title: Factor H facilitates adherence of Neisseria gonorrhoeae to complement receptor 3 on eukaryotic cells.
abstract: Neisseria gonorrhoeae can engage human complement receptor 3 (CR3) directly or through surface-bound iC3b. Factor H (fH) that binds to bacteria facilitates conversion of C3b to iC3b. fH also binds directly to CR3 on professional phagocytes. Certain nonprofessional phagocytes, such as primary cervical epithelial cells, also express CR3. We hypothesized that fH could bridge bacteria to CR3 and facilitate gonococcal association with host cells. Specificity of the fH-CR3 interaction was confirmed using human CR3-transfected Chinese hamster ovary (CHO-CR3) cells. Using recombinant proteins that comprised contiguous fH domains (fH contains 20 short consensus repeat [SCR] domains) fused to murine Fc, we observed strong binding through SCRs 18-20, whereas weaker binding occurred through SCRs 6-10. Both regions also bound to unsialylated porin (Por) B.1A-expressing N. gonorrhoeae. Accordingly, fH-related protein 1 (three of its five SCRs are highly homologous to fH SCRs 18-20) bound to CHO-CR3 and to unsialylated PorB.1A gonococci. An alternatively spliced variant of fH called fH-like protein-1 (contains fH SCRs 1-7) bound to gonococci but minimally to CHO-CR3. An fH SCRs 6-20 construct enhanced binding of unsialylated PorB.1A gonococci to CHO-CR3. However, a construct that contained only the apparently relevant SCRs (6, 7, and 18-20) bound to CHO-CR3 and to gonococci separately, but did not enhance bacteria-CR3 interactions, suggesting that the intervening SCRs (8-17) may impart a configurational and spatial requirement for fH to bridge gonococci to CR3. These results indicate adherence between fH-coated gonococci and CR3 and may provide a means for gonococci to gain sanctuary into nonprofessional phagocytes.
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA. sarika.agarwal@umassmed.edu
authors.forename: Sarika
authors.initials: S
authors.lastname: Agarwal
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ram
authors.forename: Jutamas
authors.initials: J
authors.lastname: Ngampasutadol
authors.forename: Sunita
authors.initials: S
authors.lastname: Gulati
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.forename: Peter A
authors.initials: PA
authors.lastname: Rice
mesh_terms: D000818:Animals; D016466:CHO Cells; D002469:Cell Separation; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D005434:Flow Cytometry; D006801:Humans; D016177:Macrophage-1 Antigen / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009344:Neisseria gonorrhoeae / Q000472:pathogenicity*; D014162:Transfection
chemical_list: D016177:Macrophage-1 Antigen; D017242:Complement Factor H
references.citation: Sex Transm Dis. 1984 Apr-Jun;11(2):77-80
references.pmid: 6431621
references.citation: Eur J Immunol. 1987 Oct;17(10):1485-9
references.pmid: 2445583
references.citation: Annu Rev Cell Dev Biol. 2000;16:423-57
references.pmid: 11031243
references.citation: Mol Immunol. 2006 Jan;43(1-2):31-44
references.pmid: 16011850
references.citation: Fertil Steril. 2007 Oct;88(4 Suppl):1212-9
references.pmid: 17562335
references.citation: J Exp Med. 1998 Mar 2;187(5):743-52
references.pmid: 9480984
references.citation: Clin Microbiol Rev. 2004 Oct;17(4):965-81, table of contents
references.pmid: 15489357
references.citation: Infect Immun. 2002 Oct;70(10):5808-15
references.pmid: 12228311
references.citation: Proc Natl Acad Sci U S A. 2005 May 17;102(20):7227-32
references.pmid: 15870199
references.citation: Microbes Infect. 2000 Mar;2(3):289-94
references.pmid: 10758405
references.citation: Infect Immun. 1978 Apr;20(1):267-72
references.pmid: 78895
references.citation: Mol Immunol. 2009 Sep;46(14):2808-17
references.pmid: 19477524
references.citation: Cell Tissue Res. 2001 Sep;305(3):285-98
references.pmid: 11572082
references.citation: Mol Immunol. 1999 Sep-Oct;36(13-14):809-18
references.pmid: 10698334
references.citation: J Immunol. 2007 Apr 1;178(7):4489-97
references.pmid: 17372007
references.citation: J Clin Invest. 1982 Oct;70(4):906-13
references.pmid: 6288774
references.citation: J Immunol. 2008 Aug 15;181(4):2610-9
references.pmid: 18684951
references.citation: Biochem Soc Trans. 2002 Nov;30(Pt 6):971-8
references.pmid: 12440956
references.citation: Infect Immun. 1983 May;40(2):816-9
references.pmid: 6404835
references.citation: J Biol Chem. 2001 Aug 24;276(34):32129-35
references.pmid: 11406620
references.citation: J Immunol. 2005 Nov 15;175(10):6465-72
references.pmid: 16272300
references.citation: J Immunol. 2010 Jan 15;184(2):912-21
references.pmid: 20008295
references.citation: Infect Immun. 2000 Sep;68(9):5354-63
references.pmid: 10948165
references.citation: Cell Microbiol. 2002 Sep;4(9):571-84
references.pmid: 12390350
references.citation: J Cell Biol. 1993 Feb;120(4):1031-43
references.pmid: 7679388
references.citation: Mol Microbiol. 2001 Nov;42(3):659-72
references.pmid: 11722733
references.citation: Infect Immun. 2009 May;77(5):2094-103
references.pmid: 19273554
references.citation: Biochem J. 1988 Jan 15;249(2):593-602
references.pmid: 2963625
references.citation: Int J Biochem. 1982;14(7):561-3
references.pmid: 7106355
references.citation: J Infect Dis. 1999 Jan;179(1):124-35
references.pmid: 9841831
references.citation: Cell Microbiol. 2001 Sep;3(9):611-22
references.pmid: 11553013
references.citation: Immunopharmacology. 1999 May;42(1-3):53-60
references.pmid: 10408366
references.citation: Biochem J. 1997 Sep 1;326 ( Pt 2):321-7
references.pmid: 9291099
references.citation: Exp Eye Res. 2007 Apr;84(4):635-45
references.pmid: 17292886
references.citation: Blood. 2009 Sep 17;114(12):2439-47
references.pmid: 19528535
references.citation: Infect Immun. 2005 Nov;73(11):7390-7
references.pmid: 16239538
references.citation: Trends Immunol. 2008 Aug;29(8):380-7
references.pmid: 18602340
references.citation: Methods Enzymol. 1994;236:137-47
references.pmid: 7968606
references.citation: Infect Immun. 1997 Mar;65(3):931-5
references.pmid: 9038299
references.citation: J Exp Med. 1988 Nov 1;168(5):1883-97
references.pmid: 3141555
references.citation: J Leukoc Biol. 1992 Feb;51(2):109-17
references.pmid: 1358992
references.citation: J Exp Med. 1998 Aug 17;188(4):671-80
references.pmid: 9705949
references.citation: J Immunol. 1995 Dec 15;155(12):5663-70
references.pmid: 7499851
references.citation: Semin Thromb Hemost. 2006 Mar;32(2):128-45
references.pmid: 16575688
references.citation: J Mol Biol. 2001 Jun 22;309(5):1117-38
references.pmid: 11399083
references.citation: J Infect Dis. 1985 Aug;152(2):339-43
references.pmid: 3928769
references.citation: J Immunol. 1998 Apr 15;160(8):4057-66
references.pmid: 9558116
references.citation: Mol Microbiol. 2000 Jan;35(1):32-43
references.pmid: 10632875
references.citation: J Infect Dis. 2007 Jul 1;196(1):124-33
references.pmid: 17538892
references.citation: Cell Microbiol. 2005 Aug;7(8):1197-211
references.pmid: 16008586
references.citation: Immunogenetics. 2004 May;56(2):77-82
references.pmid: 15118848
references.citation: Cell Microbiol. 2002 Sep;4(9):585-98
references.pmid: 12390351
references.citation: J Immunol. 2008 Mar 1;180(5):3426-35
references.pmid: 18292569
references.citation: J Biol Chem. 1993 Oct 15;268(29):22055-9
references.pmid: 7691822
references.citation: Infect Immun. 1981 Jun;32(3):985-94
references.pmid: 6166568
references.citation: Prog Clin Biol Res. 1995;392:49-58
references.pmid: 8524957
references.citation: Annu Rev Immunol. 2007;25:619-47
references.pmid: 17201681
references.citation: Immunol Today. 1999 Mar;20(3):135-40
references.pmid: 10203705
references.citation: Vaccine. 2008 Dec 30;26 Suppl 8:I9-14
references.pmid: 19388158