Assessing the Molecular and Cellular Impact of the Guanylate Binding Proteins on the Immune Response Against Chlamydia trachomatis
Harrison, Noah James
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CitationHarrison, Noah James. 2018. Assessing the Molecular and Cellular Impact of the Guanylate Binding Proteins on the Immune Response Against Chlamydia trachomatis. Master's thesis, Harvard Medical School.
AbstractOften overlooked in the immune response to infection is an individual cell’s ability to protect itself from intracellular pathogens, like Chlamydia trachomatis, independently of the host’s immune system. This ability, called cell-autonomous immunity, is conserved across all three domains of life. Interferon-γ (IFNγ) is a potent activator of many effectors of cell-autonomous immunity in mice and humans, including the Guanylate Binding Proteins (GBPs). The GBPs are a group of 65-73kDa GTPases, and consist of 11 proteins in mice, and 7 in humans. In mice, GBPs 1, 2, 3, 5, and 7 are located on chromosome 3, while the rest are found on chromosome 5.
Against many intracellular pathogens, knocking out the GBPs on chromosome 3 (GBPchr3-/-) increases the susceptibility of the host to infection. However, I previously demonstrated that these GBPs are not required for clearance of C. trachomatis, and may even be detrimental to the host during early infection. In this study, I confirm that knocking out the chromosome 3 GBPs reduces C. trachomatis burden by 54 hours post inoculation (hpi), and explore the molecular and cellular sequelae that may be contributing to the reduced burden in GBPchr3-/- mice.
By 54hpi, GBPchr3-/- mice have fewer uterine neutrophils, natural killer cells, natural killer T cells, and CD45+ cells than wild-type mice. Additionally, at this time point fewer neutrophils, natural killer cells, and CD45+ cells from GBPchr3-/- mice are alive relative to wild-type mice. The chromosome 3 GBPs have also been implicated in activating the canonical inflammasome during Chlamydia muridarum infection in bone marrow derived macrophages (BMDMs). I show that the chromosome 3 GBPs activate the canonical inflammasome during C. trachomatis infection in BMDMs, though possibly by a different mechanism than in C. muridarum infection. In both wild-type and GBPchr3-/- mice, however, IL-1 levels have a similar, positive correlation to C. trachomatis burden, suggesting that the chromosome 3 GBPs’ effect on the canonical inflammasome may be secondary to the amount of C. trachomatis in the uterus.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42076762