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.
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.
|López-Abarrategui, Carlos; McBeth, Christine; Mandal, Santi M et al. (2015) Cm-p5: an antifungal hydrophilic peptide derived from the coastal mollusk Cenchritis muricatus (Gastropoda: Littorinidae). FASEB J 29:3315-25|
|Zhang, Xuqing; Starnbach, Michael N (2015) An Excess of the Proinflammatory Cytokines IFN-? 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|
|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|
|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|
|Fankhauser, Sarah C; Starnbach, Michael N (2014) PD-L1 limits the mucosal CD8+ T cell response to Chlamydia trachomatis. J Immunol 192:1079-90|
|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|
|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|
|McCluskey, Andrew J; Olive, Andrew J; Starnbach, Michael N et al. (2013) Targeting HER2-positive cancer cells with receptor-redirected anthrax protective antigen. Mol Oncol 7:440-51|
|Gondek, David C; Olive, Andrew J; Stary, Georg et al. (2012) CD4+ T cells are necessary and sufficient to confer protection against Chlamydia trachomatis infection in the murine upper genital tract. J Immunol 189:2441-9|
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