Abstract
The immune system eliminates Chlamydia trachomatis infection through inflammation. However, uncontrolled inflammation can enhance pathology. In mice, TNF-related apoptosis-inducing ligand receptor (TRAIL-R), known for its effects on apoptosis, also regulates inflammation. In humans, the four homologues of TRAIL-R had never been investigated for effects on inflammation. Here, we examined whether TRAIL-R regulates inflammation during chlamydial infection. We examined TRAIL-R1 single nucleotide polymorphisms (SNPs) in an Ecuadorian cohort with and without C. trachomatis infections. There was a highly significant association for the TRAIL+626 homozygous mutant GG for infection vs no infection in this population. To confirm the results observed in the human population, primary lung fibroblasts and bone marrow-derived macrophages (BMDMs) were isolated from wildtype (WT) and TRAIL-R-deficient mice, and TRAIL-R1 levels in human cervical epithelial cells were depleted by RNA interference. Infection of BMDMs and primary lung fibroblasts with C. trachomatis strain L2, or the murine pathogen C. muridarum, led to higher levels of MIP2 mRNA expression or IL-1β secretion from TRAIL-R-deficient cells than WT cells. Similarly, depletion of TRAIL-R1 expression in human epithelial cells resulted in a higher level of IL-8 mRNA expression and protein secretion during C. trachomatis infection. We conclude that human TRAIL-R1 SNPs and murine TRAIL-R modulate the innate immune response against chlamydial infection. This is the first evidence that human TRAIL-R1 is a negative regulator of inflammation and plays a role in modulating Chlamydia pathogenesis.
Highlights
Chlamydia trachomatis is the leading cause of bacterial sexuallytransmitted diseases (STDs) and the main cause of preventable blindness worldwide _ENREF_1[1]
We investigate the effect of TRAIL-R1 single nucleotide polymorphisms (SNPs) in regulating susceptibility to C. trachomatis infection among women from a population at risk for STDs, identify TRAIL-R1 as a downregulator of inflammation in human cells, and elucidate the role of murine TNF-related apoptosis-inducing ligand receptor (TRAIL-R) in the inflammatory response against chlamydial infection in vitro
A well-defined Ecuadorian cohort with and without C. trachomatis infections was tested for the four known TRAILR1 through -R4 SNPs that could be associated with pathology due to infection
Summary
Chlamydia trachomatis is the leading cause of bacterial sexuallytransmitted diseases (STDs) and the main cause of preventable blindness worldwide _ENREF_1[1]. The 19 known serovars of C. trachomatis are categorized into three disease groups: ocular, urogenital, and the invasive lymphogranuloma venereum (LGV) The latter pathogens include the L1, L2, L2a, and L3 strains that infect the reticuloendothelial system involving predominantly the lymph nodes [3,4]. Infection of epithelial cells by chlamydiae initiates an inflammatory response through ligation of Toll-like receptors (TLRs) and Nod-like receptors [5,6]. These receptors are usually expressed by immune cells such as macrophages, dendritic cells and neutrophils, and mucosal epithelial cells [7,8,9,10]. The degradation of I-kB releases the activated nuclear factor-kB (NFkB), which allows it to translocate into the nucleus and stimulate the expression of pro-inflammatory components, such as interleukin (IL)-8, IL-6, IL-18, IL-1a and granulocyte-macrophage colony-stimulating factor (GM-CSF) that recruit and activate various immune cells [14,15,16,17]
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