title: FimH adhesin of type 1 fimbriae is a potent inducer of innate antimicrobial responses which requires TLR4 and type 1 interferon signalling.
abstract: Components of bacteria have been shown to induce innate antiviral immunity via Toll-like receptors (TLRs). We have recently shown that FimH, the adhesin portion of type 1 fimbria, can induce the innate immune system via TLR4. Here we report that FimH induces potent in vitro and in vivo innate antimicrobial responses. FimH induced an innate antiviral state in murine macrophage and primary MEFs which was correlated with IFN-beta production. Moreover, FimH induced the innate antiviral responses in cells from wild type, but not from MyD88(-/-), Trif(-/-), IFN-alpha/betaR(-/-) or IRF3(-/-) mice. Vaginal delivery of FimH, but not LPS, completely protected wild type, but not MyD88(-/-), IFN-alpha/betaR(-/-), IRF3(-/-) or TLR4(-/-) mice from subsequent genital HSV-2 challenge. The FimH-induced innate antiviral immunity correlated with the production of IFN-beta, but not IFN-alpha or IFN-gamma. To examine whether FimH plays a role in innate immune induction in the context of a natural infection, the innate immune responses to wild type uropathogenic E. coli (UPEC) and a FimH null mutant were examined in the urinary tract of C57Bl/6 (B6) mice and TLR4-deficient mice. While UPEC expressing FimH induced a robust polymorphonuclear response in B6, but not TLR4(-/-) mice, mutant bacteria lacking FimH did not. In addition, the presence of TLR4 was essential for innate control of and protection against UPEC. Our results demonstrate that FimH is a potent inducer of innate antimicrobial responses and signals differently, from that of LPS, via TLR4 at mucosal surfaces. Our studies suggest that FimH can potentially be used as an innate microbicide against mucosal pathogens.
authors.affiliation: Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Ashkar
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mossman
authors.forename: Brian K
authors.initials: BK
authors.lastname: Coombes
authors.forename: Carlton L
authors.initials: CL
authors.lastname: Gyles
authors.forename: Randy
authors.initials: R
authors.lastname: Mackenzie
mesh_terms: D018830:Adhesins, Escherichia coli / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D004926:Escherichia coli / Q000254:growth & development / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000276:immunology / Q000382:microbiology; D005260:Female; D036781:Fimbriae Proteins / Q000276:immunology* / Q000378:metabolism; D006558:Herpes Genitalis / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018258:Herpesvirus 2, Human / Q000276:immunology / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000821:virology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*; D001745:Urinary Bladder Diseases / Q000276:immunology / Q000382:microbiology; D014552:Urinary Tract Infections / Q000276:immunology / Q000382:microbiology; D014621:Vagina / Q000473:pathology
chemical_list: D018830:Adhesins, Escherichia coli; D007370:Interferon Type I; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C092426:PapG protein, E coli; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C058769:fimH protein, E coli; D036781:Fimbriae Proteins