Immune impact of commensals versus pathobionts

Abstract

Pathobiont but not commensal cutaneous colonization elicits an inflammatory response that prevents neonatal induction of microbial tolerance in the skin. Pathobiont but not commensal cutaneous colonization elicits an inflammatory response that prevents neonatal induction of microbial tolerance in the skin. CITATION Leech JM, Dhariwala MO, Lowe MM, et al. Toxin-triggered interleukin-1 receptor signaling enables early-life discrimination of pathogenic versus commensal skin bacteria. Cell Host Microbe. 2019;26:795–809. How the body maintains tolerance to commensals but not to microbes with pathogenic potential (pathobionts) such that appropriate immune responses can be mounted to the pathogens in case of barrier breach without triggering chronic inflammation to the commensals remains to be determined. Leech et al. demonstrate that neonatal skin colonization with the commensal Staphylococcus epidermidis (S. epi) induces a greater regulatory T cell (Treg) response than colonization with the pathobiont Staphylococcus aureus. The higher effector-to-Treg ratio triggered by S. aureus is due to S. aureus’ virulence factor α-toxin–dependent induction of the inflammatory cytokine IL-1β. Tregs are found in high abundance at barrier sites. The authors had previously found a temporal window after birth in which cutaneous S. epi colonization of mouse pups could elicit Treg recruitment to skin hair follicles, an event necessary to establish tolerance to S. epi and prevent immune responses to S. epi rechallenge during skin abrasion in adulthood. To compare immune responses to S. epi and S. aureus, the authors engineered the bacteria to express the model antigen 2W fused to fluorescent mCherry protein and tracked 2W-specific T cell responses with 2W:I-Ab tetramers by flow cytometry. mCherry fluorescence demonstrated similar bacterial growth and persistence of the two strains. Neonatal skin colonization with S. epi but not S. aureus resulted in protection against inflammation and neutrophil accumulation following adult bacterial challenge and skin abrasion, and a reduced frequency of Tregs among 2W-reactive CD4+ T cells was observed in the skin-draining lymph node (sdLN) of S. aureus- versus S. epi-colonized mice. Differences were not due to distinct types of skin dendritic cells picking up S. aureus versus S. epi. To investigate whether a different quality in immune priming to S. aureus than S. epi was responsible for the lack of tolerance elicited by S. aureus, the authors performed RNAseq in bulk skin Tregs and T effectors of colonized mice. Both T effectors and Tregs following S. aureus colonization were enriched in genes associated with type 1 interleukin (IL) receptor signature, and elevated levels of IL-1β transcripts were found in S. aureus-colonized skin. Supporting the importance of this pathway, 2W-reactive Treg percentages and numbers were increased in the sdLN of S. aureus-colonized Il1r-/- mice. Conversely, cutaneous application of IL-1β at the time of S. epi colonization reduced the percentage of Tregs this colonization elicited, although whether this prevented induction of tolerance to S. epi was not reported. To explore potential S. aureus virulence factors responsible for inducing active IL-1β, the authors employed S. aureus strains lacking virulence factors. Lack of α-toxin correlated with reduced production of IL-1β by myeloid cells in vitro and increased Treg induction by S. aureus colonization, whereas α-toxin application reduced Treg induction by S. epi, although the impact on tolerance was not tested. Overall, virulence factors encoded by S. aureus may be responsible for activation of the inflammasome and consequent production of active IL-1β may limit Treg induction by S. aureus colonization, thus ensuring more robust immune responses to S. aureus during subsequent barrier breach. This may be one way by which the immune system distinguishes commensals from pathobionts. Colonized organs, such as lung and intestine, have a shorter half-life following transplantation than sterile organs, such as kidney and heart, suggesting the hypothesis that microbial colonization may influence graft damage. How the recipient of a colonized graft discriminates between host commensals, donor commensals brought in by the graft and pathogens that may colonize the donor organ or the recipient’s, depending on the underlying disease driving transplantation, remains to be determined. Whether donor Tregs present in the donor organ can protect the graft recipient from excessive inflammatory immune responses to donor commensals after transplantation might be important to understand. These types of studies may help explain correlations between the presence of specific microbial taxa and the progressive loss of graft function. Dr. Alegre is a professor in the Department of Medicine at the University of Chicago. She is also section editor of “Literature Watch.”