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Respiratory viruses and the inflammasome: The double-edged sword of inflammation - PLOS Pathogens

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  • Respiratory viruses and the inflammasome: The double-edged sword of inflammation - PLOS Pathogens

    Published: December 29, 2022

    Inflammasomes,Respiratory infections,Immune receptor signaling,Influenza A virus,Respiratory physiology,Cytokines,Immune response,Inflammation


    Kody A. Waldstein, Steven M. Varga

    Alveolar macrophage sensing of viral infection


    Individuals actively infected with respiratory viruses, such as influenza A virus (IAV), respiratory syncytial virus (RSV), and coronaviruses, transmit by shedding droplets containing live virus while coughing, sneezing, or talking. Respiratory viruses subsequently enter the airways of a host either by coming in direct contact with aerosolized droplets or by an interaction with fomites [1]. The majority of respiratory virus infections are contained to the upper airways and self-limiting; however, lower respiratory tract infections (LRTIs) are a significant cause of morbidity and mortality, especially in children and the elderly [2,3]. When infiltration into the lower airways occurs, infectious viral particles encounter lung resident alveolar macrophages (AMϕ). AMϕ are self-renewing fetal-derived sentinel cells present in the airways that are tethered to the lung epithelium through αvβ6 integrin-latent TGF-β binding [4,5]. Upon direct interaction with viral particles, pro-inflammatory cytokines, or pattern/danger-associated molecular patterns (PAMPs/DAMPs), AMϕ detach from the respiratory epithelium resulting in the induction of increased effector functions and phagocytosis as well as the up-regulation of type I interferons (IFN), chemokines, and pro-inflammatory cytokines [68].

    AMϕ express a myriad of pattern recognition receptors, including multiple toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) that sense viral genetic material and proteins driving NF-κB activation, type I IFN production, and the release of pro-inflammatory cytokines [9]. Early during infection, virus utilization of TLRs as attachment receptors, such as TLR4, as well as other molecules with signaling capacity have been shown to drive innate activation [10]. Intracellular sensors responding to the viral genome including MDA5/RIG-I and TLRs 3, 7, and 8, also mediate activation signals [11]. This early “danger alarm” response by AMϕ is critical to the initiation of the innate immune response within the lung resulting in increased neutrophil and mononuclear cell infiltration and the induction of the antiviral IFN response pathways [68]. In vivo depletion of AMϕ resulted in significantly increased disease and mortality in IAV-infected mice [7]. AMϕ activation and pro-inflammatory cytokine production played a critical role in the activation of the immune system and RSV infection. Clodronate liposome depletion of AMϕ prior to infection significantly reduced RSV-induced TNF, IL-6, IFNα, and chemokine production in the lung [8]. AMϕ-depleted mice also exhibited significantly increased RSV-induced airway hyperreactivity as compared to controls [12]. Interestingly, AMϕ significantly contributed to the induction of severe disease and immunopathology following human metapneumovirus (hMPV) infection. AMϕ depletion ameliorated hMPV-induced disease and reduced lung inflammation suggesting excess pro-inflammatory responses contribute to disease [12]. Additionally, AMϕ are essential to the resolution of inflammation and return to a homeostatic state without which severe immunopathology and lung damage can occur [13]. This highlights the multifaceted ability of AMϕ to protect the respiratory epithelium and initiate the innate immune response while also playing an essential role in tissue damage control. ...

    Inflammasomes,Respiratory infections,Immune receptor signaling,Influenza A virus,Respiratory physiology,Cytokines,Immune response,Inflammation



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