Infection with Chlamydia trachomatis is responsible for significant morbidity throughout the world. Chronic genital infections with C. trachomatis can lead to pelvic inflammatory disease, infertility, and other complications in women. Our overall goal in this grant is to define how C. trachomatis interacts with and manipulates the mammalian host during infection. In the previous project period we focused on a large-scale forward genetic screen in mice to map variant alleles that affect resistance to C. trachomatis. We identified a family of Immunity-Related-GTPases (IRGs) as responsible for mouse resistance to C. trachomatis. However in humans, IRGs are not responsible for C. trachomatis resistance;instead humans resist infection through the expression of indole-2,3-dioxygenase (IDO). The identification of IRGs and IDO as the key differences between mice and humans with regard to IFNg-mediated resistance leads us now to propose the development of a mouse model that mimics human infection with C. trachomatis. To achieve this goal we will engineer strains of humanized mice in which the mouse-specific immune response driven IRGs is replaced with the human response that depends on IDO expression. Currently, no small animal model exists that recapitulates the chronic disease as it manifests itself in humans, particularly the prolonged or recurring infections that cause pathologies of the genital tract and infertility in humans. We have also shown that a number of C. trachomatis protein effectors are translocated into the host cell cytosol during infection where they cleave or otherwise alter host proteins. Because alteration of host cell protein stability appears to be a general strategy used by C. trachomatis, we are applying two novel screening methods called """"""""stable isotope labeling with amino acids in cells culture"""""""" (SILAC) and """"""""Global Protein Stability"""""""" (GPS) to analyze, on a global scale, which host proteins are perturbed during infection with C. trachomatis. Once we have identified host proteins stabilized or destabilized during C. trachomatis infection, we will test whether reducing or increasing the prevalence of these proteins in cells impairs C. trachomatis development. Although pathogen-induced alterations of the host are a key to pathogenesis, it has not previously been possible to simultaneously assess the impact of infection on individual host proteins at the scale now possible with these approaches. The methods explored in this application allow, for the first time, an appreciation of how bacterial infection globally regulates host cell proteins and pathways beyond the transcriptional level. Understanding the interaction of C. trachomatis with its human host requires a large-scale approach to catalog the changes C. trachomatis induces in host proteins during infection. Once these proteins and the pathways in which they act are understood, the impact of disrupting these Chlamydia-induced manipulations can only be appreciated using small animal models that accurately reflect the pathogenesis of human C. trachomatis infection.

Public Health Relevance

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted disease and can lead to pelvic inflammatory disease, ectopic pregnancy, infertility, and other complications in women. First, we propose to engineer mice that will, for the first time, allow us to study in mice the chronic Chlamydia infections that cause diseases such as ectopic pregnancy and infertility in humans. Second, we propose to identify the ways in which C. trachomatis manipulates the cells of humans - with the goal of disrupting these manipulations and conquering this disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Hiltke, Thomas J
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Harvard University
Schools of Medicine
United States
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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
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
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
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

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