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-β production. Moreover, FimH induced the innate antiviral responses in cells from wild type, but not from MyD88？/？, Trif？/？, IFN？α/βR？/？ or IRF3？/？ mice. Vaginal delivery of FimH, but not LPS, completely protected wild type, but not MyD88？/？, IFN-α/βR？/？, IRF3？/？ or TLR4？/？ mice from subsequent genital HSV-2 challenge. The FimH-induced innate antiviral immunity correlated with the production of IFN-β, but not IFN-α or IFN-γ. 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.
References
[1]
Biron CA (1998) Role of early cytokines, including alpha and beta interferons (IFN-alpha/beta), in innate and adaptive immune responses to viral infections. Semin Immunol 10: 383–390.
[2]
Biron CA (2001) Interferons alpha and beta as immune regulators–a new look. Immunity 14: 661–664.
[3]
Ashkar AA, Bauer S, Mitchell WJ, Vieira J, Rosenthal KL (2003) Local delivery of CpG oligodeoxynucleotides induces rapid changes in the genital mucosa and inhibits replication, but not entry, of herpes simplex virus type 2. J Virol 77: 8948–8956.
[4]
Duerst RJ, Morrison LA (2003) Innate immunity to herpes simplex virus type 2. Viral Immunol 16: 475–490.
[5]
Fawaz LM, Sharif-Askari E, Menezes J (1999) Up-regulation of NK cytotoxic activity via IL-15 induction by different viruses: a comparative study. J Immunol 163: 4473–4480.
[6]
Matsuo K, Yoshikawa T, Asanuma H, Iwasaki T, Hagiwara Y, et al. (2000) Induction of innate immunity by nasal influenza vaccine administered in combination with an adjuvant (cholera toxin). Vaccine 18: 2713–2722.
[7]
Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2: 675–680.
[8]
Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413: 732–738.
[9]
Medzhitov R, Janeway C Jr (2000) Innate immunity. N Engl J Med 343: 338–344.
[10]
Medzhitov R, Janeway CA Jr (1997) Innate immunity: the virtues of a nonclonal system of recognition. Cell 91: 295–298.
[11]
Janeway CA Jr, Medzhitov R (1998) Introduction: the role of innate immunity in the adaptive immune response. Semin Immunol 10: 349–350.
[12]
Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J, et al. (2002) Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med 8: 878–884.
[13]
Ashkar AA, Rosenthal KL (2002) Toll-like receptor 9, CpG DNA and innate immunity. Curr Mol Med 2: 545–556.
[14]
Chuang T, Ulevitch RJ (2001) Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochim Biophys Acta 1518: 157–161.
[15]
Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, et al. (2005) TLR11 Activation of Dendritic Cells by a Protozoan Profilin-Like Protein. Science.
[16]
Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, et al. (2004) A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303: 1522–1526.
[17]
Akira S, Hemmi H (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett 85: 85–95.
[18]
Akazawa T, Masuda H, Saeki Y, Matsumoto M, Takeda K, et al. (2004) Adjuvant-mediated tumor regression and tumor-specific cytotoxic response are impaired in MyD88-deficient mice. Cancer Res 64: 757–764.
[19]
Ashkar AA, Yao XD, Gill N, Sajic D, Patrick AJ, et al. (2004) Toll-like receptor (TLR)-3, but not TLR4, agonist protects against genital herpes infection in the absence of inflammation seen with CpG DNA. J Infect Dis 190: 1841–1849.
[20]
Harandi AM, Eriksson K, Holmgren J (2003) A protective role of locally administered immunostimulatory CpG oligodeoxynucleotide in a mouse model of genital herpes infection. J Virol 77: 953–962.
[21]
Pyles RB, Higgins D, Chalk C, Zalar A, Eiden J, et al. (2002) Use of immunostimulatory sequence-containing oligonucleotides as topical therapy for genital herpes simplex virus type 2 infection. J Virol 76: 11387–11396.
[22]
Sajic D, Ashkar AA, Patrick AJ, McCluskie MJ, Davis HL, et al. (2003) Parameters of CpG oligodeoxynucleotide-induced protection against intravaginal HSV-2 challenge. J Med Virol 71: 561–568.
[23]
Bellocchio S, Gaziano R, Bozza S, Rossi G, Montagnoli C, et al. (2005) Liposomal amphotericin B activates antifungal resistance with reduced toxicity by diverting Toll-like receptor signalling from TLR-2 to TLR-4. J Antimicrob Chemother 55: 214–222.
[24]
Shen H, Iwasaki A (2006) A crucial role for plasmacytoid dendritic cells in antiviral protection by CpG ODN-based vaginal microbicide. J Clin Invest 116: 2237–2243.
[25]
Wizemann TM, Adamou JE, Langermann S (1999) Adhesins as targets for vaccine development. Emerg Infect Dis 5: 395–403.
[26]
Connell I, Agace W, Klemm P, Schembri M, Marild S, et al. (1996) Type 1 fimbrial expression enhances Escherichia coli virulence for the urinary tract. Proc Natl Acad Sci U S A 93: 9827–9832.
[27]
Abraham SN, Goguen JD, Sun D, Klemm P, Beachey EH (1987) Identification of two ancillary subunits of Escherichia coli type 1 fimbriae by using antibodies against synthetic oligopeptides of fim gene products. J Bacteriol 169: 5530–5536.
[28]
Vandemaele F, Ververken C, Bleyen N, Geys J, D'Hulst C, et al. (2005) Immunization with the binding domain of FimH, the adhesin of type 1 fimbriae, does not protect chickens against avian pathogenic Escherichia coli. Avian Pathol 34: 264–272.
[29]
Meiland R, Geerlings SE, Langermann S, Brouwer EC, Coenjaerts FE, et al. (2004) Fimch antiserum inhibits the adherence of Escherichia coli to cells collected by voided urine specimens of diabetic women. J Urol 171: 1589–1593.
[30]
Hoepelman IM, Meiland R, Langermann S (2001) [Candidate vaccine against urinary tract infections]. Ned Tijdschr Geneeskd 145: 1860–1862.
[31]
Barnhart MM, Pinkner JS, Soto GE, Sauer FG, Langermann S, et al. (2000) PapD-like chaperones provide the missing information for folding of pilin proteins. Proc Natl Acad Sci U S A 97: 7709–7714.
[32]
Palaszynski S, Pinkner J, Leath S, Barren P, Auguste CG, et al. (1998) Systemic immunization with conserved pilus-associated adhesins protects against mucosal infections. Dev Biol Stand 92: 117–122.
[33]
Langermann S, Palaszynski S, Barnhart M, Auguste G, Pinkner JS, et al. (1997) Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Science 276: 607–611.
Sokurenko EV, Chesnokova V, Dykhuizen DE, Ofek I, Wu XR, et al. (1998) Pathogenic adaptation of Escherichia coli by natural variation of the FimH adhesin. Proc Natl Acad Sci U S A 95: 8922–8926.
[36]
Jones CH, Pinkner JS, Roth R, Heuser J, Nicholes AV, et al. (1995) FimH adhesin of type 1 pili is assembled into a fibrillar tip structure in the Enterobacteriaceae. Proc Natl Acad Sci U S A 92: 2081–2085.
[37]
Mossman KL, Mian MF, Lauzon NM, Gyles CL, Lichty B, Mackenzie R, Gill N, Ashkar AA (2008) FimH adhesin of type 1 fimbriae is a novel TLR4 ligand J Immunol 181: in press.
[38]
Dogan B, Klaessig S, Rishniw M, Almeida RA, Oliver SP, et al. (2006) Adherent and invasive Escherichia coli are associated with persistent bovine mastitis. Vet Microbiol 116: 270–282.
[39]
Kisiela D, Laskowska A, Sapeta A, Kuczkowski M, Wieliczko A, et al. (2006) Functional characterization of the FimH adhesin from Salmonella enterica serovar Enteritidis. Microbiology 152: 1337–1346.
[40]
Lindhorst TK, Kieburg C, Krallmann-Wenzel U (1998) Inhibition of the type 1 fimbriae-mediated adhesion of Escherichia coli to erythrocytes by multiantennary alpha-mannosyl clusters: the effect of multivalency. Glycoconj J 15: 605–613.
[41]
Kjaergaard K, Schembri MA, Klemm P (2001) Novel Zn(2+)-chelating peptides selected from a fimbria-displayed random peptide library. Appl Environ Microbiol 67: 5467–5473.
[42]
Liu Y, Dong W, Chen L, Xiang R, Xiao H, et al. (2004) BCL10 mediates lipopolysaccharide/toll-like receptor-4 signaling through interaction with Pellino2. J Biol Chem 279: 37436–37444.
[43]
Benencia F, Courreges MC (1999) Nitric oxide and macrophage antiviral extrinsic activity. Immunology 98: 363–370.
[44]
Benencia F, Gamba G, Cavalieri H, Courreges MC, Benedetti R, et al. (2003) Nitric oxide and HSV vaginal infection in BALB/c mice. Virology 309: 75–84.
[45]
Biron CA (1999) Initial and innate responses to viral infections–pattern setting in immunity or disease. Curr Opin Microbiol 2: 374–381.
[46]
Herbst MM, Pyles RB (2003) Immunostimulatory CpG treatment for genital HSV-2 infections. J Antimicrob Chemother 52: 887–889.
[47]
Gill N, Deacon PM, Lichty B, Mossman KL, Ashkar AA (2006) Induction of innate immunity against herpes simplex virus type 2 infection via local delivery of Toll-like receptor ligands correlates with beta interferon production. J Virol 80: 9943–9950.
[48]
Fischer H, Yamamoto M, Akira S, Beutler B, Svanborg C (2006) Mechanism of pathogen-specific TLR4 activation in the mucosa: fimbriae, recognition receptors and adaptor protein selection. Eur J Immunol 36: 267–277.
[49]
Docherty JJ, Lohse MA, Dellaria MF, Naugle FP, Mason CW, et al. (1984) Incidence of herpes simplex virus types 1 and 2 in penile lesions of college men. J Med Virol 13: 163–170.
[50]
Kariyawasam S, Wilkie BN, Gyles CL (2004) Resistance of broiler chickens to Escherichia coli respiratory tract infection induced by passively transferred egg-yolk antibodies. Vet Microbiol 98: 273–284.
