Microbiota-Driven Immune Cellular Maturation Is Essential for Antibody-Mediated Adaptive Immunity to Staphylococcus aureus Infection in the Eye

Abstract

bAs an immune-privileged site, the eye, and particularly the outer corneal surface, lacks resident mature immune effector cells. Physical barriers and innate mediators are the best-described effectors of immunity in the cornea. When the barriers are breached, infection can result in rapid tissue destruction, leading to loss of visual acuity and frank blindness. To determine the cellular and molecular components needed for effective adaptive immunity on the corneal surface, we investigated which immune system effectors were required for protection against Staphylococcus aureus corneal infections in mice, which are a serious cause of human eye infections. Both systemically injected and topically applied antibodies to the conserved cell surface polysaccharide poly-N-acetylglucosamine (PNAG) were effective at mediating reductions in corneal pathology and bacterial levels. Additional host factors impacting protection included intercellular adhesion molecule 1 (ICAM-1)-dependent polymorphonuclear leukocyte (PMN) recruitment, functional CD4 ؉ T cells, signaling via the interleukin-17 (IL-17) receptor, and IL-22 production. In germfree mice, there was no protective efficacy of antibody to PNAG due to the lack of LY6G ؉ inflammatory cell coeffector recruitment to the cornea. Protection was manifest after 3 weeks of exposure to conventional mice and acquisition of a resident microbiota. We conclude that in the anterior eye, ICAM-1-mediated PMN recruitment to the infected cornea along with endogenous microbiota-matured CD4 ؉ T cells producing both IL-17 and IL-22 is required for antibody to PNAG to protect against S. aureus infection.

Efficacy of Antibody to PNAG Against Keratitis Caused by Fungal Pathogens

“…aureus infections, also have shown a role for cellular effectors including T cells, IL-17, and IL-22. 28–31 Prior studies from Taylor et al 6,7 demonstrated an important role for IL-17–producing neutrophils in host immune responses to fungal keratitis. In settings where either T-cells (RAG-1 KO mice), IL-17 activity (IL-17R KO mice), or IL-22 activity (IL-22 KO mice) was not operative, we found the MAb F598 showed no significant therapeutic efficacy.…”

Impact of Microbiome on Ocular Health

“…Consistently, there was a dependence on IL-17 and IL-22 in the antibody-induced protection. 55 This paper prompted many important questions. Namely, what is the impact of microbiota on neutrophil maturation and activation and where does neutrophil priming occur?…”

“…Analysis of the mechanisms of protection mediated by Staphylococcus aureus -specific monoclonal antibody during keratitis revealed that the germ-free mice treated with the therapeutic antibody failed to mount a protective immunity against this pathogen, due to failure to recruit inflammatory cells to the site of infection. 55 The lack of protective efficacy of the monoclonal antibody in infected RAG mice or CD4 + cell–depleted mice suggested stipulation of T cell functions. Consistently, there was a dependence on IL-17 and IL-22 in the antibody-induced protection.…”

An Ocular Commensal Protects against Corneal Infection by Driving an Interleukin-17 Response from Mucosal γδ T Cells

“…Current experimental limitations are unable to resolve whether these bacteria are resident (long-term colonizers as opposed to transient, originating from the environment), metabolically active, or even alive. Although there is evidence that bacteria at the ocular surface may affect disease (de Paiva et al, 2016; Kugadas et al, 2016; Zaidi et al, 2014), this does not speak to their status as ocular surface commensals, or how they interact with the immune system to be functionally relevant to local immunity. Rather, these studies conclude that gut microbes might play a major role in disease outcome.…”