cells have been reported [61] .

NK cells make an effective role in antiviral responses through both cytokine production and cell-mediated cytotoxicity [62] . It has been reported that SARS-CoV-2 infection induces a functional exhaustion phenotype in NK cells via upregulation of NKG2A, an inhibitory receptor that recognizes peptides presented by HLA-E molecules, as well as downregulation of CD107a, IFN-γ, granzyme B, IL-2, and TNF-α [63] . Evaluation of NK cell activity against SARS-CoV and SARS-CoV-2 revealed that spike 1 peptide presented by HLA-E molecules are detected by NKG2A receptors on NK cells resulting in NK cells downregulation [64] . NKG2C on the other hand, is an activating receptor on NK cells which interacts with HLA-E on infected cells and has the potential of limiting the extent of SARS-CoV-2 infections. it has been shown that in response to certain viral respiratory infections, a subset of NKG2C + NK cells infiltrate into the lung epithelium [65] . Vietzen et al. reported that the severe form of COVID infection was associated with some specific alleles of HLA-E and NKG2C leading to NK cell response inhibition [66] . animal models. Of note, a higher viral load has been shown in CD4 + or CD8 + T cell-depleted mice [51] .

The altered number and function of CD4 + and CD8 + T cells have been shown in several reports. The percentage of these cells has been reported to be markedly decreased in severe COVID-19 patients and increased in survived patients when compared to those who were deceased [67] . Previous studies demonstrated SARS-CoV-2-specific T cells and strong T cell memory responses in people with acute COVID-19 and in patients recovering from infection with and without antibodies. Memory cells are essential for long-lasting and protective immunity [68] [69] [70] . Humoral immunity contributes to antiviral responses mainly by producing neutralizing antibodies and inhibiting the virus entry into host cells. Farshi et al reported that severe COVID-19 patients had lower B cell counts compared to mild cases, although both were within the normal range. Apparently, the significant role of humoral immunity is to prevent the SARS-CoV-2 invasion and cell entry and it is not able to eliminate the virus after the establishment of infection [51] . However, in hematologic cancer patients with COVID-19 positive results despite the impaired humoral immune response, increased numbers of antiviral CD8 + T cells provide effective protection and improve their survival [71] [42] . The profile of the antibody response to SARS-CoV-2 is currently being investigated. It is well documented that IgM and IgA antibodies can be detected early in the first week, while IgG can be measured around 14 days post symptoms onset remains detectable up to 36 months [72] . Despite the fact that SARS-CoV-2 enters the body through the mucous membrane of the airways and secretory IgA (sIgA) is fundamental for the defense of the mucosa little attention was paid to the role of sIgA in COVID-19, [73] . The presence of SARS-CoV-2-specific IgA in serum of recovered patients and in the milk of breast-feeding mothers who recovered from the disease has been demonstrated in several reports [72, 74, 75] . However, it is not clear how long these blocking antibodies stay active.

As mentioned earlier, in the chronic or latent phase of viral infections which can be correlated with the equilibrium phase of the immunoediting process, there is a balance between antiviral immune responses and viral replication. During this stage, the virus develops several evasion mechanisms by which protect itself from being recognized by immune effector cells or interfere with the host's immune effector mechanisms. The function of the immune system now results in the selection of viral variants that are better suited to survive in an immunocompetent host. In the following section, we outline different evasion mechanisms employed by SARS-Cov-2 to persist in the host [9, 10] .

SARS-CoV-2 belongs to a genus beta-coronavirus, single-stranded, with a positive-single-stranded RNA strand ( Figure 1 ). The size of the SARS-CoV-2 genome is about 29.9 kb and shares approximately 78% sequence homology with SARS-CoV [76, 77] . The two-thirds of the SARS-CoV-2 genomic RNA consists of two open reading frames (ORF1a and ORF1b) encoding pp1a and pp1b proteins which are finally cleaved into 16 nonstructural proteins (nsp): a papain-like protease (PLpro or nsp3), a 3C-like protease (3CLpro or nsp5) [78, 79] , an RNA dependent RNA polymerase (RdRp or nsp12), and nsp7-nsp8 co-factors. The 3'

terminal one-third of the genome contains several genes encoding four structural proteins, including spike glycoprotein (S), envelope (E), nucleocapsid (N), membrane (M), and some accessory proteins [79, 80] .

The S protein covers the surface of the virus and is responsible for binding to host cell receptor angiotensinconverting enzyme 2 (ACE2) [81] . S protein is composed of two subunits named S1 and S2. The S1 consists of signal peptide (SP), receptor-binding domain (RBD), subdomain 1 (SD1), and subdomain 2 (SD2) while the S2 consists of heptad repeat (HR1-HR2), and fusion peptide transmembrane (TM) [82] . RBD is responsible for direct binding to ACE2 mediating the viral entry; thereby, serves as an important target for neutralizing antibodies (NAbs) [81] . Table   1 ). The mutations may alter virus characteristics, including antigenicity, infectivity, transmissibility, and pathogenicity. These variants have been classified in the context of 'variants of concern' (VOC) (Alpha, Beta, Gamma, Delta, and Omicron) and 'variants of interest' (VOI) (Epsilon, Eta, Theta, Iota, Kappa, and Lambda) by WHO and CDC. This list is likely to grow as new variants emerge. The rate of evolution of SARS-CoV-2 was approximately two mutations per month in the world population [83] [84] [85] . Various mechanisms of mutations, such as deletion, insertion, and substitution can alter the antigenic profile of the virus and are found in both the nonstructural (ORF1a and ORF1b) and structural proteins (N, M, and S).

The majority of the mutations belong to the spike protein (RBD and NTD) which all increase the transmissibility [86] .

Pango lineage T95I  S373P  N856K  G142D  S375F  Q954H  Del143-145  K417N  N969K  Del211  N440K  L981F  L212I,  G446S  ins214EPE  S477N  T478K  E484A  Q493R  G496S  Q498R  N501Y  Y505H  T547K  D614G  H655Y N679K P681 Spike mutations are of great concern for the immune evasion of SARS-CoV-2. Epitope mapping approaches and serological analyses reveal that these mutations result in increased affinity to ACE2 and escape from pre-existing NAbs which are from natural infection immunity or vaccines [85, 87] . For instance, D614G as the most frequent mutation in the spike is common in all VOCs, highly infective, and resistant to NAbs [42] . The E484K substitution mutation facilitates immune evasion from both monoclonal and convalescent plasma antibodies [88, 89] . Furthermore, the spike amino acid substitution mutations, K417N/T, and N501Y confer a stronger affinity for the receptor [90, 91] . Mutations, like deletion (shown as Δ) in NTD Moreover, the T76I and L452Q mutations contribute to increased viral infectivity [94, 95] . Also, some mutations can introduce an additional glycosylation motif that may mask the epitopes from antibody binding like human influenza viruses [96, 97] . New variants are emerging throughout the globe, and thus it is important to understand the role of specific mutations, both individually and in combination with other mutations.

The very recent mutation belongs to the variant named Omicron, by WHO. Omicron has more than 30 mutations to its spike protein which is about 3 times more than the previous versions. It is not yet clear whether Omicron is more transmissible, or causes more severe disease than previous variants, or whether it will make the vaccines less effective. In a new pre-print study released the scientists from South Africa suggests that Omicron is three times more likely to reinfect people [98] .

Therefore, mutant variants may evade the immune systems by at least three putative mechanisms: 1) stronger ligation to the ACE2 and 2) masking the epitopes by residual glycosylation, and 3) changing the binding sites by modifying the epitopes.

As mentioned above, innate immune responses and the antiviral IFN system serve as the first line of the defense against viruses which play crucial roles in limiting viral replication and promoting the adaptive immune responses [99] . Innate immune responses are initiated by recognizing viral PAMPs via PRRs [100] .

Cytosolic RLRs including RIG-I, and MDA5, and endosomal TLRs mainly TLR-3, TLR-7, and TLR-8 are major PRRs responsible for detecting RNA virus infections such as coronaviruses and promoting the antiviral IFN pathway [101] [102] [103] [104] . Ligand binding results in triggering the downstream adaptor proteins including myeloid differentiation primary response gene 88 (MyD88) and mitochondrial antiviral signaling protein (MAVS). Triggering adaptor proteins is followed by the activation of downstream kinases, TANK binding kinase 1 (TBK1), and inhibitor of κB kinases (IKKs) which then activate transcription factors IFN regulatory factor 3 (IRF3) and IRF7, and NF-κB upon phosphorylation. After translocation to the nucleus, activated transcription factors induce expression of type IFN-I and IFN-III [105] . Both IFN-I and IFN-III activate ISGs, through binding to IFN receptor (IFNR) on the cell surface, and subsequent activation of Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), leading to phosphorylation and binding of STAT1 homodimers and STAT1/2 heterodimers to the interferon-stimulated response elements (ISREs) located in the promoter region of ISGs [102, 106, 107] . Most viruses express proteins that counter the innate immunity in different levels including inhibition of IFN production via interfering with PAMP recognition by PRRs or blocking the subsequent signaling pathways, hampering IFN downstream signaling cascades and, interfering with host biological activities.

There is some evidence that coronaviruses including SARS-CoV-2 are capable of manipulating immune responses and have evolved several strategies to evade the innate immune responses especially through hampering the IFN induction and its subsequent signaling (Figure 2) [108].

Coronaviruses have developed multiple strategies to evade the host's innate immune responses by modifying or masking potential key antigenic epitopes to avoid being recognized by immune receptors.

which is associated with a complex vesicular network comprised of double-membrane vesicles (DMVs) [109] . DMV formation is induced through coordinated function of multiple coronavirus nonstructural proteins, including Nsp3, Nsp4, and Nsp6, on the endoplasmic reticulum (ER) membrane [110] . Such ERderived structures lacking PRR's, protect viral PAMPs from being exposed to cellular PRRs [110] . SARS-CoV-2 N protein, an RNA-binding protein involved in viral genome encapsidation, drives liquid-liquid phase separation with RNA, which might also be involved in hiding viral RNAs from immune recognition [111, 112] . It has been shown that N protein directly interacts with the RIG-I protein targeting the initial step of the IFN-β response [113] .

Altered RNA modification signatures in the viral genomic RNA are another suggested strategy. The zincfinger antiviral protein (ZAP), an interferon-induced mammalian enzyme, selectively binds CpG motifs in viral RNAs and induces their degradation. Many mammalian RNA viruses have evolved CpG deficiency, thereby evading ZAP action which is associated with increased virulence. Interestingly, SARS-CoV-2 exhebits the most extreme CpG deficiency in all known betacoronavirus genomes [114] . Since CpG motifs are considered as PAMPs with the capacity to be recognized by host PRRs, decreased CpG content might be due to selective pressure evoked by host immune responses. mRNAs of coronaviruses having a cap structure at their 5′ ends, mimic cellular mRNAs and are protected from being sensed by MDA-5 and the IFN-induced protein with tetratricopeptide repeats (IFIT) family proteins that target viral RNAs for degradation [115] . The viral RNA capping machinery is composed of Nsp10, Nsp12 [116] , Nsp13, Nsp14, and Nsp16 [117] [118] [119] , which work together to make viral RNAs indistinguishable from cellular mRNAs. Moreover, Nsp15, a conserved uridine-specific endoribonuclease encoded by coronaviruses, provides another mechanism to modify viral mRNAs which are likely used by SARS-CoV-2. Nsp15 is an integral component of the RTC that cleaves 5′-polyuridines from negative-sense viral RNA preventing the formation of dsRNA intermediates which might be sensed by cytosolic dsRNA sensors and promote host interferon response [120, 121] suggesting a viral strategy to escape early events of host antiviral responses.

Modification of viral envelope proteins is another strategy utilized by coronaviruses to mask immunogenic viral protein epitopes or to enhance viral infectivity. Extensive glycosylation of the SARS-CoV-2 S glycoprotein has been evident by cryo-EM structure technique [122, 123] . Modification of S protein glycosylation is another evasion mechanism applied by SARS-CoV-2 which allows new virus strains to evade neutralization by the immune system. In addition to S protein, other coronaviral proteins undergo modification by glycosylation, phosphorylation, palmitoylation, and ADP-ribosylation [124] .

Several SARS-CoV-2 proteins have been shown antagonize IFN responses with diverse mechanisms. Both IFN-I production and downstream signaling are inhibited by ORF6. ORF6 has been shown to be uniquely enriched at the nuclear pore complex (NPC) where interferes with the nuclear translocation of IRF3 and STAT1 through direct binding to the Nup98-Rae1 complex, leading to the shutdown of downstream events [125, 126] . SARS-CoV ORF3b, a potent IFN antagonist, is localized in the mitochondria and involved in the inhibition of the MAVS-mediated IRF3 activation pathway [127] . Interestingly, SARS-CoV-2 ORF3b blocks IFN production more efficiently than the SARS-CoV ortholog due to a shortened C-terminal region.

SARS-CoV-2 ORF3b also prevents IFN downstream signaling by blocking the IRF3 translocation into the nucleus [128] . NSP12, NSP13, NSP14, and NSP15 are other coronaviral proteins suggested to suppress IRF3 nuclear localization [129, 130] . It has been reported that while Nsp13 inhibits TBK1 phosphorylation, Nsp6, another SARS-CoV-2 nonstructural protein, suppresses IRF3 phosphorylation through binding TBK1 without affecting its phosphorylation/activation status [131] . It has been shown that MERS-CoV ORF4b binds to both TBK1 and IKKε, preventing nuclear translocation of IRF3 [132] ; such mechanism might be conserved in SARS-CoV-2.

The papain-like protease (PLpro) domain of SARS-CoV-2 Nsp3 cleaves interferon-stimulated gene 15 (ISG15) from IRF3 or cleaves IRF3 directly, dampening the IFN response [133] . Moreover, SARS-CoV-2 M protein antagonizes the induction of IFN-I and -III through interaction with RIG-I, MAVS, and TBK1, which interferes with the formation of the multiprotein complex containing RIG-I, MAVS, TRAF3, and TBK1 leading to inhibition of the phosphorylation, nuclear translocation, and activation of IRF3 [134, 135] .

It has been revealed that ORF9b encoded by SARS-CoV-2 associates with TOM70, a mitochondrial import receptor, which consequently prevents the recruitment of Hsp90 to TBK1/IRF3 and suppresses IFN-I responses [79, 136] . ORF9b also inhibits IFN production through targeting the NF-κB essential modulator NEMO and interrupting its K63-linked polyubiquitination upon viral stimulation, leading to inhibition of the IκB kinase alpha (IKKα)/β/γ-NF-κB signaling [137] . SARS-CoV-2 N protein also interferes with the interaction between tripartite motif protein 25 (TRIM25) and RIG-I [138] . Moreover, the N protein restrains the association between TBK1 and IRF3, preventing the translocation of IRF3 into the nucleus [138] .

SARS-CoV-2 Nsp5 might restrict IFN induction by reducing K63-linked ubiquitination on RIG-I [139] . It has been shown that Nsp8 could inhibit type I IFN signaling through direct binding to MDA5 and blocking its K63-linked polyubiquitination [140] .

SARS-CoV-2 also can use its structural and nonstructural proteins to evade the IFN downstream pathway resulting in diminished nuclear translocation of STAT1/STAT2. Nsp14 drives lysosomal degradation of type I IFN receptor, IFNAR1 [141] . As mentioned above, ORF6 interferes with the nuclear translocation of STAT1 through direct binding to the Nup98-Rae1 complex [79] . Furthermore, SARS-CoV-2 Nsp1 inhibits IFN-I signaling by blocking STAT1 and STAT2 phosphorylation which is more efficient compared to SARS-CoV and MERS-CoV [131] . As discussed above, SARS-CoV-2 N protein antagonizes IFN induction via targeting the RNA sensing pathway. It has been shown that N protein also can act as an antagonist of IFN signaling by inhibiting the STAT1/STAT2 phosphorylation and nuclear translocation [142] . Nsp5, another SARS-CoV-2 nonstructural protein, prompts the autophagic degradation of STAT1 [139] . ORF7a of SARS-CoV-2 which is ubiquitinated at position Lys 119 (K119) inhibits IFN-α signaling by blocking STAT2 phosphorylation [143] . 

SARS-Cov-2 proteins also target intrinsic antiviral mechanisms within the cell to achieve their life cycles:

Nsp1 of SARS-CoV and MERS-CoV suppresses host protein synthesis via induction of host endogenous 5ʹ-capped mRNA degradation without affecting viral mRNAs [144] . Having a high amino acid identity with SARS-CoV Nsp1, SARS-CoV-2 Nsp1 may apply this mechanism to evade host immunity. SARS-CoV-2 Nsp1 also inhibits mRNA translation through binding ribosomal 40s subunit and thereby preventing the assembly of the translation machinery. Indeed, Nsp1 C terminus binds to 40S ribosomal subunit and obstructs the mRNA entry tunnel, thereby, blocking antiviral responses triggered by RIG-I [145] . It was also suggested that SARS-CoV-2 Nsp1 prevents mRNA nuclear export through interaction with the host mRNA export receptor heterodimer NXF1-NXT1, which is involved in nuclear export of cellular mRNAs, thereby subsequently suppressing protein synthesis [146, 147] .

Further investigations reported the direct interaction of several proteins of SARS-CoV-2 with mammalian proteins responsible for several biological processes. For example, Nsp5 interaction with epigenetic regulator histone deacetylase 2 (HDAC2), can affect the potential of HDAC2 to mediate the inflammation and interferon response through inhibiting the transport of HDAC2 into the nucleus [79] . Nsp8 and Nsp9 on the other hand, interfere with protein trafficking to the cell membrane through interaction with the 7SL RNA component of the signal recognition particle (SRP) complex [148] .

It has been shown that SARS-CoV-2 N protein and Orf3a influence the host immune system by activating pro-IL-1β gene and IL-1β secretion, leading to the induction of NF-kB signaling and NLRP3 inflammasome and generation of cytokine storm [71, 149] . ORF3a also regulates apoptotic pathways. Apoptosis is a double-edges sword in the pathogenesis of viruses. Considering apoptosis as a host defense mechanism, some viruses including SARS-CoV-2 encode anti-apoptotic proteins allowing sufficient time for viral replication. In contrast, some other types of viruses such as influenza and HIV apply apoptosis to exit the cells, spread throughout the tissue, and infect other cells which are also considered as the hallmark of SARS-CoV-2. It was recently shown that SARS-CoV-2 ORF3a activates host cell apoptosis through the extrinsic pathway in which caspase-8 cleaves Bid to tBid, leading to the release of cytochrome c from the mitochondria and subsequent formation of apoptosome and caspase-9 activation [71, 150] . As previously indicated, cell death can be considered as an escape mechanism allowing the release of more particles and helping the virus to further spread throughout the epithelium and lung. However, caspase-8 mediated apoptosis and especially necrosis as an immunogenic cell death pathway restricts the virus not only through eliminating the virus-infected cells but also by stimulating the innate and adaptive immune responses for

limiting the viral replication [151] . Finally, Orf3a is involved in the lysosomal pathway through inhibition of autophagy by blocking fusion of autophagosomes/amphisomes with lysosomes [152] while, ORF7a

interferes with autophagosome acidification [141, 152] . It has been revealed that ORF8 directly interacts with MHC-Ι molecules and mediates their down-regulation via selective targeting of these molecules for lysosomal degradation via autophagy, a mechanism which impairs the antigen presentation leading to SARS-CoV-2 immune evasion of cytotoxic T lymphocytes [153] . ORF6 protein, on the other hand, inhibits MHC class I expression through suppression of STAT1, IRF1, and NLRC5, the key transcriptional regulators of MHC-I expression [154] . Targeting NLRC5 by cancer cells through mechanisms including genetic mutations, loss of NLRC5 gene copy numbers or promoter methylation to evade anti-tumor immune responses has been shown in different tumors. Regarding similar evading approaches in some viruses and cancer cells, the disease severity and mortality in COVID-19 patients might be associated with the expression level of NLRC5 [155] .

In patients with fatal COVID-19, a dysregulated immune response results in extensive damage to the lung and other organs death and eventually to death. As described in the previous section, SARS-CoV-2 develops multiple inhibitory mechanisms against the host immune system among which are several strategies to inhibit IFN pathways leading to defective clearance of the SARS-CoV-2. The absence of IFN production or sensing, persistence of the viral infection, prolonged exposure to PAMPs, as well as the release of DAMPs, lead to activation of several innate immune pathways including persistent hyperactivation of the monocyte and macrophage [156, 157] . In critical COVID-19 patients, macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH) as well as a decreased number of different types of lymphocytes is accompanied by a systemic inflammatory response known as cytokine storm. The cytokine storm is characterized by hyperproduction of an array of pro-inflammatory cytokines and chemokines including IL-2, IL-6, IL-7, IL-8, IL-10, TNF, IFN-γ, G-CSF, GM-CSF, and MCP1 [158] . The evidence suggests a direct association between aggressive proinflammatory cytokine release with lung injury, multiorgan failure, and poor prognosis of severe COVID-19 [159, 160] . Interestingly, the serum level of IL-6 shows a strong correlation with disease mortality [161, 162] . As in tumors and other chronic viral infections, persistent inflammation or viral infection accompanied by high levels of inhibitory IL-10 can cause immune exhaustion in immune cells, particularly in T cells. Effector cytotoxic cell populations including NK cells (responsible for primary control during acute viral infection) and CD8+ T cells (critical mediators for long-term surveillance) display a terminally differentiated/senescent phenotype, poor cytotoxic response as well as reduced capacity to produce antiviral cytokine [163, 164] . Interestingly, the correlation between diminished cytotoxic potential and serum levels of IL-6 suggests a direct/indirect role for this cytokine in the impairment of cytotoxic lymphocytes. Increased expression of perforin and granzyme A in NK cells following IL-6R treatment provides further evidence for this assumption [164] .

Chronic inflammation due to a sustainable low-grade production of pro-inflammatory cytokines, such as TNF-α and IL-6, directly promotes the ARDS and influence the severity of COVID-19.

This situation is of a particular significance in patients with underlying conditions like obesity and type 2 diabetes who are at a higher risk of COVID-19 complications and even mortality [165] .

Leptin as a hormone predominantly made by adipose cells and a regulator of the immune system, has pro-inflammatory properties and upregulates the secretion of inflammatory cytokines like TNF-α, IL-6, and IL-12. Moreover, dysregulated function of classically-activated-macrophages (M1) in adipose tissue and impaired type I IFN production worsen the survival rates in COVID-19 patients with obesity [166, 167] .

Taken together, a dysfunctional immune response characterized by decreased lymphocytes numbers, hyper inflammation, impaired cytotoxic response, and immune exhaustion leading to increased viral load is observed in COVID-19 patients [168] . Aberrant or exaggerated response of the host's immune system can lead to severe disease and even death if treatment is not adequate. Indeed, the outcome of the infection is affected by both the host's immune response and viral factors. Immune response dysregulation is at least in part related to immune inhibitory strategies applied by the SARS-CoV-2. Most patients with poor prognostic features upon hospital admission eventually encounter complications with acute respiratory distress syndrome (ARDS), acute renal injury, multiorgan failure, and blood clots [161, 169] .

Since the onset of COVID-19 pandemic, tremendous efforts have been made to identify safe and effective drugs against SARS-CoV-2. Different pharmaceutical interventions have been suggested based on the interplay between the virus and the host immune responses. One potential approach would be the use of components preventing the receptor recognition thereby blocking entry of the virus to the host cells. Such approaches include antibodies targeting SARS-CoV-2 S protein or a recombinant soluble form of ACE2 [170] [171] [172] [173] . The endocytic pathway which enables entry of the virus after receptor recognition has been targeted in several studies by endosomal-tropic agents such as hydroxychloroquine sulfate or umifenovir [174] . However, once the cells were infected the rapid replication of the virus within the infected cells will drive the manifestations of the disease. In this regard, SARS-CoV-2 RNA polymerase (Nsp12-RdRp), a key enzyme for viral replication and mutagenesis, is a target for designing antiviral treatments.

Favipiravir and remdesivir, two nucleoside analogues, act via inhibition of RdRp with remdesivir being the first FDA-approved drug for COVID-19 [175, 176] .

As indicated, uncontrolled viral replication as a result of viral evasion of host's immune mechanisms together with excessive release of proinflammatory cytokines leads to tissue and organ damage. Targeting key molecular players in signaling pathways which are altered by the viral infection is another treatment strategy. IFNα-2b, an FDA-approved recombinant interferon alpha-2 protein for treatment of several cancers, also interferes with viral replication and promotes antiviral activities of immune cells through binding type-1 interferon receptors [177, 178] . IFNα-2b is currently under clinical trials for treatment of COVID-19. Clinical evidence indicates the potential effects of Anti-inflammatory and immunosuppressive treatments for COVID-19. Monoclonal antibodies against inflammatory molecules or their receptors including tocilizumab, sarilumab, siltuximab (inhibitors of IL-6 receptor), gimsilumab (GM-CSF inhibitor), and fingolimod (a sphingosine-1-phosphate receptor modulator) have been suggested to reverse the uncontrolled inflammatory response in severe COVID-19 patients through inhibition of inflammatory cytokines or trafficking of the immune cells [179] . Administration of corticosteroids including prednisone, methylprednisolone and dexamethasone have been shown to beneficial in late stage disease suppressing the pulmonary inflammation; however, their use can interfere with antiviral immune responses in the early phases of the disease [180] .

To date, none of the investigated drugs for COVID-19 in clinical trials, demonstrated to be clearly effective.

Therefore, a thorough understanding of the SARS-CoV-2 behavior in the host and its interaction with immune mechanisms would provide insights to develop more effective therapeutics.

The plentiful experimental and clinical evidence on the existence of immunoediting process from immune 

Innate immune sensing of coronavirus and viral evasion strategies

Overview of Immune Response During SARS-CoV-2 Infection: Lessons From the Past

Live): 24, 164 cases and 835,843 deaths from COVID-19 virus pandemic

Longterm effects of malnutrition on severity of COVID-19

Cellular Immune Response to COVID-19 and Potential Immune Modulators

COVID-19 and the human innate immune system

The immunobiology of cancer immunosurveillance and immunoediting

Modeling and simulations of CoViD-19 molecular mechanism induced by cytokines storm during SARS-CoV2 infection

Have Cells Harboring the HIV Reservoir Been Immunoedited?

HTLV-1 as a Model for Virus and Host Coordinated Immunoediting

The concept of immunological surveillance

The three Es of cancer immunoediting

Cancer immunoediting by the innate immune system in the absence of adaptive immunity

A Race between Tumor Immunoescape and Genome Maintenance Selects for Optimum Levels of (epi)genetic Instability

Cancer immunoediting: from surveillance to escape

Cancer immunoediting from immune surveillance to immune escape

Roles of IFN-γ in tumor progression and regression: a review

Will COVID-19 lead to myalgic encephalomyelitis/chronic fatigue syndrome?

Post-ebola syndrome among ebola virus disease survivors in montserrado county

Innate and Adaptive Immune Regulation During Chronic Viral Infections

Ebola: anatomy of an epidemic

The trinity of COVID-19: immunity, inflammation and intervention

Taking pandemic sequelae seriously: From the Russian influenza to COVID-19 long-haulers

Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2

Pathological Findings in the Testes of COVID-19 Patients: Clinical Implications

Prolonged viral shedding in feces of pediatric patients with coronavirus disease 2019

Within host RNA virus persistence: mechanisms and consequences

Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms

Pattern recognition receptors and the innate immune response to viral infection

Pattern recognition receptors and inflammation

O'garra, Type I interferons in infectious disease

Prediction and analysis of microRNAs involved in COVID-19 inflammatory processes associated with the NF-kB and JAK/STAT signaling pathways

Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Type I and type III interferons restrict SARS-CoV-2 infection of human airway epithelial cultures

Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment

Longitudinal analyses reveal immunological misfiring in severe COVID-19

Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome

Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome

Heightened innate immune responses in the respiratory tract of COVID-19 patients

Neutrophil-tolymphocyte ratio predicts severe illness patients with 2019 novel coronavirus in the early stage

Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19

Immune phenotyping based on the neutrophil-to-lymphocyte ratio and IgG level predicts disease severity and outcome for patients with COVID-19

A role for neutrophils in viral respiratory disease

In fatal COVID-19, the immune response can control the virus but kill the patient

Neutrophil extracellular traps in COVID-19

SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology

Patients with COVID-19: in the dark-NETs of neutrophils

Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

Investigation of immune cells on elimination of pulmonary-Infected COVID-19 and important role of innate immunity, phagocytes

Dendritic cells in viral infections

Maturation signatures of conventional dendritic cell subtypes in COVID-19 suggest direct viral sensing

Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome

SARS-CoV-2 induces activation and diversification of human plasmacytoid pre-dendritic cells

Biological function of eosinophil extracellular traps in patients with severe eosinophilic asthma

Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus

Relationship between blood eosinophil levels and COVID-19 mortality

Barrier epithelial cells and the control of type 2 immunity

TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes

Comparative pathology of rhesus macaque and common marmoset animal models with Middle East respiratory syndrome coronavirus

Viral modulation of NK cell immunity

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell Activation via the HLA-E/NKG2A Pathway

Enrichment of cytomegalovirus-induced NKG2C+ natural killer cells in the lung allograft

Puchhammer-Stöckl, Deletion of the NKG2C receptor encoding KLRC2 gene and HLA-E variants are risk factors for severe COVID-19

Less expression of CD4(+) and CD8(+) T cells might reflect the severity of infection and predict worse prognosis in patients with COVID-19: Evidence from a pooled analysis

Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19

Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities

SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation

Severe acute respiratory syndrome coronavirus 2− specific antibody responses in coronavirus disease patients

The role of IgA in COVID-19

Evidence of a significant secretory-IgA-dominant SARS-CoV-2 immune response in human milk following recovery from COVID-19

Serum IgA, IgM, and IgG responses in COVID-19

Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles

Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19

Structural basis of receptor recognition by SARS-CoV-2

Temporal signal and the phylodynamic threshold of SARS-CoV-2

The emergence of sars-cov-2 in europe and north america

SARS-CoV-2 variants, spike mutations and immune escape

Mutations strengthened SARS-CoV-2 infectivity

Evolutionary analysis of the delta and Delta Plus variants of the SARS-CoV-2 viruses

Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization

Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding

SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor

A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2

Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape

SARS-CoV-2 Lambda variant exhibits higher infectivity and immune resistance, bioRxiv

Infectivity and immune escape of the new SARS-CoV-2 variant of interest Lambda, medRxiv

Vulnerabilities in coronavirus glycan shields despite extensive glycosylation

Fitness costs limit influenza A virus hemagglutinin glycosylation as an immune evasion strategy

Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa

Interferons and viruses: an evolutionary arms race of molecular interactions

Pathogen recognition and innate immunity

The RNA sensor MDA5 detects SARS-CoV-2 infection

Interplay between SARS-CoV-2 and the type I interferon response

Type I and Type III Interferons -Induction, Signaling, Evasion, and Application to Combat COVID-19

Protective Role of Tolllike Receptor 3-Induced Type I Interferon in Murine Coronavirus Infection of Macrophages

Immunology of COVID-19: Current State of the Science

Jak-Stat Pathways and Transcriptional Activation in Response to Ifns and Other Extracellular Signaling Proteins

From interferons to cytokines

Ten Strategies of Interferon Evasion by Viruses

Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles

Membrane rearrangements mediated by coronavirus nonstructural proteins 3 and 4

The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA

The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membraneassociated M protein

SARS-CoV-2 Nucleocapsid Protein Interacts With RIG-I and Represses RIG-Mediated IFN-β Production

Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense

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

Cryo-EM Structure of an Extended SARS-CoV-2 Replication and Transcription Complex Reveals an Intermediate State in Cap Synthesis

Human coronavirus 229E nonstructural protein 13: characterization of duplex-unwinding, nucleoside triphosphatase, and RNA 5'-triphosphatase activities

Biochemical and structural insights into the mechanisms of SARS coronavirus RNA ribose 2'-Omethylation by Nsp16/Nsp10 protein complex

Functional screen reveals SARS coronavirus nonstructural protein Nsp14 as a novel cap N7 methyltransferase

Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating hostsensors

Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication

Structure of the SARS-CoV-2 spike receptor-binding domain bound the ACE2 receptor

Site-specific glycan analysis of the SARS-CoV-2 spike

Post-translational modifications of coronavirus proteins: roles and function

SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling

Activation and evasion of type I interferon responses by SARS-CoV-2

Molecular determinants for subcellular localization of the severe acute respiratory syndrome coronavirus open reading frame 3b protein

SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is increased by a naturally occurring elongation variant

SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists

SARS-CoV-2 nsp12 attenuates type I interferon production by inhibiting IRF3 nuclear translocation

Evasion of type I interferon by SARS-CoV-2

Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets

ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) membrane (M) protein inhibits type I and III interferon production by targeting RIG-I/MDA-5 signaling

SARS-CoV-2 membrane glycoprotein M antagonizes the MAVS-mediated innate antiviral response

SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70

SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO

SARS-CoV-2 Nucleocapsid Protein Targets RIG-I-Like Receptor Pathways to Inhibit the Induction of Interferon Response

Main Protease of SARS-CoV-2 Serves as a Bifunctional Molecule in Restricting Type I Interferon Antiviral Signaling

Suppression of MDA5-mediated antiviral immune responses by NSP8 of SARS-CoV-2, bioRxiv

Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities

SARS-CoV-2 N protein antagonizes type I interferon signaling by suppressing phosphorylation and nuclear translocation of STAT1 and STAT2

Ubiquitination of SARS-CoV-2 ORF7a Promotes Antagonism of Interferon Response

SARS coronavirus Nsp1 protein induces template-dependent endonucleolytic cleavage of mRNAs: viral mRNAs are resistant to Nsp1-induced RNA cleavage

Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2

Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression

The N-terminal domain of SARS-CoV-2 nsp1 plays key roles in suppression of cellular gene expression and preservation of viral gene expression

SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses

Severe Acute Respiratory Syndrome Coronavirus ORF3a Protein Activates the NLRP3 Inflammasome by Promoting TRAF3-Dependent Ubiquitination of ASC

The ORF3a protein of SARS-CoV-2 induces apoptosis in cells

SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation

ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation

The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι

SARS-CoV-2 inhibits induction of the MHC class I pathway by targeting the STAT1-IRF1-NLRC5 axis

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

Complex immune dysregulation in COVID-19 patients with severe respiratory failure

The signal pathways and treatment of cytokine storm in COVID-19

Clinical features of patients infected with 2019 novel coronavirus in

Clinical and immunological features of severe and moderate coronavirus disease

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?

V. Planelles, M. López-Huertas, M. Coiras, Impaired Cytotoxic Response in PBMCs From Patients With

Admitted to the ICU: Biomarkers to Predict Disease Severity

Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent

Obesity as a Risk Factor for Severe COVID-19 and Complications: A Review

Interferon-alpha 2 but not Interferon-gamma serum levels are associated with intramuscular fat in obese patients with nonalcoholic fatty liver disease

Could SCGF-Beta Levels Be Associated with Inflammation Markers and Insulin Resistance in Male Patients Suffering from Obesity-Related NAFLD?

Regenerative Medicine Approaches in COVID-19 Pneumonia

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

A human monoclonal antibody blocking SARS-CoV-2 infection

A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV

Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review

Interferon-α2b Treatment for COVID-19

Therapeutic Options for Coronavirus Disease 2019 (COVID-19) -Modulation of Type I Interferon Response as a Promising Strategy?

Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis