Kandasamy Matheswaran, Suryawanshi Amol, Tundup Smanla, Perez Jasmine T, Schmolke Mirco, Manicassamy Santhakumar, Manicassamy Balaji
Department of Microbiology, The University of Chicago, Chicago, Illinois, United States of America.
Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, United States of America.
PLoS Pathog. 2016 Jul 20;12(7):e1005754. doi: 10.1371/journal.ppat.1005754. eCollection 2016 Jul.
Retinoic acid inducible gene-I (RIG-I) is an innate RNA sensor that recognizes the influenza A virus (IAV) RNA genome and activates antiviral host responses. Here, we demonstrate that RIG-I signaling plays a crucial role in restricting IAV tropism and regulating host immune responses. Mice deficient in the RIG-I-MAVS pathway show defects in migratory dendritic cell (DC) activation, viral antigen presentation, and priming of CD8+ and CD4+ T cell responses during IAV infection. These defects result in decreased frequency of polyfunctional effector T cells and lowered protection against heterologous IAV challenge. In addition, our data show that RIG-I activation is essential for protecting epithelial cells and hematopoietic cells from IAV infection. These diverse effects of RIG-I signaling are likely imparted by the actions of type I interferon (IFN), as addition of exogenous type I IFN is sufficient to overcome the defects in antigen presentation by RIG-I deficient BMDC. Moreover, the in vivo T cell defects in RIG-I deficient mice can be overcome by the activation of MDA5 -MAVS via poly I:C treatment. Taken together, these findings demonstrate that RIG-I signaling through MAVS is critical for determining the quality of polyfunctional T cell responses against IAV and for providing protection against subsequent infection from heterologous or novel pandemic IAV strains.
维甲酸诱导基因-I（RIG-I）是一种天然RNA传感器，可识别甲型流感病毒（IAV）的RNA基因组并激活抗病毒宿主反应。在此，我们证明RIG-I信号传导在限制IAV嗜性和调节宿主免疫反应中起关键作用。RIG-I-MAVS途径缺陷的小鼠在IAV感染期间，迁移性树突状细胞（DC）激活、病毒抗原呈递以及CD8+和CD4+ T细胞反应的启动方面存在缺陷。这些缺陷导致多功能效应T细胞频率降低，并降低了对异源IAV攻击的保护作用。此外，我们的数据表明，RIG-I激活对于保护上皮细胞和造血细胞免受IAV感染至关重要。RIG-I信号传导的这些不同作用可能是由I型干扰素（IFN）的作用赋予的，因为添加外源性I型干扰素足以克服RIG-I缺陷的骨髓来源树突状细胞（BMDC）在抗原呈递方面的缺陷。此外，通过聚肌胞苷酸（poly I:C）处理激活黑色素瘤分化相关基因5（MDA5）-线粒体抗病毒信号蛋白（MAVS），可以克服RIG-I缺陷小鼠体内的T细胞缺陷。综上所述，这些发现表明，通过MAVS的RIG-I信号传导对于确定针对IAV的多功能T细胞反应的质量以及提供针对异源或新型大流行IAV毒株后续感染的保护至关重要。
