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.
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.
|Jiang, Janina; Liu, Guangchao; Kickhoefer, Valerie A et al. (2017) A Protective Vaccine against Chlamydia Genital Infection Using Vault Nanoparticles without an Added Adjuvant. Vaccines (Basel) 5:|
|Zhu, Ye; Jiang, Janina; Said-Sadier, Najwane et al. (2015) Activation of the NLRP3 inflammasome by vault nanoparticles expressing a chlamydial epitope. Vaccine 33:298-306|
|Jiang, Janina; Champion, Cheryl I; Wei, Bo et al. (2013) CD8?CXCR5? T cells regulate pathology in the genital tract. Infect Dis Obstet Gynecol 2013:813238|
|Pettengill, Matthew A; Lam, Verissa W; Ollawa, Ikechukwu et al. (2012) Ivermectin inhibits growth of Chlamydia trachomatis in epithelial cells. PLoS One 7:e48456|
|Coutinho-Silva, Robson; Ojcius, David M (2012) Role of extracellular nucleotides in the immune response against intracellular bacteria and protozoan parasites. Microbes Infect 14:1271-7|
|Saïd-Sadier, Najwane; Ojcius, David M (2012) Alarmins, inflammasomes and immunity. Biomed J 35:437-49|
|Pettengill, Matthew A; Marques-da-Silva, Camila; Avila, Maria Luisa et al. (2012) Reversible inhibition of Chlamydia trachomatis infection in epithelial cells due to stimulation of P2X(4) receptors. Infect Immun 80:4232-8|
|Kar, Upendra K; Jiang, Janina; Champion, Cheryl I et al. (2012) Vault nanocapsules as adjuvants favor cell-mediated over antibody-mediated immune responses following immunization of mice. PLoS One 7:e38553|
|Jiang, Janina; Kelly, Kathleen A (2012) Isolation of lymphocytes from mouse genital tract mucosa. J Vis Exp :e4391|
|Abdul-Sater, Ali A; Saïd-Sadier, Najwane; Padilla, Eduardo V et al. (2010) Chlamydial infection of monocytes stimulates IL-1beta secretion through activation of the NLRP3 inflammasome. Microbes Infect 12:652-661|
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