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Reversing Cigarette Smoke-Induced Antiviral Immunosuppression

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The long-term goal of our work is to understand how the human innate immune system responds to Influenza A virus (IAV) infection and to find novel methods to control the infection. Cigarette smoking is a significant public health problem, particularly among veterans. Exposure to cigarette smoke (CS) significantly increases the risk for respiratory viral infections. Influenza infection is seven times more common and is much more severe in smokers than nonsmokers. The goal of our proposed studies is to determine the severity and mechanisms of CS-mediated innate immune suppression. Induction of interferon (IFN) is a critical component of the host response to influenza infection. IFNs are further divided into type I (mainly IFN-? and ?), II (IFN-?) and III (IFN-?) subtypes, based in part on the differential use of unique receptors through which they mediate signal transduction to induce antiviral activity. Retinoic acid-inducible protein I (RIG-I) plays an important role in the recognition of, and IFN induction by, IAV. Our previous studies have shown that CS and cigarette smoke extract (CSE) suppress antiviral innate immune responses in IAV-infected human and mouse lung, especially immunosuppression due to RIG-I inhibition. This immunosuppressive effect of CS may play a critical role in the enhanced susceptibility of smokers to serious influenza infection. We have also shown that reversing the RIG-I defect prevents CS induced immunosuppression, restores all three types of IFN responses, and reduces mortality. We have also discovered a new mechanism whereby IAV and CS decreases barrier function and increases lung injury during infection through induction of cytochrome P450 family 1 subfamily B member 1 (CYP1B1). We have new preliminary data that demonstrates this effect, and that RIG-I activation appears to suppress CYP1B1 induction, and that partial loss of CYP1B1 decreases lung injury during infection. These novel findings support the idea that understanding the mechanisms of CS-induced immunosuppression may have significant therapeutic potential. Our overall hypothesis is that CS increases lung injury by suppressing RIG-I and upregulating CYP1B1. We further hypothesize that RIG-I overexpression or chemical RIG-I activation using SLR10 suppresses CYP1B1, decreases lung injury and mortality during IAV infection. We will use an in vitro human model and an in vivo mouse model to test these concepts to evaluate the role of CYP1B1-mediated lung injury and RIG-I- mediated immune restoration in smokers during IAV infection. We will test these hypotheses using the following integrated Specific Aims: AIM 1: Determine whether chemical activation of RIG-I alleviates CS-induced mortality and immunosuppression during IAV infection. AIM 2: Determine whether CYP1B1 induction by CS enhances lung injury and mortality during IAV infection. This proposal is conceptually innovative, as it addresses unanswered questions regarding whether specific stimulation of RIG-I has potential benefits in human and mouse CS models during IAV infection, and whether CS and IAV increase lung injury through induction of CYP1B1. We have extensive evidence that combustible cigarette smoking impairs antiviral responses and increases lung injury in human and mouse models. The experimental team combines experience in immunology, animal models, genetic manipulation of cell models, and bioinformatics. Our team is uniquely positioned to combine our basic and clinical research expertise and experience to determine basic mechanisms and clinical consequences of CS-mediated immunosuppression and enhanced lung injury to identify targets for new therapeutics.
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