RIG-I Signaling via MAVS Is Dispensable for Survival in Lethal Influenza Infection In Vivo.

Wenxin Wu,Jordan P. Metcalf,Wei Zhang,Sunil More,Lin Liu,Elizabeth S. Duggan,Xiaoqiu Wang,J. Leland Booth,Mikhail Dozmorov,Lili Tian

doi:10.1155/2018/6808934

Abstract

Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines. It requires interaction with an adaptor molecule, mitochondrial antiviral-signaling protein (MAVS), to activate downstream signaling pathways. To elucidate the mechanism(s) by which RIG-I-dependent recognition of IAV infection in vivo triggers innate immune responses, we infected mutant mice lacking RIG-I or MAVS with influenza A virus (IAV) and measured their innate immune responses. As has previously been demonstrated with isolated deletion of the virus recognition receptors TLR3, TLR7, and NOD2, RIG-I or MAVS knockout (KO) did not result in higher mortality and did not reduce IAV-induced cytokine responses in mice. Infected RIG-I KO animals displayed similar lung inflammation profiles as did WT mice, in terms of the protein concentration, total cell count, and inflammatory cell composition in the bronchoalveolar lavage fluid. RNA-Seq results demonstrated that all types of mice exhibited equivalent antiviral and inflammatory gene responses following IAV infection. Together, the results indicated that although RIG-I is important in innate cytokine responses in vitro, individual deletion of the genes encoding RIG-I or MAVS did not change survival or innate responses in vivo after IAV infection in mice.

Highlights

Infection with influenza A virus (IAV), a negative-sense single-strand RNA virus, is a major cause of morbidity and mortality
The results demonstrate that virus replicated in mouse lungs after IAV infection with concurrent induction of retinoic acid-inducible gene I (RIG-I)
The data demonstrate that RIG-I protein expression is deficient in RIG-I KO Alveolar Epithelial Cells (AEC) II and in RIG-I KO mouse lung, even when infected with IAV

Summary

Introduction

Infection with influenza A virus (IAV), a negative-sense single-strand RNA virus, is a major cause of morbidity and mortality. There are approximately 5 million clinical infections and 250,000–500,000 deaths resulting from yearly IAV epidemics around the globe, in people over 65 years old who account for 90% of all influenza-associated deaths in the USA [1, 2]. Innate immunity is the first line of defense against virus infection that triggers the expression of interferon (IFN). Cells of the innate immune system detect viral infection largely through pattern recognition receptors (PRRs) present either on the cell surface or within distinct intracellular compartments. The innate immune system responds to influenza through three classes of PRRs. First, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), widely expressed in various types of cells, such as myeloid dendritic cells (DC), macrophages, epithelial cells, and fibroblasts, detect intracellular ssRNAs and transcriptional intermediates

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Conclusion