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dc.contributor.authorShantz, Emily
dc.date.accessioned2019-01-15T18:57:23Z
dc.date.available2019-01-15T18:57:23Z
dc.identifier.urihttp://hdl.handle.net/10222/75080
dc.description.abstractChlamydia trachomatis (Ct) is the most common bacterial sexually transmitted infection and the leading cause of infectious blindness worldwide. A comprehensive understanding of immune responses to Ct, and how they lead to effective host defence or chronic pathology, is essential to designing an efficacious vaccine. This study investigated how mast cells and the pathogen recognition receptor toll-like receptor 2 (TLR2) contribute to host immune responses during Ct infection of the female genital tract. Primary human cord blood-derived mast cells (CBMCs) stimulated with C. trachomatis (Ct) produced a number of pro-inflammatory cytokines and chemokines, such as TNF, IL-1β, IL-6, GM- CSF, IL-23, CCL3, CCL5 and CXCL8. Transmission electron microscopy revealed that Ct is rarely taken up by CBMCs in vitro. Furthermore, Ct was unable to replicate efficiently within these cells. These data suggest that human mast cells primarily detect and respond to extracellular Ct. Similarly, murine bone marrow-derived mast cells also produced a variety of mediators in response to C. muridarum (Cm), including CXCL1, CXCL2, CCL2, CCL3, IL-6, and IL-12p70, although these responses did not reach significance due to variability across cultures. A number of these responses were diminished in TLR2-/- BMMCs, indicating that they were TLR2-dependent. To investigate the pathophysiological role of mast cells in vivo, mast cell-deficient (Wsh) mice and wildtype (WT) C57BL/6 mice were infected intravaginally with Cm for 50 days. Over the course of infection, bacterial shedding was equivalent. However, at day 50, Wsh mice had significantly reduced oviduct pathology compared to WT. When splenocytes from infected mice were restimulated with heat-inactivated Cm, cells from Wsh mice had a marked reduction of IFN-γ, IL-13, and IL-17A, compared to WT, indicating that they had broadly suppressed memory responses. This was attributed to a decreased infiltration of classical dendritic cells (cDCs), particularly CD103+ DCs, into the draining lymph node of Wsh mice at three days post-infection. Given the TLR2- dependent nature of BMMC responses to Cm, we also infected TLR2-/- and WT mice, on C57BL/6 and BALB/c backgrounds, intravaginally with Cm for 50 days. In the C57BL/6 background, TLR2-/- mice had increased bacterial loads at days 14 and 21 post-infection, but this was resolved by day 28. In the BALB/c background, TLR2-/- mice had decreased bacterial shedding compared to WT at day 3, but displayed comparable bacterial burden over the remaining course of infection. At day 50, both C57BL/6 and BALB/c TLR2-/- mice exhibited a trend toward reduced oviduct pathology, but significant differences were not observed. In both strains, TLR2-deficiency was associated with diminished IFN-γ, IL-13 and IL-17A responses when splenocytes were restimulated with heat-inactivated Cm. Taken together, these findings indicate that both mast cells and TLR2 contribute to acute inflammation and the development of chronic pathology following Chlamydia genital tract infection. To our knowledge, these are the first studies examining mast cells in the context of Chlamydia genital tract infection, and the first studies employing two strains of TLR2-/- mice. These findings have important implications for the current understanding of Chlamydia pathogenesis, and may assist in future efforts for novel immunotherapies and vaccine design.en_US
dc.language.isoenen_US
dc.subjectImmunityen_US
dc.subjectInflammationen_US
dc.subjectInfectionen_US
dc.subjectMast cellsen_US
dc.subjectChlamydiaen_US
dc.subjectTLR2en_US
dc.subjectToll-like receptor 2en_US
dc.titleThe role of mast cells and toll-like receptor 2 (TLR2) in host defence and pathology following Chlamydia infectionen_US
dc.date.defence2016-12-08
dc.contributor.departmentDepartment of Microbiology & Immunologyen_US
dc.contributor.degreeMaster of Scienceen_US
dc.contributor.external-examinerDr. Lisa Barretten_US
dc.contributor.graduate-coordinatorDr. Brent Johnstonen_US
dc.contributor.thesis-readerDr. Todd Hatchetteen_US
dc.contributor.thesis-readerDr. Tong-jun Linen_US
dc.contributor.thesis-supervisorDr. Jean Marshallen_US
dc.contributor.thesis-supervisorDr. Jun Wangen_US
dc.contributor.ethics-approvalReceiveden_US
dc.contributor.manuscriptsNot Applicableen_US
dc.contributor.copyright-releaseNot Applicableen_US
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