EPIC-STI PROJECT 1 (STARNBACH): Stimulating Protective CD4+ T Cell Immunity to Chlamydia trachomatis PROJECT SUMMARY Infection with Chlamydia trachomatis is responsible for significant morbidity throughout the world. Women infected in the upper genital tract with Chlamydia can develop severe disease pathologies leading to conditions such as infertility and ectopic pregnancy. Human infection with C. trachomatis stimulates a CD4+ T cell response that can protect against reinfection with the pathogen. However, T cell immunity in humans appears to be short-lived and may also influence the development of immunopathology. The prevention of C. trachomatis infections and their complications, derived from a better understanding of the host-parasite interaction and the development of a vaccine, could have substantial worldwide effects on both morbidity and health care costs. We will work within the EPIC-STI to dissect the function of CD4+ T cells responding to infection at the genital mucosa. We will address three major questions regarding Chlamydia-specific CD4+ T cell function;how CD4+ T cells are activated and home to the site of infection, how the IFN? derived from these cells mediates protection, and how the genital tract environment alters protective CD4+ T cell immunity. First, we will study the initial activation steps required to imprint antigen-specific CD4+ T cells to home to the genital mucosa in response to infection. These studies will identify critical antigen presenting cell populations as well as homing molecules that are required for CD4+ T cells to home to the site of C. trachomatis infection and provide protection (and determine whether those responses can be differentiated from those causing pathology). We will next investigate which IFN?-stimulated pathways are required for immunity once activated pathogen- specific CD4+ T cells traffic to the genital mucosa. These studies will be conducted in mice lacking the murine IRG response (and correlated with data from human sera obtained in EPIC-STI), allowing the discovery of IFN?-dependent pathways that may play a protective role during human infection. We will combine these studies with in vivo imaging techniques so that we can describe CD4+ T cell behavior and cell-cell interactions at the clinically relevant site of infection in real-time. Finally, we will determine whether the infected genital environment negatively impacts CD4+ T cell-mediated protection or memory development. Previous work has suggested that IFN?-induced expression of indole-2,3-dioxygenase (IDO) can directly induce a quiescent form of C. trachomatis. What remains unexplored is whether IDO or its catabolites suppress CD4+ T cell immunity in the genital mucosa. Since IDO is not strongly induced in the murine genital tract we will use newly generated humanized mice that express human IDO at the higher levels observed in people (and again confirmed with human secretion samples). In developing candidate vaccines against C. trachomatis, a key objective will be to determine if protective immunity can be driven without resulting pathology. It is towards this goal of a safe, effective C. trachomatis vaccine that these experiments are ultimately directed.

Public Health Relevance

- EPIC-STI PROJECT 1 (STARNBACH) After an initial infection with Chlamydia trachomatis the T cells of the immune system provide protection against reinfection. Although T cells mediate protection, their response also can result in pathology, leading to ectopic pregnancy and infertility. Our proposal within EPIC-STI is to define the details of the T cell response, the goal of which is to understand which aspects of the T cell response result in long-term protection vs. those that result in pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI113187-01
Application #
8769913
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of New Mexico Health Sciences Center
Department
Type
DUNS #
City
Albuquerque
State
NM
Country
United States
Zip Code
Jiang, Rosie T; Schellenbacher, Christina; Chackerian, Bryce et al. (2016) Progress and prospects for L2-based human papillomavirus vaccines. Expert Rev Vaccines 15:853-62
Gravitt, Patti E (2016) HPV Seroprevalence in the United States: Behavior, Biology, and Prevention. J Infect Dis 213:171-2
Benard, Vicki B; Castle, Philip E; Jenison, Steven A et al. (2016) Population-Based Incidence Rates of Cervical Intraepithelial Neoplasia in the Human Papillomavirus Vaccine Era. JAMA Oncol :
Saboo, Sugandha; Tumban, Ebenezer; Peabody, Julianne et al. (2016) Optimized Formulation of a Thermostable Spray-Dried Virus-Like Particle Vaccine against Human Papillomavirus. Mol Pharm 13:1646-55
Mirrashidi, Kathleen M; Elwell, Cherilyn A; Verschueren, Erik et al. (2015) Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection. Cell Host Microbe 18:109-21
Zhang, Xuqing; Starnbach, Michael N (2015) An Excess of the Proinflammatory Cytokines IFN-γ and IL-12 Impairs the Development of the Memory CD8+ T Cell Response to Chlamydia trachomatis. J Immunol 195:1665-75
Nogueira, Catarina V; Zhang, Xuqing; Giovannone, Nicholas et al. (2015) Protective immunity against Chlamydia trachomatis can engage both CD4+ and CD8+ T cells and bridge the respiratory and genital mucosae. J Immunol 194:2319-29
Stary, Georg; Olive, Andrew; Radovic-Moreno, Aleksandar F et al. (2015) VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science 348:aaa8205
Tumban, Ebenezer; Muttil, Pavan; Escobar, Carolina Andrea A et al. (2015) Preclinical refinements of a broadly protective VLP-based HPV vaccine targeting the minor capsid protein, L2. Vaccine 33:3346-53