Association of IFIH1 and DDX58 genes polymorphism with susceptibility to COVID-19.

Pattern recognition receptors of the innate immune system, such as RIG-I and MDA5, are responsible for recognizing viruses and inducing interferon production. Genetic polymorphisms in the coding regions of RLR may be associated with the severity of COVID-19. Considering the contribution of the RLR signaling in immune-mediated reactions, this study investigated the association between three SNP in the coding region of IFIH1 and DDX58 genes with the susceptibility to COVID-19 in the Kermanshah population, Iran. 177 patients with severe and 182 with mild COVID-19 were admitted for this study. Genomic DNA was extracted from peripheral blood leukocytes of patients to determine the genotypes of two SNPs, rs1990760(C>T) and rs3747517(T>C) IFIH1 gene and rs10813831(G>A) DDX58 gene using PCR-RFLP method. Our results showed that the frequency of the AA genotype of rs10813831(G>A) was associated with susceptibility to COVID-19 compared to the GG genotype (p = 0.017, OR = 2.593, 95% CI 1.173-5.736). We also observed a statistically significant difference in the recessive model for SNPs rs10813831 variant (AA versus GG + GA, p = 0.003, OR = 2.901, 95% CI 1.405-6.103). Furthermore, No significant association was found between rs1990760 (C>T) and rs3747517(T>C) of IFIH1 gene polymorphisms with COVID-19. Our findings suggest that DDX58 rs10813831(A>G) polymorphism may be associated with COVID-19 severity in the Kermanshah population, Iran.

Appearance of Anti-MDA5 Antibody-Positive Dermatomyositis After COVID-19 Vaccination.

The direct causes of dermatomyositis, a common autoimmune disease, have not yet been accurately identified, but several studies have linked this condition to various patient-associated and environmental factors, such as viral infections and area of residence. In the present report, we describe our experience with a patient presenting with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis, which developed after vaccination against coronavirus disease 2019 (COVID-19). This patient was simultaneously diagnosed with anti-glutamic acid decarboxylase (GAD) antibody-positive slowly progressive insulin-dependent diabetes (SPIDDM); her human leukocyte antigen (HLA) test revealed that she expressed the DRB1*04:05 allele. This is important as this genotype is known to increase susceptibility to both anti-MDA5 antibody-positive dermatomyositis and type I diabetes. To the best of our knowledge, this is the first case of dermatomyositis complicated by SPIDDM identified after COVID-19 vaccination against COVID-19 and presenting with an underlying susceptible genotype. The patient's genetic predisposition may also be important for the development of autoimmune disease after COVID-19 vaccination.

Infectious bronchitis virus nucleocapsid protein suppressed type I interferon production by interfering with the binding of MDA5-dsRNA and interacting with LGP2.

The type I interferon (IFN-I) is a critical component of the innate immune responses, and Coronaviruses (CoVs) from both the Alphacoronavirus and Betacoronavirus genera interfere with the IFN-I signaling pathway in various ways. Of the gammacoronaviruses that mainly infect birds, little is known about how infectious bronchitis virus (IBV), evades or interferes with the innate immune responses in avian hosts since few IBV strains have been adapted to grow in avian passage cells. Previously, we reported that a highly pathogenic IBV strain GD17/04 has adaptability in an avian cell line, providing a material basis for further study on the interaction mechanism. In the present work, we describe the suppression of IBV to IFN-I and the potential role of IBV-encoded nucleocapsid (N) protein. We show that IBV significantly inhibits the poly I: C-induced IFN-I production, accordingly the nuclear translocation of STAT1, and the expression of IFN-stimulated genes (ISGs). A detailed analysis revealed that N protein, acting as an IFN-I antagonist, significantly impedes the activation of the IFN-ß promoter stimulated by MDA5 and LGP2 but does not counteract its activation by MAVS, TBK1, and IRF7. Further results showed that IBV N protein, verified to be an RNA-binding protein, interferes with MDA5 recognizing double-stranded RNA (dsRNA). Moreover, we found that the N protein targets LGP2, which is required in the chicken IFN-I signaling pathway. Taken together, this study provides a comprehensive analysis of the mechanism by which IBV evades avian innate immune responses.

What is common to MDA5 and COVID-19?

Respiratory complaints and nonspecific systemic symptoms combined with bilateral ground glass opacities on chest imaging constitute the clinical and radiological picture of both COVID-19 disease and anti-MDA5 dermatomyositis. Those findings together with the identification of anti-MDA5 antibodies in sera of certain COVID-19-positive patients allude for a common immunogenic basis. The common pathophysiological denominator is the cytokine storm. Modulation of interferon beta pathway plays role in both diseases;this observation can direct us for potential immunomodulatory therapies for both COVID-19 and anti-MDA5 dermatomyositis. This chapter will discuss in detail the clinical, radiological, and laboratory similarities of both COVID-19 disease and anti-MDA5 dermatomyositis. © 2023 Elsevier Inc. All rights reserved.

Porcine Epidemic Diarrhea Virus nsp7 Inhibits MDA5 Dephosphorylation to Antagonize Type I Interferon Production.

Porcine epidemic diarrhea virus (PEDV) is a reemerging enteropathogenic coronavirus that causes high mortality in piglets and has catastrophic effects on the global pig industry. PEDV-encoded nonstructural protein 7 (nsp7) is an important component of the viral replication and transcription complex, and a previous study reported that it inhibits poly(I:C)-induced type I interferon (IFN) production, but the mechanism by which this occurs remains unclear. Here, we demonstrated that ectopic expression of PEDV nsp7 antagonized Sendai virus (SeV)-induced interferon beta (IFN-ß) production, as well as the activation of transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB) in both HEK-293T and LLC-PK1 cells. Mechanistically, PEDV nsp7 targets melanoma differentiation-associated gene 5 (MDA5) and interacts with its caspase activation and recruitment domains (CARDs), which sequester the interactions between MDA5 and the protein phosphatase 1 (PP1) catalytic subunits (PP1α and PP1γ), thereby suppressing MDA5 S828 dephosphorylation and keeping MDA5 inactive. Furthermore, PEDV infection attenuated MDA5 multimerization and MDA5-PP1α/-γ interactions. We also tested the nsp7 orthologs of five other mammalian coronaviruses and found that all of them except severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nsp7 inhibited MDA5 multimerization and SeV- or MDA5-induced IFN-ß production. Collectively, these results suggest that the inhibition of MDA5 dephosphorylation and multimerization may be a common strategy employed by PEDV and some other coronaviruses to antagonize MDA5-mediated IFN production. IMPORTANCE Since late 2010, a reemerging porcine epidemic diarrhea virus variant with high pathogenesis has swept through most pig farms in many countries, resulting in significant economic losses. Coronavirus nonstructural protein 7 (nsp7), conserved within the family Coronaviridae, combines with nsp8 and nsp12 to form the viral replication and transcription complex that is indispensable for viral replication. However, the function of nsp7 in the infection and pathogenesis of coronaviruses remains largely unknown. Our present study demonstrates that PEDV nsp7 specifically competes with PP1 for binding MDA5 and impedes the PP1-mediated dephosphorylation of MDA5 at S828, thereby blocking MDA5-mediated IFN production, revealing the complex mechanism utilized by PEDV nsp7 to efficiently escape host innate immunity.

Radix Isatidis polysaccharide (RIP) resists the infection of QX-type infectious bronchitis virus via the MDA5/TLR3/IRF7 signaling pathway.

Although vaccines play a major role in the prevention of infectious bronchitis (IB), Anti-IB drugs still have great potential in poultry production. Radix Isatidis polysaccharide (RIP) is a crude extract of Banlangen with antioxidant, antibacterial, antiviral, and multiple immunomodulatory functions. The aim of this study was to explore the innate immune mechanisms responsible for RIP-mediated alleviation of infectious bronchitis virus (IBV)-induced kidney lesions in chickens. Specific-pathogen-free (SPF) chicken and chicken embryo kidney (CEK) cells cultures were pretreated with RIP and then infected with the QX-type IBV strain, Sczy3. Morbidity, mortality, and tissue mean lesion scores were calculated for IBV-infected chickens, and the viral loads, inflammatory factor gene mRNA expression levels, and innate immune pathway gene mRNA expression levels in infected chickens and CEK cell cultures were determined. The results show that RIP could alleviate IBV-induced kidney damage, decrease CEK cells susceptibility to IBV infection, and reduce viral loads. Additionally, RIP reduced the mRNA expression levels of the inflammatory factors IL-6, IL-8, and IL-1ß by decreasing the mRNA expression level of NF-κB. Conversely, the expression levels of MDA5, TLR3, STING, Myd88, IRF7, and IFN-ß were increased, indicating that RIP conferred resistance to QX-type IBV infection via the MDA5, TLR3, IRF7 signaling pathway. These results provide a reference for both further research into the antiviral mechanisms of RIP and the development of preventative and therapeutic drugs for IB.

SARS-CoV-2 NSP8 suppresses type I and III IFN responses by modulating the RIG-I/MDA5, TRIF, and STING signaling pathways.

SARS-CoV-2 has developed a variety of approaches to counteract host innate antiviral immunity to facilitate its infection, replication and pathogenesis, but the molecular mechanisms that it employs are still not been fully understood. Here, we found that SARS-CoV-2 NSP8 inhibited the production of type I and III interferons (IFNs) by acting on RIG-I/MDA5 and the signaling molecules TRIF and STING. Overexpression of NSP8 downregulated the expression of type I and III IFNs stimulated by poly (I:C) transfection and infection with SeV and SARS-CoV-2. In addition, NSP8 impaired IFN expression triggered by overexpression of the signaling molecules RIG-I, MDA5, and MAVS, instead of TBK1 and IRF3-5D, an active form of IRF3. From a mechanistic view, NSP8 interacts with RIG-I and MDA5, and thereby prevents the assembly of the RIG-I/MDA5-MAVS signalosome, resulting in the impaired phosphorylation and nuclear translocation of IRF3. NSP8 also suppressed the TRIF- and STING- induced IFN expression by directly interacting with them. Moreover, ectopic expression of NSP8 promoted virus replications. Taken together, SARS-CoV-2 NSP8 suppresses type I and III IFN responses by disturbing the RIG-I/MDA5-MAVS complex formation and targeting TRIF and STING signaling transduction. These results provide new insights into the pathogenesis of COVID-19.

Age-dependent effect of the IFIH1/MDA5 gene variants on the risk of critical COVID-19.

MDA5, encoded by the IFIH1gene, is a cytoplasmic sensor of viral RNAs that triggers interferon (IFN) antiviral responses. Common and rare IFIH1 variants have been associated with the risk of type 1 diabetes and other immune-mediated disorders, and with the outcome of viral diseases. Variants associated with reduced IFN expression would increase the risk for severe viral disease. The MDA5/IFN pathway would play a critical role in the response to SARS-CoV-2 infection mediating the extent and severity of COVID-19. Here, we genotyped a cohort of 477 patients with critical ICU COVID-19 (109 death) for three IFIH1 functional variants: rs1990760 (p.Ala946Thr), rs35337543 (splicing variant, intron 8 + 1G > C), and rs35744605 (p.Glu627Stop). The main finding of our study was a significant increased frequency of rs1990760 C-carriers in early-onset patients (< 65 years) (p = 0.01; OR = 1.64, 95%CI = 1.18-2.43). This variant was also increased in critical vs. no-ICU patients and in critical vs. asymptomatic controls. The rs35744605 C variant was associated with increased blood IL6 levels at ICU admission. The rare rs35337543 splicing variant showed a trend toward protection from early-onset critical COVID-19. In conclusion, IFIH1 variants associated with reduced gene expression and lower IFN response might contribute to develop critical COVID-19 with an age-dependent effect.

Retinoic acid-inducible gene 1 (RIG-1) and IFN-ß promoter stimulator-1 (IPS-1) significantly down-regulated in the severe coronavirus disease 2019 (COVID-19).

INTRODUCTION: Retinoic acid-inducible gene 1 (RIG-1) and melanoma differentiation-associated protein 5 (MDA5) are the well-known cytoplasmic sensors that recognize microbial DNA or RNA and active down-stream molecules, including IFN-ß promoter stimulator-1 (IPS-1) and receptor interacting protein 1 (RIP1). The roles played by the networked molecules on the infection with SARS-CoV-2 needs more investigations. MATERIAL AND METHOD: In this project MDA5, RIG-1, IPS-1 and RIP1 mRNA levels were evaluated in 45 hospitalized patients suffering from coronavirus disease of 2019 (COVID-19) and 45 healthy subjects using Real Time-qPCR technique. RESULT: The results showed significant decreased RIG-1 and IPS-1 in the SARS-CoV-2 infected patients when compared to healthy cases. MDA5 and RIP1 did not change when compared two groups. Male patients had similar expression of MDA5, RIG-1, IPS-1 and RIP1 when compared to female patients. CONCLUSION: Based on the results, it seems that RIG-1 and its signaling molecule, IPS-1, play key roles in the peripheral blood immune cells against SARS-CoV-2 and, their down-regulation may be induced by the virus to escape from immune responses.

A Rare Case of MDA-5-Positive Amyopathic Dermatomyositis with Rapidly Progressive Interstitial Lung Disease Following COVID-19 mRNA Vaccination - a Case Report.

We report a rare case of new-onset MDA-5-positive amyopathic dermatomyositis with rapidly progressive interstitial lung disease (RP-ILD) following the second dose of the COVID-19 mRNA vaccine. Our patient was a previously healthy Asian female in her 60 s who presented with fatigue, dyspnea on exertion, and typical dermatomyositis (DM) rashes without muscle involvement two weeks after receiving the second dose of the COVID-19 mRNA BNT162b2 vaccine. Workup revealed high titer MDA-5 antibodies, abnormal pulmonary function tests, and ground-glass opacities on chest imaging. She had good response to early aggressive therapy with high-dose steroids, intravenous (IV) rituximab, mycophenolate mofetil, and intravenous immunoglobulin (IVIG). This case highlights the potential immunogenicity of COVID-19 mRNA vaccines and the possibility of new-onset systemic rheumatic syndromes after vaccination. More studies are needed to understand a definitive causal relationship and improve surveillance of adverse immunological events following COVID-19 vaccinations.

Roles of biomarkers in anti-MDA5-positive dermatomyositis, associated interstitial lung disease, and rapidly progressive interstitial lung disease.

BACKGROUND: Anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (MDA5+ DM) is significantly associated with interstitial lung disease (ILD), especially rapidly progressive ILD (RPILD) due to poor prognosis, resulting in high mortality rates. However, the pathogenic mechanism of MDA5+ DM-RPILD is unclear. Although some MDA5+ DM patients have a chronic course of ILD, many do not develop RPILD. Therefore, the related biomarkers for the early diagnosis, disease activity monitoring, and prediction of the outcome of RPILD in MDA5+ DM patients should be identified. Blood-based biomarkers are minimally invasive and can be easily detected. METHODS: Recent relative studies related to blood biomarkers in PubMed were reviewed. RESULTS: An increasing number of studies have demonstrated that dysregulated expression of blood biomarkers related to ILD such as ferritin, Krebs von den Lungen-6 (KL-6), surfactant protein-D (SP-D), and cytokines, and some tumor markers in MDA5+ DM may provide information in disease presence, activity, treatment response, and prognosis. These studies have highlighted the great potentials of blood biomarker values for MDA5+ DM-ILD and MDA5+ DM-RPILD. This review provides an overview of recent studies related to blood biomarkers, besides highlighted protein biomarkers, including antibody (anti-MDA5 IgG subclasses and anti-Ro52 antibody), genetic (exosomal microRNAs and neutrophil extracellular traps related to cell-free DNA), and immune cellular biomarkers in MDA5+ DM, MDA5+ DM-ILD, and MDA5+ DM-RPILD patients, hopefully elucidating the pathogenesis of MDA5+ DM-ILD and providing information on the early diagnosis, disease activity monitoring, and prediction of the outcome of the ILD, especially RPILD. CONCLUSIONS: Therefore, this review may provide insight to guide treatment decisions for MDA5+ DM-RPILD patients and improve outcomes.

Pathological Roles of Pulmonary Cells in Acute Lung Injury: Lessons from Clinical Practice.

Interstitial lung diseases (ILD) are relatively rare and sometimes become life threatening. In particular, rapidly progressive ILD, which frequently presents as acute lung injury (ALI) on lung histopathology, shows poor prognosis if proper and immediate treatments are not initiated. These devastating conditions include acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), clinically amyopathic dermatomyositis (CADM), epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-induced lung injury, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection named coronavirus disease 2019 (COVID-19). In this review, clinical information, physical findings, laboratory examinations, and findings on lung high-resolution computed tomography and lung histopathology are presented, focusing on majorly damaged cells in each disease. Furthermore, treatments that should be immediately initiated in clinical practice for each disease are illustrated to save patients with these diseases.

Nsp16 shields SARS-CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction.

Methylation of the mRNA 5' cap by cellular methyltransferases enables efficient translation and avoids recognition by innate immune factors. Coronaviruses encode viral 2'-O-methyltransferases to shield their RNA from host factors. Here, we generate recombinant SARS-CoV-2 harboring a catalytically inactive 2'-O-methyltransferase Nsp16, Nsp16mut, and analyze viral replication in human lung epithelial cells. Although replication is only slightly attenuated, we find SARS-CoV-2 Nsp16mut to be highly immunogenic, resulting in a strongly enhanced release of type I interferon upon infection. The elevated immunogenicity of Nsp16mut is absent in cells lacking the RNA sensor MDA5. In addition, we report that Nsp16mut is highly sensitive to type I IFN treatment and demonstrate that this strong antiviral effect of type I IFN is mediated by the restriction factor IFIT1. Together, we describe a dual role for the 2'-O-methyltransferase Nsp16 during SARS-CoV-2 replication in avoiding efficient recognition by MDA5 and in shielding its RNA from interferon-induced antiviral responses, thereby identifying Nsp16 as a promising target for generating attenuated and highly immunogenic SARS-CoV-2 strains and as a potential candidate for therapeutic intervention.

The intersection molecule MDA5 in Cancer and COVID-19.

The connections between pattern recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs) constitutes the crucial signaling pathways in the innate immune system. Cytoplasmic nucleic acid sensor melanoma differentiation-associated gene 5 (MDA5) serves as an important pattern recognition receptor in the innate immune system by recognizing viral RNA. MDA5 also plays a role in identifying the cytoplasmic RNA from damaged, dead cancer cells or autoimmune diseases. MDA5's recognition of RNA triggers innate immune responses, induces interferon (IFN) response and a series of subsequent signaling pathways to produce immunomodulatory factors and inflammatory cytokines. Here we review the latest progress of MDA5 functions in triggering anti-tumor immunity by sensing cytoplasmic dsRNA, and recognizing SARS-CoV-2 virus infection for antiviral response, in which the virus utilizes multiple ways to evade the host defense mechanism.

Direct Interaction of Coronavirus Nonstructural Protein 3 with Melanoma Differentiation-Associated Gene 5 Modulates Type I Interferon Response during Coronavirus Infection.

Coronavirus nonstructural protein 3 (nsp3) is a multi-functional protein, playing a critical role in viral replication and in regulating host antiviral innate immunity. In this study, we demonstrate that nsp3 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and avian coronavirus infectious bronchitis virus (IBV) directly interacts with melanoma differentiation-associated gene 5 (MDA5), rendering an inhibitory effect on the MDA5-mediated type I interferon (IFN) response. By the co-expression of MDA5 with wild-type and truncated nsp3 constructs, at least three interacting regions mapped to the papain-like protease (PLpro) domain and two other domains located at the N- and C-terminal regions were identified in SARS-CoV-2 nsp3. Furthermore, by introducing point mutations to the catalytic triad, the deubiquitylation activity of the PLpro domain from both SARS-CoV-2 and IBV nsp3 was shown to be responsible for the suppression of the MDA5-mediated type I IFN response. It was also demonstrated that both MDA5 and nsp3 were able to interact with ubiquitin and ubiquitinated proteins, contributing to the interaction between the two proteins. This study confirms the antagonistic role of nsp3 in the MDA5-mediated type I IFN signaling, highlighting the complex interaction between a multi-functional viral protein and the innate immune response.

Association between expression of ZBP1, AIM2, and MDA5 genes and severity of COVID-19.

Antiviral and inflammatory responses following the detection of the virus genome by nucleic acid sensors play a vital role in the pathogenesis and outcome of diseases. In this study, we investigated the ZBP1, AIM2, and MDA5 expression levels in COVID-19 patients with different intensities of the disease. 75 quantitative Real-Time PCR (qRT-PCR)-confirmed COVID-19 patients were included consecutively and divided into 3 groups of mild, severe, and critical based on the severity of the disease. Also, 25 healthy volunteer subjects were included. PBMCs were collected from the whole blood, and RNA was extracted using commercial kit. The expression of ZBP1, AIM2, and MDA5 genes was investigated using qRT-PCR technique. The mean age of the patients and healthy volunteers was 52.73±13.78 and 49.120±12.490, respectively. In each group, 13 out of 25 participants were male. The expression levels of ZBP1 (P=0.001), AIM2 (P=0.001), and MDA5 (P= 0.003) transcript were significantly higher in COVID-19 patients than the control group. The results also revealed that the expression levels of ZBP1, AIM2, and MDA5 were significantly higher in the critical and severe COVID-19 patients compared to those with mild disease (P<0.05). Moreover, regarding the gender, the expression levels of AIM2 and MDA5 were significantly elevated in male severe (P=0.04 and P=0.003, respectively) and critical (P=0.005 and P=0.0004, respectively) patients than the female ones. The results indicated that ZBP1, AIM2, and MDA5 genes might have an important role in the severity of COVID-19 disease. Moreover, the severity of COVID-19 disease in male and female patients might be related to AIM2, and MDA5 expression levels. More studies are recommended to be conducted to clarify this issue.

Actin cytoskeleton remodeling primes RIG-I-like receptor activation.

The current dogma of RNA-mediated innate immunity is that sensing of immunostimulatory RNA ligands is sufficient for the activation of intracellular sensors and induction of interferon (IFN) responses. Here, we report that actin cytoskeleton disturbance primes RIG-I-like receptor (RLR) activation. Actin cytoskeleton rearrangement induced by virus infection or commonly used reagents to intracellularly deliver RNA triggers the relocalization of PPP1R12C, a regulatory subunit of the protein phosphatase-1 (PP1), from filamentous actin to cytoplasmic RLRs. This allows dephosphorylation-mediated RLR priming and, together with the RNA agonist, induces effective RLR downstream signaling. Genetic ablation of PPP1R12C impairs antiviral responses and enhances susceptibility to infection with several RNA viruses including SARS-CoV-2, influenza virus, picornavirus, and vesicular stomatitis virus. Our work identifies actin cytoskeleton disturbance as a priming signal for RLR-mediated innate immunity, which may open avenues for antiviral or adjuvant design.

Mechanic's Hand Heralding Relapse in an Indian Adolescent with Anti-MDA5 Positive Juvenile Dermatomyositis.

Anti-MDA5 antibodies characterise a distinct phenotype of dermatomyositis in adults as well as children, with ethnic disparity in clinical presentation and severity. They often present as a diagnostic conundrum with rash, ulceration, and polyarthritis, but minimal muscle disease. Mechanic's hands are typically associated with anti-synthetase syndrome, but their presence in anti-MDA5 antibody positive patients, although reported, is not well known. We present the case of a boy in whom mechanic's hand heralded a relapse of juvenile dermatomyositis which was suspected based on remotely assessed patient-reported outcome measures on teleconsultation. This report suggests that mechanic's hands should also prompt testing for myositis antibodies including anti-MDA5 in Indian children with JDM. Diligent awareness of the condition, and timely use of patient reported outcome measures of muscle power and skin assessment may guide management while delivering remote care in challenging situations such as a global pandemic.

Porcine Sapelovirus 3Cpro Inhibits the Production of Type I Interferon.

Porcine sapelovirus (PSV) is the causative pathogen of reproductive obstacles, acute diarrhea, respiratory distress, or severe polioencephalomyelitis in swine. Nevertheless, the pathogenicity and pathogenic mechanism of PSV infection are not fully understood, which hinders disease prevention and control. In this study, we found that PSV was sensitive to type I interferon (IFN-ß). However, PSV could not activate the IFN-ß promoter and induce IFN-ß mRNA expression, indicating that PSV has evolved an effective mechanism to block IFN-ß production. Further study showed that PSV inhibited the production of IFN-ß by cleaving mitochondrial antiviral signaling (MAVS) and degrading melanoma differentiation-associated gene 5 (MDA5) and TANK-binding kinase 1 (TBK1) through viral 3Cpro. In addition, our study demonstrated that PSV 3Cpro degrades MDA5 and TBK1 through its protease activity and cleaves MAVS through the caspase pathway. Collectively, our results revealed that PSV inhibits the production of type I interferon to escape host antiviral immunity through cleaving and degrading the adaptor molecules.

Anti-MDA5 Antibody Linking COVID-19, Type I Interferon, and Autoimmunity: A Case Report and Systematic Literature Review.

Introduction: The SARS-CoV-2 infection has been advocated as an environmental trigger for autoimmune diseases, and a paradigmatic example comes from similarities between COVID-19 and the myositis-spectrum disease associated with antibodies against the melanoma differentiation antigen 5 (MDA5) in terms of clinical features, lung involvement, and immune mechanisms, particularly type I interferons (IFN). Case Report: We report a case of anti-MDA5 syndrome with skin manifestations, constitutional symptoms, and cardiomyopathy following a proven SARS-CoV-2 infection. Systematic Literature Review: We systematically searched for publications on inflammatory myositis associated with COVID-19. We describe the main clinical, immunological, and demographic features, focusing our attention on the anti-MDA5 syndrome. Discussion: MDA5 is a pattern recognition receptor essential in the immune response against viruses and this may contribute to explain the production of anti-MDA5 antibodies in some SARS-CoV-2 infected patients. The activation of MDA5 induces the synthesis of type I IFN with an antiviral role, inversely correlated with COVID-19 severity. Conversely, elevated type I IFN levels correlate with disease activity in anti-MDA5 syndrome. While recognizing this ia broad area of uncertainty, we speculate that the strong type I IFN response observed in patients with anti-MDA5 syndrome, might harbor protective effects against viral infections, including COVID-19.