title: Diversion of the immune response to Neisseria gonorrhoeae from Th17 to Th1/Th2 by treatment with anti-transforming growth factor β antibody generates immunological memory and protective immunity.
abstract: The immune response to Neisseria gonorrhoeae is poorly understood, but its extensive antigenic variability and resistance to complement are thought to allow it to evade destruction by the host's immune defenses. We propose that N. gonorrhoeae also avoids inducing protective immune responses in the first place. We previously found that N. gonorrhoeae induces interleukin-17 (IL-17)-dependent innate responses in mice and suppresses Th1/Th2-dependent adaptive responses in murine cells in vitro through the induction of transforming growth factor β (TGF-β). In this study using a murine model of vaginal gonococcal infection, mice treated with anti-TGF-β antibody during primary infection showed accelerated clearance of N. gonorrhoeae, with incipient development of Th1 and Th2 responses and diminished Th17 responses in genital tract tissue. Upon secondary reinfection, mice that had been treated with anti-TGF-β during primary infection showed anamnestic recall of both Th1 and Th2 responses, with the development of antigonococcal antibodies in sera and secretions, and enhanced resistance to reinfection. In mouse knockout strains defective in Th1 or Th2 responses, accelerated clearance of primary infection due to anti-TGF-β treatment was dependent on Th1 activity but not Th2 activity, whereas resistance to secondary infection resulting from anti-TGF-β treatment during primary infection was due to both Th1- and Th2-dependent memory responses. We propose that N. gonorrhoeae proactively elicits Th17-driven innate responses that it can resist and concomitantly suppresses Th1/Th2-driven specific adaptive immunity that would protect the host. Blockade of TGF-β reverses this pattern of host immune responsiveness and facilitates the emergence of protective antigonococcal immunity.
  
  
  OBJECTIVE
  Pathogen-host interactions during infectious disease are conventionally thought of as two-way reactions, that of the host against the pathogen and vice versa, with the outcome dependent on which one ultimately prevails. We propose that Neisseria gonorrhoeae, a pathogen that has become extremely well adapted to its exclusive human host, proactively directs the manner in which the host responds in ways that are beneficial to its own survival but detrimental to the host. Gonorrhea is a widely prevalent sexually transmitted infection, and naturally occurring gonococcal strains are becoming resistant to most available antibiotics, yet no effective vaccine has been developed. These new insights into the immune response to N. gonorrhoeae should lead to novel therapeutic strategies and facilitate new approaches to vaccine development.
authors: Department of Microbiology and Immunology and Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo, Buffalo, New York, USA.
authors: Yingru
authors: Y
authors: Liu
authors: Michael W
authors: MW
authors: Russell
references: Microbes Infect. 2011 Feb;13(2):167-78
references: 21034849
references: Mol Microbiol. 1999 Nov;34(3):538-51
references: 10564495
references: Infect Immun. 2009 Nov;77(11):5170-80
references: 19720754
references: J Infect Dis. 1994 Mar;169(3):532-7
references: 8158024
references: Infect Immun. 1999 Aug;67(8):3937-46
references: 10417159
references: J Exp Med. 2001 Feb 5;193(3):281-95
references: 11157049
references: Mucosal Immunol. 2010 May;3(3):312-21
references: 20107432
references: FEMS Immunol Med Microbiol. 2011 Feb;61(1):129-32
references: 21214637
references: Immunology. 2009 Feb;126(2):177-85
references: 19125888
references: Trends Microbiol. 1998 Dec;6(12):489-95
references: 10036728
references: Annu Rev Immunol. 2006;24:99-146
references: 16551245
references: Am J Reprod Immunol. 2006 Nov-Dec;56(5-6):321-8
references: 17076676
references: Immunol Rev. 2008 Dec;226:248-62
references: 19161429
references: Am J Reprod Immunol. 2010 Jun;63(6):544-65
references: 20367623
references: Nat Immunol. 2010 Dec;11(12):1093-101
references: 20953201
references: Infect Immun. 1999 Nov;67(11):5699-708
references: 10531218
references: Infect Immun. 2005 Jul;73(7):4171-9
references: 15972507
references: Am J Epidemiol. 1999 Feb 15;149(4):353-8
references: 10025478
references: J Infect Dis. 1998 Sep;178(3):742-51
references: 9728543
references: Front Microbiol. 2011 Mar 22;2:52
references: 21833308
references: Vaccine. 2008 Oct 23;26(45):5741-51
references: 18762223
references: Infect Immun. 2010 Jan;78(1):433-40
references: 19901062
references: Mucosal Immunol. 2009 Sep;2(5):403-11
references: 19587639
references: Infect Immun. 2005 Mar;73(3):1330-42
references: 15731030
references: Clin Exp Immunol. 2007 Jul;149(1):155-61
references: 17403059
references: Annu Rev Immunol. 2009;27:485-517
references: 19132915
references: Semin Immunol. 2007 Dec;19(6):377-82
references: 18054248
references: Nat Protoc. 2007;2(10):2307-11
references: 17947970
references: Nat Immunol. 2002 Mar;3(3):229-36
references: 11850628
references: Microb Pathog. 1995 Dec;19(6):365-77
references: 8852278