title: Role of MyD88 in adenovirus keratitis.
abstract: Pattern recognition receptors (PRRs) are critical to the early detection and innate immune responses to pathogens. In particular, the toll-like receptor (TLR) system and its associated adaptor proteins have essential roles in early host responses to infection. Epidemic keratoconjunctivitis, caused by the human adenovirus, is a severe ocular surface infection associated with corneal inflammation (stromal keratitis). We previously showed that adenovirus capsid was a key molecular pattern in adenovirus keratitis, with viral DNA having a lesser role. We have now investigated the role of the adaptor molecule MyD88 in a mouse model of adenovirus keratitis in which there is no viral replication. In MyD88-/-mice infected with human adenovirus type 37, clinical keratitis was markedly reduced, along with infiltration of CD45+cells, and expression of inflammatory cytokines. Reduction of inflammatory cytokines was also observed in infected primary human corneal fibroblasts pretreated with a MyD88 inhibitory peptide. Keratitis similar to wild type mice was observed in TLR2, TLR9 and IL-1R knockout mice, but was reduced in TLR2/9 double knockout mice, consistent with synergy of TLR2 and TLR9 in the response to adenovirus infection. MyD88 co-immunoprecipitated with Src kinase in mice corneas and in human corneal fibroblasts infected with adenovirus, and MyD88 inhibitory peptide reduced Src phosphorylation, linking MyD88 activation to inflammatory gene expression through a signaling cascade previously shown to be directed by Src. Our findings reveal a critical role for the PRRs TLR2 and 9, and their adaptor protein MyD88, in corneal inflammation upon adenovirus infection.
authors.affiliation: Howe Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Howe Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: Mirja
authors.initials: M
authors.lastname: Ramke
authors.affiliation: Howe Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: Ashish V
authors.initials: AV
authors.lastname: Chintakuntlawar
authors.affiliation: Howe Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: Jeong Yoon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Howe Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: Jaya
authors.initials: J
authors.lastname: Rajaiya
authors.affiliation: Howe Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Chodosh
mesh_terms: D000072283:A549 Cells; D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000257:Adenoviridae Infections / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D000818:Animals; D003315:Cornea / Q000473:pathology / Q000821:virology; D005260:Female; D006801:Humans; D007634:Keratitis / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D053586:Virus Internalization; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D019061:src-Family Kinases