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

IF 8.4 2区 医学 Q1 ALLERGY
Amit K Maiti
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Abstract

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.

MDA5 是 COVID-19 重症患者出现症状的主要决定因素。
除了皮肤和粘膜免疫屏障外,人体免疫系统的第一道防线还包括 MDA5(ifih1 基因),它是某些病毒(包括 SARS-CoV-2 病毒)的细胞感应蛋白。与病毒 RNA 结合后,MDA5 会激活细胞内在先天免疫、体液反应和 MAVS(线粒体抗病毒信号)。MAVS 信号可诱导 I 型和 III 型干扰素(IFN)的表达,从而进一步诱导 ISGs(干扰素刺激基因)的表达,启动人体细胞介导的免疫反应并抑制病毒复制。SARS-CoV-2 通过产生 NSP1、NSP2、NSP3、NSP5、NSP7、NSP12、ORF3A、ORF9、N 和 M 蛋白进行对抗,并引导抗 MDA5 抗体的产生,这可能是为了拮抗 IFN 信号转导。此外,COVID-19 与携带抗 MDA5 抗体的几种疾病相似,目前的 COVID-19 疫苗可诱导健康人产生抗 MDA5 表型。全基因组关联研究(GWAS)在 ifih1-ifn 通路基因中发现了几个多态性(SNPs),包括与 COVID-19 密切相关的 ifih1 中的 rs1990760,相关的风险等位基因与 IFN 生成减少有关。ifih1和ifih1-ifn通路基因中SNPs的遗传关联加强了分子研究结果,即MDA5在感知SARS-CoV-2和随后的IFN反应以抑制病毒复制和宿主免疫逃避中起着关键作用。因此,MDA5 或其通路基因可作为 COVID-19 治疗开发的靶点。
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来源期刊
CiteScore
22.30
自引率
1.10%
发文量
58
审稿时长
6-12 weeks
期刊介绍: Clinical Reviews in Allergy & Immunology is a scholarly journal that focuses on the advancement of clinical management in allergic and immunologic diseases. The journal publishes both scholarly reviews and experimental papers that address the current state of managing these diseases, placing new data into perspective. Each issue of the journal is dedicated to a specific theme of critical importance to allergists and immunologists, aiming to provide a comprehensive understanding of the subject matter for a wide readership. The journal is particularly helpful in explaining how novel data impacts clinical management, along with advancements such as standardized protocols for allergy skin testing and challenge procedures, as well as improved understanding of cell biology. Ultimately, the journal aims to contribute to the improvement of care and management for patients with immune-mediated diseases.
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