Variants in toll-like receptor 1 and 4 genes are associated with chlamydia trachomatis among women with pelvic inflammatory disease

Chlamydia trachomatis is the most common bacterial sexually transmitted infection in the United States [1] and can lead to serious complications such as pelvic inflammatory disease (PID) and its subsequent sequelae, including ectopic pregnancy, infertility, and chronic pelvic pain [2, 3]. However, some women may develop PID and reproductive sequelae following chlamydial infection, whereas others may not [1, 4–6]. As the mechanisms underlying the pathogenesis of C. trachomatis have yet to be completely elucidated, the reasons for this variability in outcome are unknown. It is known that Chlamydia spp. can infect epithelial cells, causing secretion of proinflammatory cytokines [7–9]. Researchers have suggested that this inflammatory response may be responsible for disease progression [9], especially among those with chronic infections. Thus, it is possible that variations in host innate immune receptor genes may contribute to the variability in outcomes following chlamydial genital tract infection. The innate immune system serves as the first line of defense after exposure to pathogens and depends on pattern recognition receptors (PRRs) for microbial recognition [10–12]. A conserved family of PRRs called the Toll-like receptor (TLR) family [11] is responsible for induction of inflammatory cytokine and chemokine genes and priming of the adaptive immune system that leads to microbial elimination. Ten different TLRs (TLRs 1–10) have been identified in humans, and the overlap between them allows identification of a diverse range of pathogens through ligand binding [10–12]. Adaptor molecules, including myeloid differentiation primary response protein 88 (MyD88) and Toll/interleukin 1 receptor domain–containing adaptor protein (TIRAP), help to mediate TLR signaling [10]. However, as important as TLRs and their adaptor molecules are for a healthy immune response, variations in these genes may lead to an overexuberant or inadequate response, possibly influencing disease progression. Because TLRs are expressed in the reproductive tract [12] and can stimulate proinflammatory genes after binding to a bacterial ligand, it is possible that they may play a role in chlamydial pathogenesis. Studies have examined TLR pathways in chlamydial infections and have suggested a role for TLR2 in cytokine production [13, 14]. O’Connell et al [14] found that TLR2 was required for interleukin 8 (IL-8) expression, whereas TLR4/MD-2 had minimal effects on cytokine production in vitro. Darville et al [13], using a murine model of genital tract infection, found that mice genetically deficient for TLR2 exhibited reduced oviduct pathology and production of select proinflammatory cytokines, whereas TLR4-deficient mice had outcomes similar to wild-type mice. However, very few studies have examined TLRs in C. trachomatis pathogenesis among human subjects. Studies among Dutch white populations have been unable to show any significant associations between functional polymorphisms in the TLR4 and TLR2 genes and C. trachomatis [15–17]. Our objective was to explore the role of TLR2, TLR4, TLR6, MyD88, and TIRAP gene polymorphisms in C. trachomatis infection among women with clinically suspected PID.