Infection with Chlamydia trachomatis is responsible for significant morbidity throughout the world. Work from our lab suggests that T cells are a key mediator of immune protection against C. trachomatis. The reagents we developed in the previous funding period have allowed us to use contemporary approaches in cellular immunology to define how Chlamydia-specific T cells respond to infection. Our long-term goal has been to gain an understanding of how CD8+ T cells are stimulated in response to C. trachomatis infection. Work from our lab and others have shown that Chlamydia must manipulate host cell structures and functions to replicate in the mammalian host. One way in which Chlamydia manipulates host cells is through the secretion of bacterial effector proteins that embed in the vacuolar membrane or translocate into the host cell cytosol. In the genital tract, the cytosolic localization of these effectors allows CD8+ T cells to target the epithelial cells that harbor the organism during replication. We have shown that transfer of cultured Chlamydia-specific CD8+ T cells into mice can protect against infection, yet surprisingly, a protective CD8+ T cell response is not stimulated following natural infection of mice or people. The apparent failure of the adaptive immune system to effectively clear the organism and/or prevent repeat infection is a hallmark of human infection with C. trachomatis. It is inability to clear C. trachomatis or prevent reinfection that promotes sequelae of infection such as permanent reproductive tract damage. Consistent with the findings in humans, we have observed that CD8+ T cells respond extremely well to primary infection, yet the memory cells that result from initial infection are impaired in their capacity to robustly respond to subsequent encounters with the organism. Our goal is to understand the molecular basis for this impaired recall response and develop methods to overcome it. First, we will identify and characterize an expanded subset of secreted effectors from Chlamydia that give rise to CD8+ T cell responses. With this expanded subset we will be able to explore CD8+ T cell function during infection beyond the limited number of antigens we have previously studied. Of particular interest is how responses to differentially regulated C. trachomatis proteins may lead either to resolution of infection and protection, or failure to resolve infection and pathology. Second, we will investigate the mechanism by which CD8+ T cells are inhibited during infection. By identifying antigens that stimulate protective immunity and determining conditions where development of CD8+ T cell memory is not inhibited, we will be able to harness this critical arm of adaptive immunity against Chlamydia infection. Ultimately we anticipate this work will drive selection of appropriate antigens for vaccine development and inform the design of vaccines that provide robust protection against reinfection.

Public Health Relevance

After an initial infection with most pathogens the immune system provides protection against reinfection with the same pathogen. Infection of the female reproductive tract with Chlamydia trachomatis does not provide protection against reinfection, and reoccurring infections can cause permanent damage to fertility. The goal of this application is to 1) characterize the cells of the immune system that should respond to C. trachomatis, 2) determine why they fail to provide protection, and 3) see if they can be reprogrammed to provide protection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039558-18
Application #
8599741
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
1996-07-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
18
Fiscal Year
2014
Total Cost
$594,637
Indirect Cost
$241,578
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Olive, Andrew J; Haff, Madeleine G; Emanuele, Michael J et al. (2014) Chlamydia trachomatis-induced alterations in the host cell proteome are required for intracellular growth. Cell Host Microbe 15:113-24
Davila, Sergio J; Olive, Andrew J; Starnbach, Michael N (2014) Integrin ?4?1 is necessary for CD4+ T cell-mediated protection against genital Chlamydia trachomatis infection. J Immunol 192:4284-93
Fankhauser, Sarah C; Starnbach, Michael N (2014) PD-L1 limits the mucosal CD8+ T cell response to Chlamydia trachomatis. J Immunol 192:1079-90
Olive, A J; Gondek, D C; Starnbach, M N (2011) CXCR3 and CCR5 are both required for T cell-mediated protection against C. trachomatis infection in the murine genital mucosa. Mucosal Immunol 4:208-16
Gondek, David C; Roan, Nadia R; Starnbach, Michael N (2009) T cell responses in the absence of IFN-gamma exacerbate uterine infection with Chlamydia trachomatis. J Immunol 183:1313-9