Microbiota regulation of viral infections through interferon signaling

Abstract

The interferon (IFN) response is the major early innate immune response against invading viral pathogens and is even capable of mediating sterilizing antiviral immunity without the support of the adaptive immune system. Cumulative evidence suggests that the gut microbiota can modulate IFN responses, indirectly determining virological outcomes. This review outlines our current knowledge of the interactions between the gut microbiota and IFN responses and dissects the different mechanisms by which the gut microbiota may alter IFN expression to diverse viral infections. This knowledge offers a basis for translating experimental evidence from animal studies into the human context and identifies avenues for leveraging the gut microbiota-IFN-virus axis to improve control of viral infections and performance of viral vaccines.

Keywords: antiviral immunity; bacterial metabolites; gut microbiota; interferon-α/β; interferon-λ; viral infection.

Key figure. Figure 1.. Potential mechanisms underlying microbiota regulation of interferon (IFN) antiviral immunity

(A) The gut microbiota regulates basal homeostatic IFN expression. The gut microbiota can induce homeostatic type I IFN expression (shown in blue) from macrophages and plasmacytoid dendritic cells (pDCs) and homeostatic type III IFN (shown in orange) from intestinal epithelial cells (left panel). Type I IFN from macrophages is required for the priming of natural killer (NK) cell and CD8⁺ T cell function [18] (left panel). Type I IFN from pDCs is required for epigenetic programming of conventional dendritic cells (cDCs) so that they can prime NK cells and CD8⁺ T cells [19] (middle panel). When the gut microbiota is depleted, signals from the gut microbiota are diminished, leading to the reduction of basal homeostatic type I [18,19] and type III IFN, and impaired priming and functionality of cDCs, NK cells, and CD8⁺ T cells (right panel) [37]. (B) Gut microbiota-derived pathogen recognition receptor (PRR) ligands activate IFN expression. Components of the commensal gut microbiota generate molecular patterns that can bind to PRRs. For instance, Bacillus spp. poly-γ-glutamic acid [44] and Bacteroides fragilis polysaccharide A (PSA) [9] bind to TLR4, while the nucleic acids of lactic acid bacteria (LAB) can bind to either TLR3 [45], RIG-I-like receptors (RLRs) or cGAS [47]. This pattern recognition results in downstream signaling and type I IFN production. Depending on the type of PRR ligands and the PRR sensors, type I IFN production has been shown to block viral replication. (C) Gut microbiota-derived metabolites activate IFN expression. Gut commensals, such as members of the family Lachnospiraceae, can produce short-chain fatty acids (SCFAs) that can activate type I IFN expression in a GPR43-dependent manner to block the replication of respiratory syncytial virus (RSV) [17]. Clostridium scindens can transform primary bile acids (BAs) into secondary BAs. These secondary BAs can activate both the expression of type I IFN from pDCs to inhibit chikungunya virus (CHIKV) replication [14] and type III IFN from intestinal epithelial cells (IECs) to inhibit murine norovirus (MNV) replication [13]. cGAS, cyclic GMP-AMP synthase; IRFs, interferon regulatory factors; MAVS, mitochondrial antiviral-signaling protein; MYD88, myeloid differentiation primary response 88; TRIF, Toll–IL-1 receptor domain-containing adaptor inducing IFN-β; STING, stimulator of interferon genes. See references [9,11,15,18,19,30,38,41,43]. The figure was created with BioRender.com.

Figure 2.. Future translation of microbiota–interferon(IFN)–viral interaction into the human context.

The triangular relationship between the gut microbiota–host IFN response–viral infections has been extensively described in animal models. However, the translation of these interactions into the human setting for therapeutic purposes remains a major challenge. Recent computational tools, such as the systems biology approach and experimental tools such as human organoid platforms, may aid further exploration of this interaction, paving the way to microbiota-based therapies in viral control and viral vaccination. The figure was created with BioRender.com.