Eyeworld

EW CORNEA 120 October 2017 by Liz Hillman EyeWorld Staff Writer with various conditions such as dry eye, various types of conjunctival inflammations, and contact lens wearers. We can now say with a lot more confidence that at least some of the bacteria found in the eye may actually live there, for better or worse," Dr. Caspi said. Questions that remain, accord- ing to Dr. Caspi, include: What makes C. mast an effective commen- sal, while other related bacteria do not colonize in a similar fashion or induce a level of immunity? What is it about C. mast that makes it stimu- late a gamma delta T cell response? What microorganisms stimulate other types of T cells (αβ) in the conjunctiva that do not respond to C. mast? "These questions will require ad- ditional studies," Dr. Caspi said. For now, the study's lead author, Anthony St. Leger, PhD, research fellow, Laboratory of Immunology, NEI, said the research has estab- lished a proof of concept of a central ocular microbiome. "It is well known that there are good bacteria in the gut that modu- late the immune response. Now we show that this relationship exists in the eye. That's important for how we think about treating ocular disease," he said in a press release statement. EW Reference 1. St Leger AJ, et al. An ocular commensal protects against corneal infection by driving an interleukin-17 response from mucosal γδ T cells. Immunity. 2017;47:148–58. Editors' note: Dr. Caspi has no finan- cial interests related to her comments. Contact information Caspi: caspir@nei.nih.gov immune responses, primarily made by mucosal gamma delta T cells— induced neutrophil recruitment and release of antimicrobials into the tears, both of which contribute to the host defense at the ocular surface. The investigators exposed mice with and without C. mast to the fungus Candida albicans, finding that the mice without C. mast developed fungal infections, while those with C. mast did not. This confirmed that C. mast was contributing to the im- mune response, but just how C. mast stimulates the immune response without being annihilated itself is still unknown. Triggering an immune response is not the "purpose" of a commensal relationship, rather, it is a necessary outcome, Dr. Caspi explained. "By eliciting this level of immu- nity, the host keeps the commensal in check and does not allow it to overgrow, and derives the benefit of having protection from other, potentially more dangerous mi- crobes taking hold," Dr. Caspi said. "There are many examples of beneficial bacteria on other mucosal surfaces (gut, skin, genital tract), keeping the bad ones away by mech- anisms that are only now beginning to be understood and are collectively called 'colonization resistance.' This can happen not only by triggering local immunity, but also compe- tition for nutrients, secretion of substances that are inhibitory or toxic to other types of bacteria, and possibly other methods that we have yet to discover." When it comes to translating this research to humans, Dr. Caspi said many researchers have suggest- ed the human eye has a "microbi- ome," but there is a lack of proof. "Healthy volunteers are being studied and compared to patients surface of the eye is not by itself proof that the 'owners' of that DNA are alive and survive on the eye for the long term. The eye is exposed to the atmosphere and is bombarded by airborne bacteria, and we rub our eyes with our (bacteria-laden) fingers many times a day. The ocular surface is very good at eliminating these microbes, so even if someone grows a bacterium or two from the surface of the eye, it could have been on its way to a better world 5 minutes later." With previous research linking topical antibiotic use to increases in fungal infections, Dr. Caspi and her team concluded that antibiotics may be disrupting the ocular immune response, so they set out to identify a microbe that could be causing a reaction with the immune system. Initially, researchers cultured C. mast from conjunctival homoge- nates of mice who had the bacteria. From this, they were able to show that C. mast can be passed from dam to pup; however, C. mast was not transferred between adult mice liv- ing in the same cage. Serendipitous- ly, mice purchased from commercial vendors did not have detectable C. mast, so researchers were able to inoculate eyes of vendor mice and definitively link C. mast to its associ- ated immune response. "We were lucky that mice pur- chased from commercial vendors lacked the bacterium that we cul- tured from eyes of our mice and that it could not be casually acquired from the environment (no transfer to cage mates that lacked it) but had to be acquired from the mother. This allowed us to conclude that if the bacteria, which we purposely inoculated into the eyes of adult vendor 'clean' mice, were still there many weeks after the inoculation, they actually 'set up shop,' prolifer- ate, and live on the ocular surface for the long term," Dr. Caspi said. In the study, researchers inoculated mice with other bacterium types as well that have been identified on the eye, but did not observe them in detectable levels over time nor did they see a similar immune response to that elicited by C. mast. Further research established that interleukin-17—a protein that stim- ulates antifungal and antibacterial Study provides first evidence of a bacterium taking up long-term residence on ocular surface F or the first time research is showing that a bacteri- um has learned to live on the ocular surface of mice, providing a commensal re- lationship that helps ward off other infections. According to the research led by investigators from the National Eye Institute (NEI), Corynebacterium mastitidis (C. mast), a commensal bacterium also found in humans, has shown its ability to colonize the ocular surface and stimulate the mouse immune system by eliciting interleukin-17 production from mu- cosal gamma delta T cells. This, the researchers wrote, triggers the release of antimicrobials into tears that pro- tect the eye from other pathogens. 1 The study, Rachel Caspi, PhD, head of the Immunoregulation Section, chief of the Laboratory of Immunology, NEI, said, provides "a strong argument against indiscrim- inate use of antibiotics for conjunc- tivitis, as this may bring more harm than good." "When justified, antibiotics should be used for the shortest peri- od possible," Dr. Caspi said. "Also, in the future, probiotic therapies could be developed for the eye to make less the use of antibiotics. Probiotics are already being used for intestinal conditions. For the eye, perhaps we would not want them necessar- ily based on live bacteria, but on bacterial extracts or defined bacterial components, to stimulate natural immunity on the ocular surface and promote the body's own defenses to reduce the need for antibiotics." Other mucosal tissues are known to have a commensal mi- crobiome, but prior to this research, whether the ocular surface had such a relationship with microbes was questionable. "Many scientists were skeptical that bacteria can survive on the oc- ular surface, whereas others thought there is a microbiome because bacterial DNA can be detected," Dr. Caspi explained. "The problem is that finding bacterial DNA on the Ocular commensal identified in mice, found to help protect against infections Research highlight " Many scientists were skeptical that bacteria can survive on the ocular surface. " —Rachel Caspi, PhD

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