Innate immune recognition of the microbiota promotes host-microbial symbiosis

Abstract

Pattern-recognition receptors (PRRs) are traditionally known to sense microbial molecules during infection to initiate inflammatory responses. However, ligands for PRRs are not exclusive to pathogens and are abundantly produced by the resident microbiota during normal colonization. Mechanism(s) that underlie this paradox have remained unclear. Recent studies reveal that gut bacterial ligands from the microbiota signal through PRRs to promote development of host tissue and the immune system, and protection from disease. Evidence from both invertebrate and vertebrate models reveals that innate immune receptors are required to promote long-term colonization by the microbiota. This emerging perspective challenges current models in immunology and suggests that PRRs may have evolved, in part, to mediate the bidirectional cross-talk between microbial symbionts and their hosts.

Figures

Figure 1. PRRs in invertebrate systems

(a) Macroscopic view of Drosophilia and the midgut. (b)| PGRP-LC expression on the cell surface senses DAP-PGN (from Gram-negative bacteria), triggering the Imd pathway and the production of additional PGRPs, AMPs, Caudal and Pirk ( negative regulators of the Imd pathway). The amidase PGRP-LB, induced upon Imd activation, cleaves microbiota-derived PGN, blocking additional activation of the Imd pathway. (c) | Macroscopic view of the Hydra body plan consisting of two layers of epithelial cells, with the outermost layer exposed to bacterial symbionts. (d) | PRR signaling in Hydra is mediated by the HyLRR-2-HyTRR-1 complex, where HyLRR-2 serves as the receptor and HyTRR-1 serves as the transmembrane domain. Upon MAMP stimulation, MyD88 is recruited, triggering the production of AMPs such as periculin-1. Maternal expression of periculin-1 is responsible for shaping bacterial colonization in embryos, and re-establishing bacterial homeostasis in adults. (e) | Macroscopic view of the bobtail squid (E. scolopes) and the maturation of the light organ, induced upon colonization with V. fisheri. (f) | E. scolopes expresses four PGRPs. EsPGRP-3 and -4 function as cell surface receptors that recognize MAMPs, resulting in signaling activation. EsPGRP-2 is secreted by epithelial cells and crypts of the light organ, and detoxifies PGN via amidase activity to dampen immune responses. Loss of EsPGRP-1 upon colonization by V. fisheri results in apoptosis and loss of appendages, marking the maturation of the light organ.

Figure 2. | PRRs in vertebrate systems

(a)| Macroscopic view of zebrafish and its intestinal tract. (b)| LPS stimulation of TLR4 in zebrafish results in MyD88 recruitment and triggers the production of intestinal alkaline phosphatase (IAP) in epithelial cells. Induction of IAP is critical in maintaining gut homeostasis through dephosphorylation of microbiota-derived LPS. (c)| Macroscopic view of mouse and its gastrointestinal tract. (d)| Under steady-state conditions, TLR and NOD1/2 signaling by microbiota-derived MAMPs results in the recruitment of MyD88 and production of AMPs (such as PGRPs, RegIIIγ and defensins) and other mediators of intestinal homeostasis. (e)| Under inflammatory conditions, pathogen-derived MAMPs trigger various TLRs, NLRs and RLRs. Invasive microbes, as well as non-invasive pathogens possessing a secretion system, are able to stimulate cytosolic and endosomal PRRs. This infectious process results in a pro-inflammatory response, leading to pathogen clearance.

Figure 3. | PRR signaling promotes immune homeostasis

(a)| The small intestine and colon are comprised of a single layer of intestinal epithelial cells separating the abundant microbiota from host tissues. A complex mucus layer coats the epithelium, protecting the gastrointestinal tract from potential invasion. Additional protective mechanisms are present to maintain intestinal homeostasis, many of which are controlled by PRR signaling by commensal microbes. In the small intestine, AMPs such as PGRPs, RegIIIγ and defensins are induced upon PRR stimulation by commensals. In the colon, commensal microbes B. fragilis and B. breve signal through TLR2 to induce Treg cells. The MAMP polysaccharide A (PSA), expressed by B. fragilis, drives the development of IL-10-producing Foxp3+ Treg cells via TLR2. B. breve, however, induces IL-10-producing Foxp3- TR1 cells via CD103+ DCs in a TLR2 dependent manner. Additionally, B cell intrinsic MyD88 signaling promotes IgM secretion. The secretion of IgM is important in controlling systemic spread of bacteria after intestinal injury. (b)| Peptidoglycan derived from the gut microbiota is necessary to prime neutrophils in bone marrow stores in a Nod1-dependent manner. (c)| MyD88 signaling in B cells suppresses serum IgE and inhibits the differentiation of basophils in systemic sites. (d)| Commensal gut microbiota induces the production of pro-IL-1β and pro-IL-18 during steady state (signal 1). During an influenza infection in the lungs, caspase-1 mediated activation of IL-1β and IL-18 (signal 2) is critical for clearance of influenza.