Novel ways to prevent upper GT infection

点击翻译按钮获取中文摘要

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.