TLR3 Deficiency Leads to a Dysregulation in the Global Gene-Expression Profile in Murine Oviduct Epithelial Cells Infected with Chlamydia muridarum

Abstract

Chlamydia trachomatis replicates primarily in the epithelial cells lining the genital tract and induces the innate immune response by triggering cellular pathogen recognition receptors (PRRs). Our previous studies showed that Toll-like receptor 3 (TLR3) is expressed in murine oviduct epithelial (OE) cells, is the primary PRR triggered by C. muridarum (Cm) early during infection to induce IFN-β synthesis, and that TLR3 signaling regulates the chlamydial induced synthesis of a plethora of other innate inflammatory modulators including IL-6, CXCL10, CXCL16 and CCL5. We also showed that the expression of these cytokines induced by Chlamydia was severely diminished during TLR3 deficiency; however, the replication of Chlamydiain TLR3 deficient OE cells was more robust than in WT cells. These data suggested that TLR3 had a biological impact on the inflammatory response to Chlamydia infection; however, the global effects of TLR3 signaling in the cellular response to Chlamydia infection in murine OE cells has not yet been investigated. To determine the impact of TLR3 signaling on Chlamydia infection in OE cell at the transcriptome level, we infected wild-type (OE-WT) and TLR3-deficient (OE-TLR3KO) cells with Cm, and performed transcriptome analyses using microarray. Genome-wide expression and ingenuity pathway analysis (IPA) identified enhanced expression of host genes encoding for components found in multiple cellular processes encompassing: (1) pro-inflammatory, (2) cell adhesion, (3) chemoattraction, (4) cellular matrix and small molecule transport, (5) apoptosis, and (6) antigen-processing and presentation. These results support a role for TLR3 in modulating the host cellular responses to Cm infection that extend beyond inflammation and fibrosis, and shows that TLR3 could serve a potential therapeutic target for drug and/or vaccine development.

Host–Pathogen Interactions of Chlamydia trachomatis in Porcine Oviduct Epithelial Cells

“…Based on the role in transcriptional and translational interference, MX1 and MX2 upregulation by pOECs could aim to limit Ct propagation and thereby Ct infection within the genital tract. Regarding CMPK2, studies using murine genital tract epithelial cells have also shown an upregulation of CMPK2 mRNA upon C. muridarum infection [60]. The enzyme CMPK2 not only supplies deoxyribonucleotides for the synthesis of mitochondrial DNA (mtDNA) [61] but it also possesses immunomodulatory and antiviral activities: CMPK2 was shown to limit dengue virus infection of murine and human cells in an IFN-dependent and IFN-independent manner [62].…”

Potential IFNγ Modulation of Inflammasome Pathway in Chlamydia trachomatis Infected Synovial Cells

“…It is well known that C. trachomatis infects mainly the epithelial cells of the genital tract, but it can also replicate into different cell types, including synovial cells, human placental trophoblasts, and testicular human Sertoli cells [5][6][7][8][9][10]. Following chlamydial infection, the host cell response begins with the activation of a complex network of immune receptors and their unique downstream signaling pathways, resulting in the induction of proinflammatory cytokines involved in either the elimination of C. trachomatis or tissue damage related to chronic inflammatory state.…”

“…Following chlamydial infection, the host cell response begins with the activation of a complex network of immune receptors and their unique downstream signaling pathways, resulting in the induction of proinflammatory cytokines involved in either the elimination of C. trachomatis or tissue damage related to chronic inflammatory state. In particular, Toll-like receptors (TLRs), TLR2, TLR3 and TLR4, and oligomerization domain (NOD)-like receptors (NLRs), NOD1, as well as the respective downstream signaling pathways, like NFκb, IRF9 and MyD88, have been identified in the immune recognition of C. trachomatis in several in vivo and in vitro models [5,[7][8][9][10][11].…”