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

Abstract

BackgroundRetinoic 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.MethodsWe 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).ResultsRIG-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.ConclusionsOur 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.

Apigenin suppresses influenza A virus‐induced RIG‐I activation and viral replication

“…12 Although in vitro and in vivo evidence suggests that RIG-I signaling is crucial for IFNs production to limit virus replication, particularly in the early stages of viral infection, long term overproduction of IFNs and cytokines can cause immunopathologic lung injury following acute IAV infection. [13][14][15][16][17] Thus, targeting RIG-I signaling to suppress RIG-I long-lasting hy- After 4 days, the number of plaques was then counted.…”

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

“…There might be extensive cooperative and/or competitive interactions among different PRRs that support and regulate antiviral sensing and induction of innate immune responses. Our previous publication demonstrated that RIG-I overexpression in the lung improves survival of cigarette smoke-exposed mice during IAV infection [ 17 ]. This suggests that, although solitary PRR deficiency might be dispensable in innate response to IAV, overexpression of one major PRR is sufficient to restore the innate response to IAV infection in an immunosuppressed cohort.…”

“…Gene-specific primers for mouse PRRs, cytokines, and the β -actin housekeeping genes were used. The primers' sequences were the same as in our earlier publication [ 17 ]. qRT-PCR was performed using 100 ng sample RNA and SYBR Green (Quanta Biosciences, Gaithersburg, MD) in a Bio-Rad CFX96™ Touch Real-Time PCR Detection System.…”

“…RIG-I is essential for IFN induction during RNA virus infections of non-pDC cell types, and mice that are deficient in RIG-I-like receptor signaling pathways are extremely susceptible to other RNA viruses [ 14 – 16 ]. Our previous work using RIG-I transgenic mice showed that RIG-I overexpression in mice protects against cigarette smoke enhanced susceptibility of these animals to influenza infection [ 17 ]. Although PRRs are important in innate cytokine response in vitro , the deletion of genes encoding PRRs other than RIG-I does not worsen survival during IAV infection in vivo .…”

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

“…RIG-I is essential for IFN induction during RNA virus infections of non-pDC cell types, and mice that are deficient in RIG-I-like receptor signaling pathways are extremely susceptible to other RNA viruses [14][15][16]. Our previous work using RIG-I transgenic mice showed that RIG-I overexpression in mice protects against cigarette smoke enhanced susceptibility of these animals to influenza infection [17]. Although PRRs are important in innate cytokine response in vitro, the deletion of genes encoding PRRs other than RIG-I does not worsen survival during IAV infection in vivo.…”