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.

IMPORTANCE

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.