key: cord-0743144-yhni0jze authors: Toro, Ayelen; Ruiz, María Sol; Lage-Vickers, Sofia; Sanchis, Pablo; Sabater, Agustina; Pascual, Gaston; Seniuk, Rocio; Cascardo, Florencia; Ledesma-Bazan, Sabrina; Vilicich, Felipe; Vazquez, Elba; Gueron, Geraldine title: A Journey into the Clinical Relevance of Heme Oxygenase 1 for Human Inflammatory Disease and Viral Clearance: Why Does It Matter on the COVID-19 Scene? date: 2022-01-29 journal: Antioxidants (Basel) DOI: 10.3390/antiox11020276 sha: 82b5fdf2a80c95c9f96f4ac322dc348348bb703e doc_id: 743144 cord_uid: yhni0jze Heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme degradation, is involved in the maintenance of cellular homeostasis, exerting a cytoprotective role by its antioxidative and anti-inflammatory functions. HO-1 and its end products, biliverdin, carbon monoxide and free iron (Fe(2+)), confer cytoprotection against inflammatory and oxidative injury. Additionally, HO-1 exerts antiviral properties against a diverse range of viral infections by interfering with replication or activating the interferon (IFN) pathway. Severe cases of coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are characterized by systemic hyperinflammation, which, in some cases, leads to severe or fatal symptoms as a consequence of respiratory failure, lung and heart damage, kidney failure, and nervous system complications. This review summarizes the current research on the protective role of HO-1 in inflammatory diseases and against a wide range of viral infections, positioning HO-1 as an attractive target to ameliorate clinical manifestations during COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 in Wuhan, China. The World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic health emergency as of 31 January 2020. The treatment goal in COVID-19 patients is to prevent or to decrease the strong virus induced inflammatory stimuli associated with a wide spectrum of poor prognosis clinical manifestations [1] . Heme oxygenase 1 (HO-1) is a microsomal enzyme with a primary antioxidant and antiinflammatory role involved in heme degradation, generating carbon monoxide (CO), biliverdin (BV), and free iron (Fe 2+ ) [2] . Hence, HO-1 induction is a useful approach for inflammatory diseases treatment [3] [4] [5] [6] . Additionally, HO-1 displays antiviral properties against a wide range of viruses [7] . Hemin, a previously Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved drug for acute intermittent porphyria treatment [8, 9] , is a well known inducer of HO-1 that increases its plasma concentration in humans. Thus, hemin rises as a promising drug candidate against the replication of different viruses, including SARS-CoV-2. In this review, we summarize host specific molecules that are released during cell injury or necrotic death, defined as damage associated molecular patterns, such as nucleic acids and adenosine triphosphate (ATP) [33] . During the early stages of inflammation, innate immune cells and endothelial cells (EC) release a diverse set of cytokines: chemotactic cytokines, such as monocyte chemotactic protein-3 (MCP-3) and interferon (IFN) γ-induced protein 10 (IP- 10) , and recruit other immune cells to the site of infection or inflammation. Proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-1β [35, 36] , are also released and trigger the activation of inflammatory pathways, including the mitogen activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways [34] . Some pathogenic viruses (i.e., highly virulent subtypes of influenza) and bacteria (i.e., Francisella tularensis) can induce the acute dysregulated production of inflammatory cytokines, known as "cytokine storm" or hypercytokinemia [37] . The hypercytokinemia and exacerbated secondary events, such as coagulation, eventually result in widespread necrosis, organ failure and death [33, 38] . Once SARS-CoV-2 infects target cells, innate immune cells are recruited to the infection site, where they release cytokines and initiate the activation cascade of adaptive B and T cell immune responses [39] . In most cases, the immune system is able to eliminate virus infected cells and resolve the immune response. However, in some patients, this process is dysfunctional, impairing the effective clearance of infected cells, and causing severe damage to the host [40] . During viral infections, pattern recognition receptors are stimulated to produce IFN by the innate immune cells. IFNs are crucial for the induction of an antiviral state via autocrine and paracrine signaling. There are three types of IFNs: type I, type II and type III. Type I (IFNα, IFNβ, IFNω, IFNτ, IFNε) and Type III (IFNλ1, IFNλ2/3, IFNλ4) share similar dynamics after binding to its receptor, as cross-phosphorylation between JAK1 and tyrosine kinase 2 (TYK2) occurs [41] . Subsequently, a docking site for STAT1 is exposed, STAT1 is phosphorylated, translocates to the nucleus, and induces the transcription of interferon stimulated genes (ISGs). The IFNs biological effects are wide, including immuno-regulation, antiviral, anti-angiogenic, and pro-apoptotic functions [42] . However, many pathogens have evolved to elude the action mechanisms of these powerful cytokines [43] [44] [45] . In critically ill COVID-19 patients, a hyperinflammation state prevails. In March 2020, a retrospective study on 150 patients from Wuhan, China, found elevated levels of IL-6 and C-reactive protein (CRP) in SARS-CoV-2 infected patients that died compared with discharged patients [46] . An independent report based on 50 COVID-19 patients with moderate to severe disease, identified IP-10, MCP-3, and IL-1 receptor antagonist (IL-1ra) as independent predictors for disease severity [47] . A longitudinal analysis showcased IL-18 and IFN-α as top biomarkers for predicting mortality. Consequently, higher counts of inflammatory monocytes, plasmablast like neutrophils and eosinophils have been described in patients with severe disease [39] . Blanco-Melo et al. reported an impairment in the response of type I and type III IFNs against SARS-CoV-2 infection [40] . In contrast, a recent study found that severe COVID-19 cases showed an exacerbated expression of type I IFNs, which could lead to augmented inflammation [48] . Several clinical trials evaluating IFNs have been carried out in COVID-19 patients. Two different studies showed a reduction in the mortality rate after IFNβ-1a and IFNβ-1b treatment [49, 50] . Another study, using IFNα-2b, reported a decrease in detectable SARS-CoV-2 in the upper respiratory tract associated with lower inflammatory cytokines levels, such as IL-6 and CRP [51] . In addition, peginterferon λ treatment was associated with a reduction in viral RNA [52] . Furthermore, there are several ongoing clinical trials, using recombinant human IFNs or IFNs combined with other drugs [53] [54] [55] . These evidences highlight IFNs as potential targets for COVID-19 treatment. In the next section we will focus on the stimulation of IFN pathway by HO-1 induction. Heme oxygenases (HO) are metabolic enzymes that partake in the degradation of the heme group [2] . To date, three isoforms of this protein have been found: HO-1, which can be induced by external factors (such as hypoxia, oxidative stress, heat shock, reactive oxygen species (ROS), among others) [56] ; HO-2, a constitutively expressed isoform; and HO-3, a nonfunctional isoform in humans [57] . In particular, HO-1, encoded by the HMOX1 gene, is involved in the maintenance of cellular homeostasis, exerting a cytoprotective role by its anti-inflammatory, anti-oxidative and anti-apoptotic functions, as revealed in a human case of genetic HO-1 deficiency [58] . This enzyme participates not only in normal physiological processes, but also performs a protective role in inflammatory physiopathological conditions, such as kidney disease [59] , cancer [60, 61] , cardiovascular disease [62] , asthma [63] and inflammatory bowel diseases [4, 64] . HO-1 is expressed in most cell types and tissues; however, its capacity to counteract inflammation seems to be critically dependent on its specific functions in myeloid cells and in EC [65] . In myeloid cells, HO-1 acts as a key regulator of the TLR4/TLR3/IRF3 induced production of IFN-β and primary IRF3 target genes in macrophages [66] and modulates maturation and specific functions of dendritic cells [67, 68] . Moreover, HO-1 over-expression in macrophages negatively regulates the expression of diverse proinflammatory molecules and increases the expression of anti-inflammatory cytokines [69] [70] [71] . Among HO-1 effects on EC, it is significant to mention its ability to inhibit the expression of pro-inflammatory genes related to EC activation, such as the TNF-α-induced adhesion molecules, E-selectin and VCAM-1, via a mechanism associated with the inhibition of NF-κB activation [72] . HO-1 cleaves the heme group generating BV, CO and Fe 2+ . Heme is usually bound to a myriad of proteins and it is involved in several homeostatic functions [56] . However, elevated concentrations of heme can cause cell damage because it is a pro-oxidant molecule. It can diffuse through cell membranes and deliver a redox active iron, producing ROS [73] . Excessive amounts of these molecules are toxic and induce oxidative stress that, in turn, generates DNA and protein damage, aggregation and lipid peroxidation, triggering cells permeability and driving cell lysis and death [73] . Several studies highlight heme catabolism end products as potential therapeutic targets in vascular disease, based on their anti-inflammatory and antiproliferative functions [74] . BV and its reduced form, bilirubin (BR), are powerful antioxidants that are able to scavenge ROS and counteract the oxidative stress. BV and BR are critical for the regulation of inflammation by exerting immunosuppressive effects [75] , as they have been reported to have potent anti-inflammatory activity against insulin resistance by reducing visceral obesity and adipose tissue inflammation [76] . In addition, CO is considered an anti-apoptotic [77] , antiproliferative and antiinflammatory factor [78] . CO contributes to blood vessel development [79] and promotes angiogenesis, a crucial process involved in tissue reparation after a pathological state [80] . Interestingly, CO also reduces inflammation and inhibits apoptosis by interacting with antigenpresenting cells and suppressing T cell proliferation [81] . Moreover, it has been reported that it downregulates proinflammatory cytokines via the p38/MAPK pathway in RAW 264.7 macrophages and C57BL/6 mice [70] , by the c-Jun N-terminal kinase (JNK) pathway in a murine model of sepsis [82] and through the extracellular signal regulated kinase (ERK) signaling pathway in CD4 + T cells [81] . Further, HO-1/CO induced downregulation of the NLRP3 (NOD-, LRR-and pyrin domain-containing protein 3) inflammasome activation has been demonstrated in different models of murine hepatic and lung inflammatory injury [83] [84] [85] . Moreover, the HO-1 mediated increase in Fe 2+ concentration upregulates the expression of ferritin, an iron chelating protein [86] . Ferritin exerts antioxidative and cytoprotective effects [74] , as this product scavenges redox active Fe 2+ , rendering it not harmful for cells and avoiding subsequent production of ROS via Fenton reaction. Fe 2+ performs its function by inhibiting IL-2 and IgG production, and downregulating the MAPK and NF-κB signaling pathways [56, 75, 87] . As HO-1 and its reaction products exert protective anti-inflammatory effects in different preclinical models [3] [4] [5] [88] [89] [90] , the induction of the HO-1 system has emerged as a promising potential therapy for chronic inflammatory diseases. Most of the studied strategies are based on the use of the traditional pharmacological inducers: hemin [91, 92] , an FDA and EMA approved drug, and cobalt protoporphyrin IX (CoPP) [5, 93, 94] . In addition, many phytochemicals, such as quercetin, curcumin and resveratrol, are currently under investigation, due to their potential as HO-1 alternative inducers to counteract inflammation processes with lower cytotoxic secondary effects [95] [96] [97] . Alternatively, there are also a few approved drugs, such as 5-aminosalicylic acid (5-ASA), dimethyl fumarate (DMF), and 5-aminolevulinic acid (5-ALA), whose beneficial properties in inflammatory conditions are explained, at least in part, by their capacity to induce HO-1 [96, 98, 99] (Figure 1 ). Additionally, another effective option is the use of BV/BR based therapies, which have proven to be effective for these chronic pathologies [100] [101] [102] and/or the direct administration of CO via inhalation, CO-releasing molecules (CORMs) or hybrid carbon monoxide-releasing molecules (HYCOs). HYCOs are a type of compound where CORMs are combined with DMF, causing a powerful anti-inflammatory action due to its effect on the NRF2/HO-1 pathway [5,100,103-106] ( Figure 1 ). Moreover, the HO-1 mediated increase in Fe 2+ concentration upregulates the expression of ferritin, an iron chelating protein [86] . Ferritin exerts antioxidative and cytoprotective effects [74] , as this product scavenges redox active Fe 2+ , rendering it not harmful for cells and avoiding subsequent production of ROS via Fenton reaction. Fe 2+ performs its function by inhibiting IL-2 and IgG production, and downregulating the MAPK and NF-κB signaling pathways [56, 75, 87] . As HO-1 and its reaction products exert protective anti-inflammatory effects in different preclinical models [3] [4] [5] [88] [89] [90] , the induction of the HO-1 system has emerged as a promising potential therapy for chronic inflammatory diseases. Most of the studied strategies are based on the use of the traditional pharmacological inducers: hemin [91, 92] , an FDA and EMA approved drug, and cobalt protoporphyrin IX (CoPP) [5, 93, 94] . In addition, many phytochemicals, such as quercetin, curcumin and resveratrol, are currently under investigation, due to their potential as HO-1 alternative inducers to counteract inflammation processes with lower cytotoxic secondary effects [95] [96] [97] . Alternatively, there are also a few approved drugs, such as 5-aminosalicylic acid (5-ASA), dimethyl fumarate (DMF), and 5-aminolevulinic acid (5-ALA), whose beneficial properties in inflammatory conditions are explained, at least in part, by their capacity to induce HO-1 [96, 98, 99] (Figure 1) . Additionally, another effective option is the use of BV/BR based therapies, which have proven to be effective for these chronic pathologies [100] [101] [102] and/or the direct administration of CO via inhalation, CO-releasing molecules (CORMs) or hybrid carbon monoxide-releasing molecules (HYCOs). HYCOs are a type of compound where CORMs are combined with DMF, causing a powerful anti-inflammatory action due to its effect on the NRF2/HO-1 pathway [5,100,103-106] ( Figure 1 ). There is extensive literature about the role of HO-1 in lung diseases. This protein is expressed in type II pneumocytes and in alveolar macrophages and contributes to the protection of the lung tissue. The main HO-1 inducers in the lungs are pro-inflammatory cytokines, such as TNF-α and IL-6, the heme group and nitric oxide (NO), as well as hypoxia (Figure 2 ). There is sound evidence that states that HO-1 induction is a critical defense factor during acute and chronic lung processes [109] [110] [111] . HO-1 has immunomodulatory properties on the innate immune response and there is compelling evidence suggesting that it also plays a central role in the modulation of adaptive immunity. HO-1 displays antiviral properties against a wide range of viruses [7] ( Figure 3 ). Several reports have demonstrated that HO-1 induction is associated with the activation of the IFN pathway. However, the mechanism underlying the antiviral properties of HO-1 exerted by both its classical and noncanonical activities are yet to be fully elucidated. As mentioned earlier, during COVID-19 disease, the number of immune cells infiltrating lung tissues and the pro-inflammatory cytokines levels are augmented [112] . Consequently, anti-inflammatory proteins have a crucial role in halting the cytokine storm and the sequelae generated by viral infection [113] . In particular, ALI and ARDS are the most prevalent diseases emerging from an extended diversity of lung injuries [114, 115] . ALI and ARDS are pathophysiologically characterized by lung damage, inflammatory infiltration, and an exacerbation of the host immune response [116] . Several reports indicate that ALI and ARDS might be explained by the presence of high ROS levels, where HO-1 acts as a protective factor against oxidative stress under pharmacological induction [117] . HO-1 induction by hemin shows a protective role against ventilator induced lung injury in rabbits with ALI/ARDS, increasing anti-inflammatory cytokine levels, such as IL-10, as well as decreasing the inflammatory infiltrate of immune system cells and the secretion of inflammatory cytokines, such as TNFα and IL-8 [118] (Figure 2 ). Furthermore, it has been found that HO-1 confers protection against ischemia-reperfusion injury (LIRI) [119] . HO-1 regulates diverse signaling pathways that are affected during pulmonary diseases. In rats, HO-1 inhibits the PERK/eIF2-α/ATF4/CHOP pathway, which is involved in the endoplasmic reticulum stress (ERS) characteristic in ALI, and also promotes the decrease in intrapulmonary cell apoptosis [120] . It was also reported that the PI3K/Akt pathway attenuates oxidative damage during ALI/ARDS through HO-1 regulation [121] . In pathologies such as silicosis, characterized by excessive ROS production, lung injury is attenuated by HO-1 induction. The mechanism underlying this cytoprotective effect relies on the ERK pathway inhibition by HO-1, CO and BV [122] . Reaction products derived from the HO-1 mediated heme catalysis have protective roles in lung pathologies as well. CO is known to provide protection against ALI and ARDS by reducing cytokine and chemokine levels [105, 117, 123] . CO decreases EGR-1 (early growth response protein 1), a proinflammatory protein that regulates the expression of TNF-α and IL-2 [124] , in mice lungs [123] . Fujita et al. demonstrated that Hmox1 deficient mice had increased mortality after lung ischemia, an effect reverted by CO administration [125] . Furthermore, BV exerted antioxidative, anti-inflammatory and anti-apoptotic effects in a rat model of LIRI [126] . BV administration protected against hemorrhagic shock induced ALI through a decrease in the inflammatory infiltrate and proinflammatory cytokines levels [127] . HO-1 has immunomodulatory properties on the innate immune response and there is compelling evidence suggesting that it also plays a central role in the modulation of adaptive immunity. HO-1 displays antiviral properties against a wide range of viruses [7] ( Figure 3 ). Several reports have demonstrated that HO-1 induction is associated with the activation of the IFN pathway. However, the mechanism underlying the antiviral properties of HO-1 exerted by both its classical and noncanonical activities are yet to be fully elucidated. Influenza A virus (IAV) is a single stranded RNA virus whose infection remains a persistent global health threat with high morbidity and mortality [128] . An estimate of 4.0 to 8.8 deaths per 100,000 individuals with seasonal influenza associated respiratory occur Influenza A virus (IAV) is a single stranded RNA virus whose infection remains a persistent global health threat with high morbidity and mortality [128] . An estimate of 4.0 to 8.8 deaths per 100,000 individuals with seasonal influenza associated respiratory occur annually (all types of influenza virus) [129] . Considering that the inhibition of virus induced ROS formation impairs IAV replication, proteins such as HO-1 are useful to counteract IAV infections in the host cell [130] . Wang et al. studied the effect of hemin in IAV infections and demonstrated that hemin attenuates the lymphocytopenia caused by IAV infection both in vitro and in vivo [131] . These results suggest that the anti-influenza effect of hemin may be mediated by HO-1's ability to regulate systemic and local inflammatory responses [131] . Furthermore, Hashiba et al. reported that HO-1 gene transfer is a potential strategy to treat lung injury caused by IAV [132] and Cummins et al. suggested that the therapeutic induction of HO-1 expression may represent a novel adjuvant to enhance influenza vaccine effectiveness [133] . It has also been reported that the HO-1 inducers rupestonic acid derivative YZH-106 and the flavonoid 6-demethoxy-4 -O-methylcapillarisin (DMO-CAP) inhibited IAV replication by activating the HO-1 mediated IFN response [134, 135] . Additionally, Ma et al. evaluated the effect of CoPP in IAV infection, focusing on the IFN pathways. The authors demonstrated that HO-1 induction attenuates IAV replication, and the most intriguing finding was that the catalytic function of HO-1 was not essential for the anti-IAV effect of CoPP. Interestingly, they found that HO-1 interacts with IFN regulatory factor 3 (IRF3) promoting its phosphorylation and nuclear translocation, thus activating the IFN pathway. Consequently, CoPP treatment increased the expression of IFITM3, PKR and OAS1, three ISGs markedly involved in the anti-IAV response [128] . Respiratory syncytial virus (RSV) is an RNA virus of the Pneumoviridae family and the most common cause of lower respiratory tract infections in children worldwide [136] . It interacts with host cells' toll-like receptors in the primary airway epithelium, and promotes the expression and secretion of inflammatory cytokines [137] , under the NF-κB pathway's regulation [138] . Similar to IAV, CoPP HO-1 induction inhibited RSV replication and viral particle production in lung adenocarcinoma (A549) and HEp-2 cells. Most importantly, in vivo assays in BALB/cJ mice treated prophylactically with CoPP also showed a reduction in viral replication and viral particle production, alongside a decrease in inflammatory cell infiltration, and inhibition of proinflammatory cytokine or chemokine secretion during RSV infection [139] . The mentioned reports suggest that HO-1 is involved in host cellular defense mechanisms against IAV and RSV infections. Of note, HO-1's antiviral effects are mediated by its classical and noncanonical functions. The human immunodeficiency virus-1 (HIV-1) genome consists of two identical single stranded RNA molecules and it is the causative agent of acquired immune deficiency syndrome (AIDS). HIV infection has become a clinically manageable disease since the development of combination antiretroviral therapy (ART). Globally, 1 million people died from HIV/AIDS in 2016; without ART, more than twice as many people would have died from this disease [140] . In 2020, the United Nations Programme on HIV/AIDS (UNAIDS) reported that of all people with HIV worldwide, 66% were virally suppressed [141, 142] . However, emerging drug resistance and limitations in access and adherence to ART impose a threat to controlling the spread of the virus [143] . Current drugs do not eradicate the virus, making lifelong treatment necessary [143] . Several reports from in vitro and in vivo models, and HIV infected subjects, have linked HO-1 with HIV replication and its effects on HIV mediated neurodegeneration. In cultured monocytes and HIV infected mice, hemin efficiently inhibited viral replication; the effect observed in vitro was mediated by HO-1 enzymatic activity [144] . Using an in vitro model of HIV mediated neurotoxicity, HIV infection dysregulated the macrophage antioxidant response and reduced levels of HO-1. Restoration of HO-1 expression in HIV-infected monocyte derived macrophages (MDM) reduced neurotoxin release without altering HIV replication [145] . In HIV infected subjects, HO-1 protein levels were reduced in the dorsolateral prefrontal cortex, which correlated with central nervous system (CNS) viral load markers of immune activation. In a model of human astrocytes treated with IFNγ, an HIV associated CNS immune activator, HO-1 was degraded by the immunoproteasome [146] . Additionally, the use of CoPP reduced HIV-MDM glutamate release and neurotoxicity, suggesting a role for HO-1 in HIV associated neurocognitive disorders pathogenesis [147] . Altogether, these reports propose HO-1 induction as a protective mechanism against HIV infection. In particular, the HO-1's classical functions mediate its antiviral properties against HIV. Ebola virus (EBOV) is a negative-sense RNA virus that belongs to the Filoviridae family [148, 149] . From 2013 to 2015 there was an important outbreak in West Africa, which caused >25,000 infections and >10,000 deaths. The average EBOV case fatality rate is~50% and case fatality rates has ranged from 25% to 90% in past outbreaks [15] . Hemin treatment significantly reduced EBOV replication and delayed pathogenesis in vitro, by stimulating the cellular innate response against the infection [150, 151] . In MDM, hemin treatment inhibited EBOV infection in a dose dependent manner. A similar effect was observed in other cell lines, such as HeLa and human foreskin fibroblasts cells, in which hemin also reduced viral replication [150] . Furthermore, it has been reported that the ebola virus protein 35 (VP35) is a critical protein involved in the inhibition of IRF3 phosphorylation as a mechanism that might counteract the antiviral response [152] . Thus, considering that HO-1 promotes IRF3 phosphorylation and activation, its induction may represent a novel therapeutic strategy against EBOV infection. The cited studies place HO-1 as a novel therapeutic target against EVOB infection. Notably, HO-1's noncanonical functions are involved in the present example of antiviral action. Hepatitis C virus (HCV), a single stranded positive sense RNA virus, is associated with chronic hepatitis, cirrhosis, steatosis and hepatocellular carcinoma [153] . HCV treatment includes a combination of pegylated IFN-α and ribavirin, which has low efficacy and important side effects. With the development of direct-acting antiviral agents, such as sofosbuvir and simeprevir, patient outcomes have greatly improved; however, the disease remains a concern [154] . Since HCV infection generates oxidative damage to hepatocytes, the modulation of HO-1 expression emerges as an attractive therapeutic approach to reduce chronic liver disease. Abdalla et al. observed lower HO-1 mRNA and protein levels in HCV infected patients' livers, while this alteration was not found in patients with other chronic liver diseases. The authors also reported HO-1 downregulation in hepatocyte cell lines expressing the HCV core protein [155] . Further, the overexpression or hemin-induction of HO-1 in the hepatoma cell line Huh7 decreased HCV replication and conferred protection against oxidative injury [156] . This effect of HO-1 on HCV replication might be explained partly by the iron dependent inactivation of the HCV RNA polymerase NS5B [157] , and by the BV mediated inhibition of HCV NS3/4A protease and induction of an antiviral response by IFNα2 and IFNα17 [153, 158] . Moreover, overexpression of miR-let-7c, which interferes with the production of proinflammatory cytokines in osteoarthritis and rheumatoid arthritis synovial fibroblasts [159] , can reduce HCV replication by targeting HO-1 transcriptional repressor Bach1 [160] . Hepatitis B virus (HBV) is a DNA virus that causes serious liver diseases, representing the most common etiological agent for these pathologies [161] . It has been shown that pharmacological and genetic HO-1 overexpression attenuates viral replication both in vivo and in vitro in HepG2 cells [161] [162] [163] , while also playing a hepatoprotective role [162] . The effect of HO-1 induction using hemin and CoPP mitigated the effects of HBV replication [6, 161, 162] . On the other hand, blocking HO-1 by siRNA reversed the inhibition of viral replication [6] . Interestingly, Protzer et al. evaluated the effect of HO-1 on HBV core protein by pulse-chase metabolic labeling experiments finding that HO-1 can destabilize structural proteins to prevent the formation of viral capsids, highlighting a direct HO-1 antiviral mechanism rather than limiting its effect to its anti-inflammatory properties [6] . Hence, the summarized reports established the antiviral effects of HO-1 by impairing HCV's and HBV's replication. Dengue virus (DENV) is a single stranded positive sense RNA virus [164] that induces oxidative stress by the activation of inflammatory regulators, such as NF-κB, and leads to the progression and pathogenesis of DENV [165] . In this pro-oxidant scenario, Tseng et al. demonstrated that HO-1 promoter activity and protein synthesis gradually increased during the early stages of DENV infection (6 to 12 h), but they were markedly decreased at later stages (24 to 72 h) [166] . Strikingly, pharmacological and genetic HO-1 induction after infection impaired viral protein synthesis and replication, and reduced DENV mortality. This effect was due to BV but not CO nor Fe 2+ production [166] . The authors demonstrated that BV inhibits NS2B/NS3 DENV protease, thus promoting the antiviral IFN response and impairing its blockage by this protease [166] . Accordingly, Su et al. showed the anti-DENV activity of miR-155, which inhibits Bach1, a protein that negatively regulates the expression of many oxidative stress-response genes, including HMOX1 [167] . This, in turn, results in the induction of HO-1, boosting the IFN responses against DENV replication by the activation of interferon induced protein kinase R (PKR), 2'-5'-oligoadenylate synthetase 1 (OAS1), OAS2, and OAS3 expression [167] . Interestingly, the summarized studies demonstrate that HO-1's antiviral effects against DENV infection involve both, its canonical, in this case mediated by BV, and noncanonical functions. Zika virus (ZIKV), a single stranded positive sense RNA, is the causative pathogen of Zika fever in humans [168] . Using A549 and embryonic kidney (HEK-293) cell lines, El Kalamouni et al. demonstrated that ZIKV infection downregulated HO-1 expression by triggering endoplasmic-reticulum-associated protein degradation, thus halting its antiviral effects [168] . This report highlights HO-1's protective role relevance, as it demonstrates that ZIKV infection promotes the decrease in HO-1 expression levels as an evasion mechanism. Herpes simplex virus (HSV) includes HSV-1 and HSV-2, two double stranded DNA viruses that belong to Herpesviridae family. HSV produces recurring lesions in skin and mucosae and can also latently infect neurons of the trigeminal or dorsal root ganglia. HSV infection can result in encephalitis and meningitis [169] . Ibañez et al. demonstrated that pharmacological induction of HO-1 by CoPP hampered HSV-2 propagation in epithelial and neuronal cells. Furthermore, by CORM-2 treatment the authors also showed that the effects of HO-1 were partly mediated by CO [170] . Enterovirus 71 (EV71) is a single stranded positive sense RNA virus that belongs to the Picornaviridae family and is the causative agent of hand foot and mouth disease in children [171] . It was demonstrated that the overexpression of HO-1, as well as CO treatment, decreased viral replication in SK-N-SH cells suggesting that the antiviral effect is mediated by the downregulation of EV71 induced ROS levels [172] . Regarding neurotropic viruses, the summarized reports showcase that HO-1 displays protective effects against HSV-2 and EV71 involving its enzymatic function. SARS-CoV-2, is the novel beta coronavirus of the Coronaviridae family whose genome is composed of a single stranded RNA molecule [173] . It has been shown that hemin, hemoglobin and protoporphyrin IX bind to SARS-CoV-2 proteins, blocking its adsorption and replication independently from HO-1 induction [174] . However, the current literature regarding HO-1's antiviral effect against SARS-CoV-2 remains unclear. Maestro et al. showed that hemin does not inhibit SARS-CoV-2 viral replication in vitro [175] . Kidney epithelial Vero-E6 and lung Calu3 cell lines were treated with hemin and results showed that, despite a strong activation of HO-1 in both cell lines, there was no effect on SARS-CoV-2 viral replication, measured by the amplification of the N viral gene by RT-qPCR [175] . However, a more recent report proposed hemin as a potential drug for treating COVID-19 via HO-1 induction [176] . Interestingly, authors observed a reduction in SARS-CoV-2 replication, both when pretreating and after SARS-CoV-2 infection treatment of Vero76 with this drug. Genetic induction or silencing of HO-1 in Vero76 cells demonstrated that the antiviral effect of hemin relies on this protein. Strikingly, this effect was mediated not only by Fe 2+ and BV, but also by an HO-1 enzymatic independent mechanism. Further, they showed that hemin induced HO-1 boosted ISG15, OAS1 and MX1 protein expression in SARS-CoV-2 infected cells, highlighting the importance of stimulating the host cell's IFN response against this virus [176] . Of note, there are reports from our laboratory showcasing that MX1 gene expression is increased in COVID-19 patients. However, MX1 expression is lower in elderly patients, where the disease has been shown to be more severe than in younger people. Additionally, through an in depth proteomics analysis, we described MX1 as a novel HO-1 interactor in prostate cancer (PCa) cell lines [177] . Moreover, genetic and pharmacological HO-1 induction in PCa cells triggered an increase in MX1 at mRNA and protein levels, and altered HO-1 cellular localization, showcasing a clear association between both proteins. Further, MX1 silencing with a specific siRNA significantly decreased the expression of ERS genes (HSPA5, DDIT3 and XBP1), demonstrating the role of MX1 in pro-death events [177] . In summary, the induction of the host infected cells antiviral response appears to be critical for COVID-19 treatment, which could be partly achieved by hemin mediated HO-1 induction, also preventing viral adsorption and replication by binding SARS-CoV-2 proteins. These antiviral effects are mediated by canonical and noncanonical HO-1's functions. There are mainly two different approaches to develop antiviral therapies: (1) therapies directed against viral factors; or (2) therapies targeting the host immune system. To date, the second strategy has received increasing attention due to the fact that targeting viral factors might cause viruses to mutate, increasing the rate of resistance to antiviral drugs [178] . In contrast to the viral genome, host cells' DNA does not have a high mutational frequency. Therefore, overpowering viral infection by targeting host factors involved in the antiviral response is conceivably an effective strategy to counteract the severe consequences, while also fighting the infection [179] . During the last two years, several reports have focused on the understanding of the virus-host interaction underlying COVID-19 disease. The worrying situation of the SARS-CoV-2 pandemic and the threat of new variants, such as Omicron, which is spreading across the globe at an unprecedented rate, drive the interest of scientists to seek for new anti-SARS-CoV-2 strategies. Its enhanced transmissibility compared to the Delta variant could be explained in part by its increased rate of replication in human primary airway cultures, higher binding to ACE2, and ability to efficiently enter cells in a TMPRSS2-independent manner [180] . Fortunately, preliminary data of the Omicron variant suggest a lower virus load in both lower and upper respiratory tract, associated to less inflammatory processes in the lungs, using a mouse model of severe disease [181] . However, exceptionally high transmissibility could result in a great burden on healthcare systems across the globe. In this context, HO-1 emerges as a potential target to boost the host's response to fight the infection and prevent severe COVID-19. Certainly, HO-1 and its reaction products possess beneficial effects for the host during viral infections: it reduces inflammation and exerts antiviral actions. The most serious COVID-19 complications are: sepsis like inflammation, coagulopathy, and cardiovascular or respiratory complications. Furthermore, respiratory failure triggers hypoxia which, in combination with neuroinflammation, generates neurological complications [182] . When inflammation is not modulated, it turns into hyperinflammation and results in tissue damage or organ failure [183] . Enhancing HO-1 expression might help avoid the severe consequences of this disease. For example, it has been reported that HO-1 induction decreases inflammation, inhibits platelet aggregation, and increases fibrinolysis and phagocytosis, thus preventing tissue damage, thrombosis and sepsis [184] . Additionally, hemin is an activator of neuroglobin, a protein involved in oxygen transport and storage in neurons that increases oxygen's intracellular partial pressure in neurons, and is crucial to protect neurons from hypoxic injury [185] [186] [187] . In addition, as mentioned above, HO-1 has a reported antiviral activity against multiple viruses. This effect depends on its classical activity involving its reaction subproducts (BR, BV, CO and Fe 2+ ) and the activation of the IFN pathway; interestingly, its noncanonical activity is also involved in the antiviral effect of HO-1. HO-1 expression is essentially regulated at the transcriptional level by NRF2. It has been reported that SARS-CoV-2 infection suppresses the NRF2 antioxidant gene expression pathway, and that NRF2 agonists limit viral replication and repress the proinflammatory response of SARS-CoV-2 [188] . This evidence highlights the relevance of the NRF2 signaling pathway on the antiviral response, suggesting that the activation of NRF2 might be a useful strategy against COVID-19 [189] . As explained before, clinical complications associated with COVID-19 disease have been described in different organs, including vascular, cardiac, renal, hepatic, endocrine and neurological complications [190] (Figure 4 ). Interestingly, HO-1 has been reported to be associated with a reduction in tissue damage, mainly through its anti-inflammatory and antioxidative functions in different organs [4, 97, 147, [191] [192] [193] [194] [195] [196] [197] [198] [199] [200] [201] [202] [203] [204] [205] [206] [207] (Figure 3 ). It would be interesting to address HO-1's vasoprotective and antithrombotic effects for the prevention of thromboembolic events caused by SARS-CoV-2. As explained before, clinical complications associated with COVID-19 disease have been described in different organs, including vascular, cardiac, renal, hepatic, endocrine and neurological complications [190] (Figure 4) . Interestingly, HO-1 has been reported to be associated with a reduction in tissue damage, mainly through its anti-inflammatory and antioxidative functions in different organs [4, 97, 147, [191] [192] [193] [194] [195] [196] [197] [198] [199] [200] [201] [202] [203] [204] [205] [206] [207] (Figure 3 ). It would be interesting to address HO-1′s vasoprotective and antithrombotic effects for the prevention of thromboembolic events caused by SARS-CoV-2. Drug repurposing is an attractive proposition, since it involves the use of derisked and previously approved compounds, with lower development costs and shorter development times [209] . Since the onset of the COVID-19 pandemic, we have witnessed a plethora of alternative drugs as potential therapeutic avenues to fight the disease. Thus, hemin, a previously FDA and EMA approved drug for acute intermittent porphyria treatment, rises as a promising drug candidate, inducing HO-1 plasma concentration in humans, and posing a host defense advantage to fight SARS-CoV-2. Further work on optimal drug concentrations, pharmacokinetics and pharmacodynamics should be performed in order to prove hemin's effectiveness (either alone or in combination with other drugs) to halt infection. SARS-CoV-2 Inflammatory Syndrome. Clinical Features and Rationale for Immunological Treatment New insights into intracellular locations and functions of heme oxygenase-1 Heme oxygenase-1: A new therapeutic target for inflammatory bowel disease Heme oxygenase-1 prevents murine intestinal inflammation Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation Antiviral Activity and Hepatoprotection by Heme Oxygenase-1 in Hepatitis B Virus Infection Modulation of Antiviral Immunity by Heme Oxygenase-1 Open-label study of hemin for acute porphyria: Clinical practice implications The SARS-CoV-2 outbreak: What we know Characteristics of SARS-CoV-2 and COVID-19 WHO Summary of Probable SARS Cases with Onset of Illness from 1 WHO's World Health Report Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia A Novel Coronavirus from Patients with Pneumonia in China SARS-CoV-2 Transmission from People Without COVID-19 Symptoms Neuroinvasion of SARS-CoV-2 in human and mouse brain SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery Novel therapeutic targets for SARS-CoV-2-induced acute lung injury: Targeting a potential IL-1β/neutrophil extracellular traps feedback loop Pathological findings of COVID-19 associated with acute respiratory distress syndrome Cytokine storm in COVID-19: Pathogenesis and overview of anti-inflammatory agents used in treatment Cytokine Storm in COVID-19-Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper. Front Pathogenic human coronavirus infections: Causes and consequences of cytokine storm and immunopathology COVID-19 and multiorgan failure: A narrative review on potential mechanisms Long-Term Respiratory and Neurological Sequelae of COVID-19 Antioxidants 2022 High-dimensional characterization of post-acute sequelae of COVID-19 Omicron escapes the majority of existing SARS-CoV-2 neutralizing antobodies Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients Features, Evaluation, and Treatment of Coronavirus (COVID-19) Genomic characterization of a novel SARS-CoV-2 The Emerging Concern and Interest SARS-CoV-2 Variants Targeting the "cytokine storm" for therapeutic benefit Inflammatory responses and inflammationassociated diseases in organs Recognition of microorganisms and activation of the immune response Role of endothelial chemokines and their receptors during inflammation The signal pathways and treatment of cytokine storm in COVID-19 The trinity of COVID-19: Immunity, inflammation and intervention Longitudinal analyses reveal immunological misfiring in severe COVID-19 Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19 Type I and Type III Interferons-Induction, Signaling, Evasion, and Application to Combat COVID-19 Direct Effects of Type I Interferons on Cells of the Immune System The Virus Battles: IFN Induction of the Antiviral State and Mechanisms of Viral Evasion Interferons: Cell signalling, immune modulation, antiviral response and virus countermeasures Viral inhibition of interferon signal transduction Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19 The type I interferon response in COVID-19: Implications for treatment Randomized Clinical Trial of the Efficacy and Safety of Interferon β-1a in Treatment of Severe COVID-19 Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial Interferon-α2b Treatment for COVID-19 Peginterferon lambda for the treatment of outpatients with COVID-19: A phase 2, placebo-controlled randomised trial IFN-beta 1b and Remdesivir for COVID19 Experimental Trial of rhIFNα Nasal Drops to Prevent 2019-nCOV in Medical Staff Efficacy and Safety of IFN-α2β in the Treatment of Novel Coronavirus Patients Free heme toxicity and its detoxification systems in human Characterization of rat heme oxygenase-3 gene. Implication of processed pseudogenes derived from heme oxygenase-2 gene Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency Human Heme Oxygenase-1 Induced by Interleukin-6 via JAK/STAT3 Pathways Is a Tumor Suppressor Gene in Hepatoma Cells Critical Role of Endogenous Heme Oxygenase 1 as a Tuner of the Invasive Potential of Prostate Cancer Cells Heme oxygenase-1 and cardiovascular disease Heme oxygenase-1 alleviates eosinophilic inflammation by inhibiting STAT3-SOCS3 signaling An anti-inflammatory role for carbon monoxide and heme oxygenase-1 in chronic Th2-mediated murine colitis Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential Myeloid heme oxygenase-1 regulates innate immunity and autoimmunity by modulating IFN-β production Heme oxygenase-1 ameliorates ischemia/reperfusion injury by targeting dendritic cell maturation and migration Heme oxygenase-1 expression inhibits dendritic cell maturation and proinflammatory function but conserves IL-10 expression Heme Oxygenase-1 Modulates Early Inflammatory Responses Evidence from the Heme Oxygenase-1-Deficient Mouse Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice Endothelial Cell Activation of Adhesion Molecules Associated with Heme Oxygenase-1 Modulates the Expression Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases Heme oxygenase-1/carbon monoxide: From basic science to therapeutic applications Heme Catabolic Pathway in Inflammation and Immune Disorders Bilirubin reduces visceral obesity and insulin resistance by suppression of inflammatory cytokines Carbon Monoxide Generated by Heme Oxygenase 1 Suppresses Endothelial Cell Apoptosis Heme oxygenase-1 inhibits TNF-α-induced apoptosis in cultured fibroblasts Heme oxygenase-1 and the vascular bed: From molecular mechanisms to therapeutic opportunities VEGF Receptor Signaling and Endothelial Function Carbon Monoxide Produced by Heme Oxygenase-1 Suppresses T Cell Proliferation via Inhibition of IL-2 Production Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1 NLRP3 inflammasome activation in d-galactosamine and lipopolysaccharide-induced acute liver failure: Role of heme oxygenase-1. Free Radic Hemin inhibits NLRP3 inflammasome activation in sepsis-induced acute lung injury, involving heme oxygenase-1 Heme oxygenase-1 protects airway epithelium against apoptosis by targeting the proinflammatory NLRP3-RXR axis in asthma Pharmacological and clinical aspects of heme oxygenase The effect of anti-inflammatory properties of ferritin light chain on lipopolysaccharide-induced inflammatory response in murine macrophages Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice Inhibition of Nrf2/HO-1 signaling leads to increased activation of the NLRP3 inflammasome in osteoarthritis Heme oxygenase-1 induction attenuates imiquimod-induced psoriasiform inflammation by negative regulation of Stat3 signaling Sirt1 mediates the effect of the heme oxygenase inducer, cobalt protoporphyrin, on ameliorating liver metabolic damage caused by a high-fat diet Hemin exerts multiple protective mechanisms and attenuates dextran sulfate sodium-induced colitis Heme oxygenase-1 plays an important protective role in experimental autoimmune encephalomyelitis Analysis of intestinal haem-oxygenase-1 (HO-1 ) in clinical and experimental colitis Pang, Q. feng Curcumin ameliorates hepatic chronic inflammation induced by bile duct obstruction in mice through the activation of heme oxygenase-1 Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells Naturally Derived Heme-Oxygenase 1 Inducers and Their Therapeutic Application to Immune-Mediated Diseases Oxidized 5-aminosalicylic acid activates Nrf2-HO-1 pathway by covalently binding to Keap1: Implication in anti-inflammatory actions of 5-aminosalicylic acid. Free Radic 5-Aminolevulinic acid combined with ferrous iron enhances the expression of heme oxygenase-1 Heme Oxygenase-1-Generated Biliverdin Ameliorates Experimental Murine Colitis Bilirubin nanomedicine alleviates psoriatic skin inflammation by reducing oxidative stress and suppressing pathogenic signaling Redox Functions of Heme Oxygenase-1 and Biliverdin Reductase in Diabetes Heme Oxygenase-1 Induction by Carbon Monoxide Releasing Molecule-3 Suppresses Interleukin-1β-Mediated Neuroinflammation Antioxidants 2022 Therapeutic applications of carbon monoxide-releasing molecules The therapeutic potential of carbon monoxide Therapeutic effects of CO-releaser/Nrf2 activator hybrids (HYCOs) in the treatment of skin wound, psoriasis and multiple sclerosis Crystal structure of human heme oxygenase-1 in a complex with biliverdin PubChem Compound Summary for CID 4971, Protoporphyrin IX The role of heme oxygenase-1 in pulmonary disease Heme oxygenase-1 and carbon monoxide in pulmonary medicine Targeting the Heme Oxygenase 1/Carbon Monoxide Pathway to Resolve Lung Hyper-Inflammation and Restore a Regulated Immune Response in Cystic Fibrosis SARS-CoV-2: A storm is raging Mast cells contribute to coronavirus-induced inflammation: New anti-inflammatory strategy Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms Acute Lung Injury A Clinical and Molecular Review The role of macrophages in the pathogenesis of ali/ards Could heme oxygenase-1 be a new target for therapeutic intervention in malaria-associated acute lung injury/acute respiratory distress syndrome? Front Protective effects of hemin in an experimental model of ventilator-induced lung injury Protective effect of ischemic postconditioning on lung ischemia-reperfusion injury in rats and the role of heme oxygenase-1 Heme Oxygenase-1 Reduces Sepsis-Induced Endoplasmic Reticulum Stress and Acute Lung Injury Effect of Heme Oxygenase-1 on Mitofusin-1 protein in LPS-induced ALI/ARDS in rats Regulatory role of heme oxygenase-1 in silica-induced lung injury Therapeutic Potential of Heme Oxygenase-1 and Carbon Monoxide in Acute Organ Injury, Critical Illness, and Inflammatory Disorders Cigarette smoke-induced pulmonary inflammatory responses are mediated by EGR-1/GGPPS/MAPK signaling Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis Biliverdin protects the isolated rat lungs from ischemia-reperfusion injury via antioxidative, anti-inflammatory and anti-apoptotic effects Effects of Biliverdin Administration on Acute Lung Injury Induced by Hemorrhagic Shock and Resuscitation in Rats heme oxygenase-1 agonist CoPP suppresses influenza virus replication through IRF3-mediated generation of IFN-α/β Estimates of global seasonal influenza-associated respiratory mortality: A modelling study Bax Inhibitor-1 Acts as an Anti-Influenza Factor by Inhibiting ROS Mediated Cell Death and Augmenting Heme-Oxygenase 1 Expression in Influenza Virus Infected Cells Hemin ameliorates influenza pneumonia by attenuating lung injury and regulating the immune response Adenovirus-Mediated Transfer of Heme Oxygenase-1 cDNA Attenuates Severe Lung Injury Induced by the Influenza Virus in Mice Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice DMO-CAP inhibits influenza virus replication by activating heme oxygenase-1-mediated IFN response Rupestonic acid derivative YZH-106 suppresses influenza virus replication by activation of heme oxygenase-1-mediated interferon response. Free Radic Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: A systematic review and meta-analysis New perspectives in Respiratory Syncitial Virus infection Respiratory Syncytial Virus-Mediated NF-B p65 Phosphorylation at Serine 536 Is Dependent on RIG-I, TRAF6, and IKK Heme Oxygenase-1 Modulates Human Respiratory Syncytial Virus Replication and Lung Pathogenesis during Infection Antiretroviral Therapy has Saved Millions of Lives from AIDS and Could Save More UNAIDS: Joint United Nations Programme on HIV/AIDS. Available online Global Statistics CD8+ T cells in HIV control, cure and prevention Hemin Activation Ameliorates HIV-1 Infection via Heme Oxygenase-1 Induction Dimethyl fumarate, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and macrophage-mediated neurotoxicity: A novel candidate for HIV neuroprotection Degradation of heme oxygenase-1 by the immunoproteasome in astrocytes: A potential interferon-γ-dependent mechanism contributing to HIV neuropathogenesis Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders Ebola virus disease Ebolavirus and Marburgvirus: Insight the Filoviridae family Therapeutic potential of the heme oxygenase-1 inducer hemin against Ebola virus infection The cytoprotective enzyme heme oxygenase-1 suppresses Ebola virus replication The Ebola Virus VP35 Protein Inhibits Activation of Interferon Regulatory Factor 3 The heme oxygenase 1 product biliverdin interferes with hepatitis C virus replication by increasing antiviral interferon response Hepatitis C virus molecular evolution: Transmission, disease progression and antiviral therapy Antioxidants 2022 Down-Regulation of Heme Oxygenase-1 by Hepatitis C Virus Infection In Vivo and by the In Vitro Expression of Hepatitis C Core Protein Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus Biliverdin inhibits hepatitis C virus nonstructural 3/4A protease activity: Mechanism for the antiviral effects of heme oxygenase? miR-let-7c-5p and miR-149-5p inhibit proinflammatory cytokine production in osteoarthritis and rheumatoid arthritis synovial fibroblasts MicroRNA-let-7c suppresses hepatitis C virus replication by targeting Bach1 for induction of haem oxygenase-1 expression Dynamic correlation between induction of the expression of heme oxygenase-1 and hepatitis B viral replication Heme and HO-1 Inhibition of HCV, HBV, and HIV HO-1 is a favorable prognostic factor for HBV-HCC patients who underwent hepatectomy Dengue virus Cellular Oxidative Stress Response Controls the Antiviral and Apoptotic Programs in Dengue Virus-Infected Dendritic Cells Human heme oxygenase 1 is a potential host cell factor against dengue virus replication MicroRNA-155 inhibits dengue virus replication by inducing heme oxygenase-1-mediated antiviral interferon responses Subversion of the Heme Oxygenase-1 Antiviral Activity by Zika Virus. Viruses Herpes simplex virus 2 infection: Molecular association with HIV and novel microbicides to prevent disease Pharmacological Induction of Heme Oxygenase-1 Impairs Nuclear Accumulation of Herpes Simplex Virus Capsids upon Infection Enteroviruses as agents of emerging infectious diseases Enterovirus 71 induces integrin β1/EGFR-Rac1-dependent oxidative stress in SK-N-SH cells: Role of HO-1/CO in viral replication Emerging coronaviruses: Genome structure, replication, and pathogenesis SARS-CoV-2 Proteins Bind to Hemoglobin and Its Metabolites Heme oxygenase-1 inducer hemin does not inhibit SARS-CoV-2 virus infection Hemin as a novel candidate for treating COVID-19 via heme oxygenase-1 induction Myxovirus Resistance Protein 1 (MX1), a Novel HO-1 Interactor, Tilts the Balance of Endoplasmic Reticulum Stress towards Pro-Death Events in Prostate Cancer Antiviral strategies Influenza-Time to Target the Host? The SARS-CoV-2 Variant, Omicron, Shows Enhanced Replication in Human Primary Nasal Epithelial Cells SARS-CoV-2 Omicron-B.1.1.529 Variant leads to less severe disease than Pango B and Delta variants strains in a mouse model of severe COVID-19 A Review of Neurological Complications of COVID-19. Cureus 2020, 12, e8192 COVID-19 as an Acute Inflammatory Disease The HMOX1 Pathway as a Promising Target for the Treatment and Prevention of SARS-CoV-2 of 2019 (COVID-19) Hemin induces neuroglobin expression in neural cells A novel effective chemical hemin for the treatment of acute carbon monoxide poisoning in mice Systemic hemin therapy attenuates blood-brain barrier disruption after intracerebral hemorrhage SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate Can Activation of NRF2 Be a Strategy against COVID-19? Extrapulmonary manifestations of COVID-19 Pharmacological activation of heme oxygenase (HO)-1/carbon monoxide pathway prevents the development of peripheral neuropathic pain in Wistar rats The spike protein of SARS-CoV-2 virus induces heme oxygenase-1: Pathophysiologic implications Heme oxygenase-1 and acute kidney injury Glomerular epithelial cells-targeted heme oxygenase-1 over expression in the rat: Attenuation of proteinuria in secondary but not primary injury Protective role of heme oxygenase-1 in atrial remodeling Protection from cardiac injury by induction of heme oxygenase-1 and nitric oxide synthase in a focal ischaemia-reperfusion model Curcumin attenuates dimethylnitrosamine-induced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1 Tissue-resident macrophages protect the liver from ischemia reperfusion injury via a heme oxygenase-1-dependent mechanism Heme oxygenase 1 improves glucoses metabolism and kidney histological alterations in diabetic rats Investigation of COVID-19 comorbidities reveals genes and pathways coincident with the SARS-CoV-2 viral disease Targeting heme oxygenase-1 in vascular disease Induction of heme oxygenase-1 is a beneficial response in a murine model of venous thrombosis Carbon monoxide may be an important molecule in migraine and other headaches Carbon monoxide reduces neuropathic pain and spinal microglial activation by inhibiting nitric oxide synthesis in mice Astrocyte Overexpression of Heme Oxygenase-1 Improves Outcome after Intracerebral Hemorrhage Upregulation of heme oxygenase-1 protected against brain damage induced by transient cerebral ischemia-reperfusion injury in rats Tissue-based map of the human proteome Drug repurposing: Progress, challenges and recommendations We thank Javier Cotignola for his helpful comments and critical revision of this article. The authors declare no conflict of interest.