MDA5 Is a Major Determinant of Developing Symptoms in Critically Ill COVID-19 Patients

• Published in: Clinical reviews in allergy & immunology 2024-12, Vol.67 (1), p.58-72
• Main Author: Maiti, Amit K.
• Format: Article
• Language: English
• Subjects: Allergology; COVID-19; COVID-19 - immunology; COVID-19 vaccines; Critical Illness; Genome-wide association studies; Genome-Wide Association Study; Humans; Humoral immunity; Immune response (cell-mediated); Immunity, Innate; Immunology; Innate immunity; Interferon; Interferon-Induced Helicase, IFIH1 - genetics; Interferon-Induced Helicase, IFIH1 - immunology; Interferon-Induced Helicase, IFIH1 - metabolism; Interferons - metabolism; Internal Medicine; M protein; Medicine; Medicine & Public Health; Mucosal immunity; Phenotypes; Polymorphism, Single Nucleotide; Replication; Review; RNA viruses; SARS-CoV-2 - immunology; Severe acute respiratory syndrome coronavirus 2; Signal Transduction; Single-nucleotide polymorphism
• ISSN: 1559-0267; 1080-0549; 1559-0267
• DOI: 10.1007/s12016-024-09008-z

Apart from the skin and mucosal immune barrier, the first line of defense of the human immune system includes MDA5 ( ifih1 gene) which acts as a cellular sensor protein for certain viruses including SARS-CoV-2. Upon binding with viral RNA, MDA5 activates cell-intrinsic innate immunity, humoral responses, and MAVS (mitochondrial antiviral signaling). MAVS signaling induces type I and III interferon (IFN) expressions that further induce ISGs (interferon stimulatory genes) expressions to initiate human cell-mediated immune responses and attenuate viral replication. SARS-CoV-2 counteracts by producing NSP1, NSP2, NSP3, NSP5, NSP7, NSP12, ORF3A, ORF9, N, and M protein and directs anti-MDA5 antibody production presumably to antagonize IFN signaling. Furthermore, COVID-19 resembles several diseases that carry anti-MDA5 antibodies and the current COVID-19 vaccines induced anti-MDA5 phenotypes in healthy individuals. GWAS (genome-wide association studies) identified several polymorphisms (SNPs) in the ifih1-ifn pathway genes including rs1990760 in ifih1 that are strongly associated with COVID-19, and the associated risk allele is correlated with reduced IFN production. The genetic association of SNPs in ifih1 and ifih1-ifn pathway genes reinforces the molecular findings of the critical roles of MDA5 in sensing SARS-CoV-2 and subsequently the IFN responses to inhibit viral replication and host immune evasion. Thus, MDA5 or its pathway genes could be targeted for therapeutic development of COVID-19.