RIG-I overexpression decreases mortality of cigarette smoke exposed mice during influenza A virus infection

Respiratory Research, Sep 2017

Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines which participate in clearing viral infections. Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. We generated a RIG-I transgenic (TG) mouse strain that expresses the RIG-I gene product under the control of the human lung specific surfactant protein C promoter. We compared the mortality and host immune responses of RIG-I TG mice and their litter-matched wild type (WT) mice following challenge with influenza A virus (IAV). RIG-I overexpression increased survival of IAV-infected mice. CS exposure increased mortality in WT mice infected with IAV. Remarkably, the effect of RIG-I overexpression on survival during IAV infection was enhanced in CS-exposed animals. CS-exposed IAV-infected WT mice had a suppressed innate response profile in the lung compared to sham-exposed IAV-infected WT mice in terms of the protein concentration, total cell count and inflammatory cell composition in the bronchoalveolar lavage fluid. RIG-I overexpression restored the innate immune response in CS-exposed mice to that seen in sham-exposed WT mice during IAV infection, and is likely responsible for enhanced survival in RIG-I TG mice as restoration preceded death of the animals. Our results demonstrate that RIG-I overexpression in mice is protective for CS enhanced susceptibility of smokers to influenza infection, and that CS mediated RIG-I suppression may be partially responsible for the increased morbidity and mortality of the mice exposed to IAV. Thus, optimizing the RIG-I response may be an important treatment strategy for CS-enhanced lung infections, particularly those due to IAV.

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RIG-I overexpression decreases mortality of cigarette smoke exposed mice during influenza A virus infection

Wang et al. Respiratory Research RIG-I overexpression decreases mortality of cigarette smoke exposed mice during influenza A virus infection Xiaoqiu Wang 0 1 Wenxin Wu 0 1 Wei Zhang 1 J. Leland Booth 1 Elizabeth S. Duggan 1 Lili Tian 1 Sunil More 4 Yan D. Zhao 3 Ravindranauth N. Sawh 2 7 Lin Liu 4 Ming-Hui Zou 6 Jordan P. Metcalf 1 2 5 0 Equal contributors 1 Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center , Oklahoma City, OK , USA 2 Veterans Affairs Medical Center , Oklahoma City, OK , USA 3 Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center , Oklahoma City, OK , USA 4 The Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University , Stillwater, OK , USA 5 Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center , Oklahoma City, OK , USA 6 Center of Molecular and Translational Medicine, Georgia State University , Atlanta, GA , USA 7 Department of Pathology, University of Oklahoma Health Sciences Center , Oklahoma City, OK , USA Background: Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines which participate in clearing viral infections. Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. Methods: We generated a RIG-I transgenic (TG) mouse strain that expresses the RIG-I gene product under the control of the human lung specific surfactant protein C promoter. We compared the mortality and host immune responses of RIG-I TG mice and their litter-matched wild type (WT) mice following challenge with influenza A virus (IAV). Results: RIG-I overexpression increased survival of IAV-infected mice. CS exposure increased mortality in WT mice infected with IAV. Remarkably, the effect of RIG-I overexpression on survival during IAV infection was enhanced in CS-exposed animals. CS-exposed IAV-infected WT mice had a suppressed innate response profile in the lung compared to sham-exposed IAV-infected WT mice in terms of the protein concentration, total cell count and inflammatory cell composition in the bronchoalveolar lavage fluid. RIG-I overexpression restored the innate immune response in CS-exposed mice to that seen in sham-exposed WT mice during IAV infection, and is likely responsible for enhanced survival in RIG-I TG mice as restoration preceded death of the animals. Conclusions: Our results demonstrate that RIG-I overexpression in mice is protective for CS enhanced susceptibility of smokers to influenza infection, and that CS mediated RIG-I suppression may be partially responsible for the increased morbidity and mortality of the mice exposed to IAV. Thus, optimizing the RIG-I response may be an important treatment strategy for CS-enhanced lung infections, particularly those due to IAV. Influenza virus; Lung; Smoking; Cytokine; RIG-I; Transgenic mouse Background Influenza A virus (IAV), a negative-sense single strand RNA virus, is a highly contagious agent that causes upper and lower respiratory tract infection resulting in 200,000 hospitalizations and 36,000 deaths in the United States per year [ 1, 2 ]. IAV is responsible for seasonal epidemics and, infrequently, global pandemics. In 2009, a new pandemic caused by an H1N1 influenza strain emerged and spread globally, the first influenza pandemic in more than 40 years. Although recognizing and responding to pathogens in a non-specific manner, the innate immune system provides immediate protection against infection. 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. The member of the first class of PRRs that most cells use to detect IAV is the cytosolic sensor, retinoic acid inducible gene I (RIG-I) [ 3 ]. The second PRR class, endosomal Toll-like receptors (TLRs), are also involved. TLR3, a doublestrand RNA sensor, may be used by some epithelial cells to detect the viral replicative intermediate dsRNA [ 4 ]. Immune cells such as macrophages and dendritic cells (DCs) that are also present in the respiratory system, detect viruses using PRR’s, and produce proinflammatory cytokines upon activation. Myeloid DCs mainly sense IAV through RIG-I and TLR3, while plasmacytoid dendritic cells (pDCs) use TLR7 to recognize influenza genomic RNA upon release in late endosomes [ 5 ]. Finally, the third class of PRRs, the nucleotide-binding domain and leucine-rich-repeat-containing proteins (NLRP), including NLRP3, and nucleotide-binding oligomerization domain 2 (NOD2), may serve as intracellular mediators of IAV initiated host-cell signaling via the regulation of caspase-1 [ 6–8 ]. NLRP (...truncated)


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Xiaoqiu Wang, Wenxin Wu, Wei Zhang, J. Leland Booth, Elizabeth S. Duggan, Lili Tian, Sunil More, Yan D. Zhao, Ravindranauth N. Sawh, Lin Liu, Ming-Hui Zou, Jordan P. Metcalf. RIG-I overexpression decreases mortality of cigarette smoke exposed mice during influenza A virus infection, Respiratory Research, 2017, pp. 166,