The Role of the Microbiota in Shaping Infectious Immunity

Abstract

Humans are meta-organisms that maintain a diverse population of microorganisms on their barrier surfaces, collectively named the microbiota. Since most pathogens either cross or inhabit barrier surfaces, the microbiota plays a critical and often protective role during infections, both by modulating immune system responses and by mediating colonization resistance. However, the microbiota can also act as a reservoir for opportunistic microorganisms that can 'bloom', significantly complicating diseases of barrier surfaces by contributing to inflammatory immune responses. This review discusses our current understanding of the complex interactions between the host, its microbiota, and pathogenic organisms, focusing in particular on the intestinal mucosa.

Figure 1. Innate and Adaptive Immune Responses Against the Microbiota

A) Sensing of the microbiota by innate immune receptors engenders multiple mechanisms to foster the host/microbiota relationship and clear invasive organisms. LPS signaling induces the fucosylation on the surface of the intestine which supports the heathy microbiota and limits invasion by Proteobacteria such as Citrobacter. Microbial signals also induce IL-23 from dendritic cells and IL-1β from macrophages which, in turn activates IL-17A and IL-22 from ILCs and T cells, leading to the production of antimicrobial peptides (AMPs) that can kill intestinal bacteria. B) Dendritic cells carrying antigens from the microbiota traffic from the intestine to the mesenteric lymph nodes (MLN) where they predominantly drive the differentiation of regulatory T cells (T_regs) and Th17 T cells. Both T_regs and Th17 T cells are capable of inducing the differentiation and class switching of IgA producing plasma B cells which secrete large amounts of dimeric IgA (sIgA). IL-17 produced by Th17 cells also drives the production of the polymeric-Ig receptor (pIgR), allowing for greater secretion of IgA into the intestinal lumen. The microbiota directly shapes this interaction with metabolites such as short-chain fatty acids (SCFA), which drives the production of T_regs from migratory dendritic cells.

Figure 2. Shifts in the Host-Microbiota Relationship Induced by Infection

A) Infections, particularly those that cause translocation of the microbiota, can lead to the activation of inflammatory microbiota and pathogen-specific T cells. B) Infection-induced traffic of effector T cells, neutrophils (NΦ) and inflammatory monocytes (IM) can drive significant inflammation in the GI tract via the production of cytokines such as tumor necrosis factor (TNFα) and interferon-γ (IFN) -γ in addition to the secretion of nitrate and superoxide compounds into the intestinal lumen, driving shifts in the microbiota. C) Shifts in the microbiota, induced by infection lead to increased penetration of the host tissue and thereby further driving chronic inflammation and interfering with healing. D) Some infections, (Yersinia pseudotuberculosis) can induce immunological scarring that is compounded by chronic inflammation and dysbiosis, and reduces the fidelity of traffic through the lymphatics to the lymph node, leading to further inflammation in the adipose tissue.