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.
- 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.
|Lijek, Rebeccah S; Helble, Jennifer D; Olive, Andrew J et al. (2018) Pathology after Chlamydia trachomatis infection is driven by nonprotective immune cells that are distinct from protective populations. Proc Natl Acad Sci U S A 115:2216-2221|
|Frietze, Kathryn M; Lijek, Rebeccah; Chackerian, Bryce (2018) Applying lessons from human papillomavirus vaccines to the development of vaccines against Chlamydia trachomatis. Expert Rev Vaccines 17:959-966|
|Yokoyama, Christine C; Baldridge, Megan T; Leung, Daisy W et al. (2018) LysMD3 is a type II membrane protein without an in vivo role in the response to a range of pathogens. J Biol Chem 293:6022-6038|
|Castle, Philip E; Wheeler, Cosette M; Campos, Nicole G et al. (2018) Inefficiencies of over-screening and under-screening for cervical cancer prevention in the U.S. Prev Med 111:177-179|
|Arrossi, Silvina; Temin, Sarah; Garland, Suzanne et al. (2017) Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline. J Glob Oncol 3:611-634|
|Zhai, Lukai; Peabody, Julianne; Pang, Yuk-Ying Susana et al. (2017) A novel candidate HPV vaccine: MS2 phage VLP displaying a tandem HPV L2 peptide offers similar protection in mice to Gardasil-9. Antiviral Res 147:116-123|
|Ramírez-Peinado, Silvia; Ignashkova, Tatiana I; van Raam, Bram J et al. (2017) TRAPPC13 modulates autophagy and the response to Golgi stress. J Cell Sci 130:2251-2265|
|Cuzick, Jack; Myers, Orrin; Lee, Ji-Hyun et al. (2017) Outcomes in Women With Cytology Showing Atypical Squamous Cells of Undetermined Significance With vs Without Human Papillomavirus Testing. JAMA Oncol 3:1327-1334|
|Peabody, Julianne; Muttil, Pavan; Chackerian, Bryce et al. (2017) Characterization of a spray-dried candidate HPV L2-VLP vaccine stored for multiple years at room temperature. Papillomavirus Res 3:116-120|
|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|
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