title: Impact of Microbiota on Resistance to Ocular Pseudomonas aeruginosa-Induced Keratitis.
abstract: The existence of the ocular microbiota has been reported but functional analyses to evaluate its significance in regulating ocular immunity are currently lacking. We compared the relative contribution of eye and gut commensals in regulating the ocular susceptibility to Pseudomonas aeruginosa-induced keratitis. We find that in health, the presence of microbiota strengthened the ocular innate immune barrier by significantly increasing the concentrations of immune effectors in the tear film, including secretory IgA and complement proteins. Consistent with this view, Swiss Webster (SW) mice that are typically resistant to P. aeruginosa-induced keratitis become susceptible due to the lack of microbiota. This was exemplified by increased corneal bacterial burden and elevated pathology of the germ free (GF) mice when compared to the conventionally maintained SW mice. The protective immunity was found to be dependent on both eye and gut microbiota with the eye microbiota having a moderate, but significant impact on the resistance to infection. These events were IL-1ß-dependent as corneal IL-1ß levels were decreased in the infected GF and antibiotic-treated mice when compared to the SPF controls, and neutralization of IL-1ß increased the ocular bacterial burden in the SPF mice. Monocolonizing GF mice with Coagulase Negative Staphylococcus sp. isolated from the conjunctival swabs was sufficient to restore resistance to infection. Cumulatively, these data underline a previously unappreciated role for microbiota in regulating susceptibility to ocular keratitis. We predict that these results will have significant implications for contact lens wearers, where alterations in the ocular commensal communities may render the ocular surface vulnerable to infections.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Abirami
authors.initials: A
authors.lastname: Kugadas
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Stig Hill
authors.initials: SH
authors.lastname: Christiansen
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Saiprasad
authors.identifier: http://orcid.org/0000-0002-5035-9041
authors.initials: S
authors.lastname: Sankaranarayanan
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Neeraj K
authors.identifier: http://orcid.org/0000-0002-9544-2551
authors.initials: NK
authors.lastname: Surana
authors.affiliation: Department of Pediatrics and Anesthesia, UMass Memorial Children's Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Stefanie
authors.identifier: http://orcid.org/0000-0003-4825-5371
authors.initials: S
authors.lastname: Gauguet
authors.affiliation: Thermo Fisher Scientific Center for Multiplexed Proteomics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Kunz
authors.affiliation: Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Raina
authors.initials: R
authors.lastname: Fichorova
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0002-4140-6563
authors.initials: T
authors.lastname: Vorup-Jensen
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Gadjeva