Novel ways to prevent upper GT infection

描述（由申请人提供）：本项目的长期目标是鉴定重组穹窿纳米颗粒（经工程改造含有免疫原性肽）如何产生生殖器粘膜1型辅助性T细胞（Th 1）。有几个许可的疫苗保护粘膜组织中的感染，即因为我们缺乏对设计疫苗，诱导粘膜免疫的理解。我们假设，中空的，重组的拱顶，小微生物的大小，可以被设计成诱导粘膜免疫，并被用作一种工具，以确定关键的免疫触发器，产生的Th 1细胞，交通到生殖器粘膜组织。我们选择了病原体沙眼衣原体的感染，它依赖于Th 1粘膜免疫应答来消除，是医疗保健的重大负担，并且没有有效的疫苗。C.沙眼是性传播感染（STI）的主要原因和女性生殖功能障碍的诱发者，在美国每年有超过100万例。小鼠适应的C. trachomatis、C. muridarum诱导类似于人衣原体STI的STI，并且可以通过阴道组织内Th 1的存在来预防。我们发现用含有C.与其它MOMP候选疫苗相比，鼠伤寒沙门氏菌（MOMP-vault）表现出对攻击感染的上级保护，并增强了T细胞向生殖器粘膜组织的迁移。在体外，MOMP-穹窿激活称为炎性小体的复合物，独立于已知的鼠Toll样受体（TLR），并引起树突状细胞（DC）分泌选择性细胞因子。拱顶似乎通过溶酶体不稳定激活炎性体，佐剂明矾也是如此。了解穹窿诱导Th 1生殖器粘膜免疫的机制将进一步发展其他粘膜病原体的指导性免疫疗法。在这个提议中，我们希望确定工程拱顶如何刺激生殖器粘膜Th 1免疫。我们将重点关注穹窿激活炎性小体的能力，其允许分泌促炎细胞因子如白细胞介素-12（IL-12），并确定穹窿诱导的炎性小体激活如何刺激感染动物模型中生殖器粘膜Th 1细胞免疫的产生。对所提出的目标的调查将提高我们对开发针对衣原体性传播感染的衣原体疫苗的认识，并有助于确定更有针对性的方法来设计针对感染粘膜组织的其他病原体的疫苗。 公共卫生相关性：粘膜免疫应答提供了对抗感染性疾病的上级保护，但目前大多数许可的疫苗产生抗体应答而不是Th 1粘膜免疫，因为我们缺乏诱导粘膜免疫应答，特别是生殖器粘膜Th 1细胞免疫的知识。沙眼衣原体引起粘膜感染，是性传播感染（STI）的主要原因，在美国每年有超过100万例病例。对由此产生的女性生殖功能障碍的治疗每年给美国卫生保健系统带来数十亿美元的负担，并且该提议直接解决了鉴定如何诱导生殖器粘膜Th 1细胞免疫以生产针对诸如C.沙眼性传播感染

DESCRIPTION (provided by applicant): The long term goal of this project is to identify how recombinant vault nanoparticles, engineered to contain immunogenic peptides, generate genital mucosal T helper type 1 (Th1) cells. There are few licensed vaccines for protection against infections in mucosal tissues, namely because we lack an understanding for designing vaccines that induce mucosal immunity. We hypothesize that the hollow, recombinant vaults, the size of small microbes, could be engineered to induce mucosal immunity and be used as a tool to identify key immune triggers which produce Th1 cells that traffic to genital mucosal tissue. We chose infection by the pathogen, Chlamydia trachomatis, which relies on Th1 mucosal immune responses for elimination, is a significant burden on health care, and for which there is no effective vaccine. C. trachomatis is a prominent cause of sexually transmitted infection (STI) and instigator of female reproductive dysfunction, with over 1 million cases in the U.S. annually. Vaginal delivery of the mouse-adapted strain of C. trachomatis, C. muridarum, induces an STI similar to human chlamydial STI and can be prevented by the presence of Th1 within vaginal tissues. We found that mice immunized with recombinant vaults engineered to contain the major outer membrane protein of C. muridarum (MOMP-vault) demonstrated superior protection to a challenge infection as compared to other MOMP vaccine candidates and enhanced migration of T cells to genital mucosal tissues. In vitro, MOMP-vaults activated complexes called inflammasomes independently of known murine Toll-like receptors (TLRs) and caused the secretion of select cytokines from dendritic cells (DCs). Vaults appear to activate inflammasomes via lysosome destabilization as does the adjuvant, alum. Understanding the mechanisms whereby the vault induces Th1 genital mucosal immunity will further the development of instructive immunotherapy for other mucosal pathogens. In this proposal we wish to identify how engineered vaults stimulate genital mucosal Th1 immunity. We will focus on the ability of the vaults to activate inflammasomes, which allow secretion of pro- inflammatory cytokines such as interleukin-12 (IL-12), and determine how vault-induced inflammasome activation stimulates production of genital mucosal Th1-cell immunity in an animal model of infection. Investigations of the proposed aims will enhance our knowledge for developing chlamydial vaccines against Chlamydia STIs and help to define more targeted approaches for designing vaccines against other pathogens infecting mucosal tissues. PUBLIC HEALTH RELEVANCE: Mucosal immune responses provide superior protection against infectious disease, but most currently- licensed vaccines produce antibody responses instead of Th1 mucosal immunity because we lack knowledge for inducing mucosal immune responses, particularly genital mucosal Th1 cell immunity. Chlamydia trachomatis induces a mucosal infection and is a prominent cause of sexually transmitted infection (STI) with over 1 million cases in the U.S annually. Treatment for the resulting female reproductive dysfunction burdens the US health care system by billions of dollars annually and this proposal directly addresses the problem of identifying how to induce genital mucosal Th1 cell immunity for production of a vaccine against infections such as C. trachomatis STIs.