The obligate intracellular pathogen Chlamydia trachomatis is the most common cause of sexually transmitted disease in the developed world, causing both overt disease and infertility, and is also the leading cause of preventable blindness worldwide Infection with C. trachomatis results in a specific immune response against the organism, and CD8+ T cells specific for C. trachomatis can be cultured from infected mice. Over the previous funding period we have developed a method to identify antigens recognized by Chlamydia-specific CD8+ T cells, explored the requirements for stimulating these responses, and studied the expansion and effector functions of CD8+ T cells stimulated during Chlamydia infection. In this competing continuation we propose to expand our work characterizing the T cell response to C. trachomatis. We plan to determine the expansion kinetics and trafficking of both naive and memory T cells in response to infection. Because T cells specific for any single antigen are a miniscule fraction of the total number of cells present in a naive mice, we have been unable to study how T cells respond to C. trachomatis during primary infection. Even in immune mice the number of antigen-specific T cells is so low that they must be cultured in vitro to obtain enough cells for adoptive transfer. One tool that has been available for the study of model antigens such as ovalbumin is the T cell receptor transgenic (TCRtg) mouse. TCRtg mice provide a rich source of both naive and effector T cells of fixed specificity. We are in the process of generating a series of TCRtg mice that produce CD4+ or CD8+ T cells specific for either human or mouse biovars of C. trachomatis.
In Aim 1 of this proposal, naive and memory T cells will be obtained from these animals and used to study the response to infection and the establishment of memory.
In Aim 2 we will address an ongoing debate about the protective capacity of CD8+ T cells stimulated following C. trachomatis infection. Several research groups have found the response of CD4+ T cells more critical than the response of CD8+ T cells, yet we have shown that C. trachomatis-specific CD8+ T cells have a protective effect when transferred into mice or stimulated with subunit vaccines. We have recently obtained evidence that may begin to explain this discrepancy. When T cells are stimulated by C. trachomatis infection, the resulting antigen-specific memory populations do not show robust recall upon challenge.
In Aim 2 of this proposal we plan to characterize whether this defect results from poor stimulation of memory CD8+ T cells and/or direct effects of the bacteria on T cells during initial stimulation.
In Aim 3, we propose to determine whether C. trachomatis proteins shown to be secreted by the Shigella flexneri type III secretion system serve as CD8+ T cell antigens during infection with C. trachomatis. For proteins that stimulate CD8+ T cells we will determine their subcellular localization and developmental regulation during infection of cells and investigate their interaction with host-cell proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039558-15
Application #
7857946
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
1996-07-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
15
Fiscal Year
2010
Total Cost
$543,427
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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Laborde, Rady J; Sanchez-Ferras, Oraly; Luzardo, María C et al. (2017) Novel Adjuvant Based on the Pore-Forming Protein Sticholysin II Encapsulated into Liposomes Effectively Enhances the Antigen-Specific CTL-Mediated Immune Response. J Immunol 198:2772-2784
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

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