A long-distance relationship: the commensal gut microbiota and systemic viruses

Abstract

Recent advances defining the role of the commensal gut microbiota in the development, education, induction, function, and maintenance of the mammalian immune system inform our understanding of how immune responses govern the outcome of systemic virus infection. While characterization of the impact of the local oral, respiratory, dermal and genitourinary microbiota on host immune responses and systemic virus infection is in its infancy, the gut microbiota interacts with host immunity systemically and at distal non-gastrointestinal tract sites to modulate the pathogenesis of systemic viruses. Gut microbes, microbe-associated molecular patterns, and microbe-derived metabolites engage receptors expressed on the cell surface, in the endosome, or in the cytoplasm to orchestrate optimal innate and adaptive immune responses important for controlling systemic virus infection.

Figure 1. Receptor-mediated signaling pathways that modulate host immune responses during virus infection.

The interaction of microbe-associated molecular patterns and microbe-derived metabolites with host receptors such as pathogen-recognition receptors alters the type I interferon and/or pro-inflammatory cytokine response following viral infection. IFNAR, interferon-α/β receptor; Jak, Janus Kinase; STAT, Signal transducer and activator of transcription ;IRF, IFN-regulatory factor; poly (I:C), polyinosinic:polycytidylic acid; CpG ODN, CPG oligodeoxynucleotide; IAV, Influenza Virus; LCMV, Lymphocytic choriomeningitis virus; TLR, Toll-Like Recptor; TRIF, TIR-domain-containing adaptor protein inducing IFNβ; MyD88, myeloid differentiation primary-response gene 88; IFN, interferon; MCMV, Murine Cytomegalovirus; LPS, lipopolysaccharide; PG, peptidoglycan; HBV, Hepatitis B Virus; TRAF, TNF receptor-associated factor; IRAK1, Interleukin-1 receptor-associated kinase 1; TBK1, TANK-binding kinase 1; IKKβ, inhibitor of nuclear factor kappa-B kinase subunit beta; TAK1, TGF-β-activated Kinase 1; TRADD, Tumor necrosis factor receptor type 1-associated DEATH domain; NFκB, Nuclear Factor Kappa Beta; MDA5, melanoma-differentiation-associated gene 5; MAVS, mitochondrial antiviral signaling; RIG-I, retinoic-acid-inducible gene; NOD, nucleotide-binding oligomerization domain; RICK, receptor-interacting serine/threonine kinase; IPAF, ICE-protease-activating factor; ASC, apoptosis-associated speck-like protein containing a CARD (caspase-recruitment domain; SYK, spleen tyrosine kinase; NLRP, NOD-like receptor protein; MDP, muramyl dipeptide; IL, interleukin; TNF, tumor necrosis factor; DAT, desaminotyrosine; Tyk2, tyrosine kinase.