Control of antiviral immunity by pattern recognition and the microbiome

Abstract

Human skin and mucosal surfaces are in constant contact with resident and invasive microbes. Recognition of microbial products by receptors of the innate immune system triggers rapid innate defense and transduces signals necessary for initiating and maintaining the adaptive immune responses. Microbial sensing by innate pattern-recognition receptors is not restricted to pathogens. Rather, proper development, function, and maintenance of innate and adaptive immunity rely on continuous recognition of products derived from the microorganisms indigenous to the internal and external surfaces of mammalian host. Tonic immune activation by the resident microbiota governs host susceptibility to intestinal and extra-intestinal infections, including those caused by viruses. This review highlights recent developments in innate viral recognition leading to adaptive immunity, and discusses potential links between viruses, microbiota, and the host immune system. Furthermore, we discuss the possible roles of microbiome in chronic viral infection and pathogenesis of autoimmune disease and speculate on the benefit for probiotic therapies against such diseases.

Figure 1. Proposed mechanism by which the gut microbiota support respiratory immunity against influenza virus infection

Caspase-1-mediated inflammasome activation and IL-1β released from hematopoietic cells is required for protective adaptive immune defense against influenza virus infection (56). We speculate that the microbiota enable the host to respond optimally to influenza infection (115) through the following mechanism. (i) A selective population of gut-resident microbiota releases low levels of microbial ligands into systemic circulation. (ii) In the respiratory tract, commensal bacteria-derived microbial products induce transcriptional and translational activation of pro-IL-1β, pro-IL-18 and NLRP3 (signal 1) at steady state. (iii) In influenza-infected cells, virus-inflicted damage including ionic perturbation caused by the viral M2 proton channel expressed in the acidic trans-Golgi network provides signal 2 needed for the formation of NLRP3 inflammasome and the activation of caspase-1 (35). (iv) Active caspase-1 proteolytically cleaves the pro-IL-1β and pro-IL-18 into their mature forms for release into the extracellular space following influenza virus infection. (v) inflammasome-dependent cytokine released in the lung in turn modulate the ability of dendritic cells to upregulate the expression of costimulatory molecules and migrate to the draining lymph node where they present the processed viral antigens to activate naïve antigen-specific T cells.