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Negative Regulators of Toll-Like Receptors During Chlamydia trachomatis Infection

  • Author(s): Al-Kuhlani, Mufadhal Mohammed
  • Advisor(s): Ojcius, David
  • Manilay, Jennifer O
  • et al.
Abstract

Chlamydia trachomatis is the most common bacterial sexually-transmitted disease (STD) around the world. The response of the immune system to eliminate C. trachomatis infection through inflammation is a very efficient process. However, persistent infection or uncontrolled inflammation causes a complication in the upper genital tract, which can ultimately lead to infertility and chronic pelvic pain. Therefore, inflammation has to be tightly regulated to avoid an uncontrolled immune response. The genetic factors that regulate inflammation during Chlamydia infection have not been clearly characterized. SIGIRR, Triad3A and TRAIL-R are proteins that have been shown to manipulate inflammation in response to various pathogens and diseases. However, little is known about their role during C. trachomatis infection.

Our results indicate that in the absence of SIGIRR, epithelial cells induce higher levels of proinflammatory cytokines in response to chlamydia infection. In addition, overexpression analysis reveals that SIGIRR associates with MyD88 and localizes around the inclusion of the Chlamydia and the nucleus of the infected cell. Additionally, our data indicates that the absence of Triad3A in HEK cells that express individual TLRs does not affect the levels of IL-8 in TLR2, TLR3 or TLR4, when activated by C. trachomatis. However, the absence of Triad3A in cells that express both TLR2 and TLR4 induces lower level of IL-8 compared to wild type cells as a result of the inhibitory effect that TLR4 exerts on TLR2.

Ex-vivo analysis shows that Chlamydia infection of bone marrow derived macrophages (BMDM) and primary lung fibroblasts from TRAIL-R deficient mice, induces higher levels of MIP2 mRNA expression and IL-1β secretion compared to cells from the wild type mice. In addition, in vitro study of human TRAILR1 shows that reduction of TRAIL-R1 expression on HeLa cells correlates with an increase of IL-8 expression and secretion in Chlamydia-infected cells.

Taken together, our data shows that SIGIRR, Triad3A and for the first time human TRAIL-R1, function as regulators of the immune response to C. trachomatis infection. This finding provides an insight into the immune-pathogenesis ofC. trachomatis that can be used to develop novel intervention and diagnostic strategies to treat and identify individuals at high risk.

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