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.
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.
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作者：
Liu Y;Russell MW
对淋球菌的免疫反应知之甚少，但其广泛的抗原变异性和对补体的抵抗力被认为使其能够逃避宿主免疫防御的破坏。我们认为，淋病奈瑟菌也避免在一开始就诱导保护性免疫反应。我们先前发现淋球菌通过诱导转化生长因子β(转化生长因子β)在体外诱导小鼠白介素17(IL-17)依赖的先天反应，并抑制小鼠细胞Th1/Th2依赖的适应性反应。在使用小鼠阴道淋球菌感染模型的研究中，在初次感染期间接受抗转化生长因子-β抗体治疗的小鼠表现出加速了淋球菌的清除，生殖道组织中Th1和Th2应答的早期发展和Th17应答的减弱。在二次再感染时，初次感染期间接受抗转化生长因子-β治疗的小鼠表现出对Th1型和Th2型应答的记忆回忆，血清和分泌物中出现抗淋球菌抗体，并增强了对再次感染的抵抗力。在Th1或Th2应答缺陷的小鼠基因敲除株中，抗转化生长因子-β治疗加速初次感染的清除依赖于Th1活性而不依赖于Th2活性，而在初次感染期间抗转化生长因子-β治疗对二次感染的抵抗是由于Th1和Th2依赖的记忆反应。我们认为，淋病奈瑟菌主动诱导Th17驱动的先天性反应，它可以抵抗，并同时抑制Th1/Th2驱动的特异性适应性免疫，以保护宿主。阻断转化生长因子-β逆转了这种宿主免疫应答的模式，促进了保护性抗淋球菌免疫的产生。在传染病期间，病原体与宿主的相互作用通常被认为是双向反应，即宿主对病原体的反应，反之亦然，结果取决于哪一种最终占上风。我们认为，淋病奈瑟菌，一种已经变得非常适应其唯一的人类宿主的病原体，主动指导宿主以有利于自身生存但对宿主不利的方式做出反应。淋病是一种广泛流行的性传播感染，自然发生的淋球菌对大多数可用的抗生素都产生了抗药性，但还没有开发出有效的疫苗。这些对淋病奈瑟菌免疫反应的新见解应该会导致新的治疗策略，并促进疫苗开发的新方法。
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. 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.