Host genetic variation plays a large role in the outcome of infection. Therefore, genetic analysis of resistance to infectious disease can reveal genes important for affecting the severity of disease course. This type of genetic analysis has been very successful in the mouse for a variety of infection models, and this data has pointed the way to candidate genes that could affect human infections. For the proposed genetic experiments, we have decided to focus on mouse infections with the human pathogen Chlamydia trachomatis. It is a major cause of blindness in endemic regions, and may be the most common source of bacterial sexually transmitted disease in the world. Based on the results of studies of human and animal infections with Chlamydia, it seems likely that at least some of the variations in disease symptoms result from genetic differences in host susceptibility to distinct elements of chlamydial disease. Therefore, we want to study the role of host genetic background in the severity of Chlamydia infections, using a mouse models of a human chlamydial disease. For our first Aim, we will utilize mouse genetics as a means to refine the location of Quantitative Trait Loci (QTL) that influence the outcome of an acute systemic infection with C. trachomatis, which is designed to model elements of the human sexually transmitted disease called lymphogranulum venereum. For the second Aim, we will identify the genes that underlie the effects of those QTL. For the third Aim, we will study the genes isolated in the first 2 Aims, to determine their effects on intracellular bacterial replication. This project will attempt to define mouse genes that affect susceptibility to disease caused by infections with Chlamydia trachomatis. It is likely that humans will have similar gene functions that will influence similar susceptibilities to infectious disease. Since infections with Chlamydia trachomatis are common in the human population, it is possible that knowledge of these genes could help to design diagnostics or therapies for this infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062827-05
Application #
7760843
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Hiltke, Thomas J
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$399,608
Indirect Cost
Name
Harvard University
Department
Genetics
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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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