Response toNeisseria gonorrhoeaeby Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling

Abstract

Toll-like receptors (TLRs) have recently been identified as fundamental components of the innate immune response to bacterial pathogens. We investigated the role of TLR signaling in immune defense of the mucosal epithelial cells of the lower female genital tract. This site provides first line defense against microbial pathogens while remaining tolerant to a complex biosystem of resident microbiota. Epithelial cells derived from normal human vagina, ectocervix, and endocervix expressed mRNA for TLR1, -2, -3, -5, and -6. However, they failed to express TLR4 as well as MD2, two essential components of the receptor complex for LPS in phagocytes and endothelial cells. Consistent with this, endocervical epithelial cells were unresponsive to protein-free preparations of lipooligosaccharide from Neisseria gonorrhoeae and LPS from Escherichia coli. However, they were capable of responding to whole Gram-negative bacteria and bacterial lysates, as demonstrated by NF-κB activation and proinflammatory cytokine production. The presence of soluble CD14, a high-affinity receptor for LPS and other bacterial ligands, enhanced the sensitivity of genital tract epithelial cells to both low and high concentrations of bacteria, suggesting that soluble CD14 can act as a coreceptor for non-TLR4 ligands. These data demonstrate that the response to N. gonorrhoeae and other Gram-negative bacteria at the mucosal surface of the female genital tract occurs in the absence of endotoxin recognition and TLR4-mediated signaling.

TREM-2 binds to lipooligosaccharides of Neisseria gonorrhoeae and is expressed on reproductive tract epithelial cells

“…In our examination of TREM-2 expression by cell types relevant to the pathogenesis of gonorrhea, we found that human TREM-2 is constitutively expressed by genitourinary epithelial cells and by the fallopian tube epithelium, both of which are primary targets of gonococcal invasion (12,38,39). To our knowledge, this is the first report of the expression of human TREM-2 by cells deriving from a non-myeloid lineage.…”

“…We next determined whether human TREM-2 is constitutively expressed by reproductive tract epithelial cells that are known to be invaded by N. gonorrhoeae (12,38,39). Constitutive expression of TREM-2 by cultured human ectocervical, endocervical, vaginal, ME-180, and HeLa cells was detected by flow cytometry (Figure 7).…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…Some observed the presence of TLR4, [60][61][62] while others reported the absence. 63,64 In normal human intestinal epithelial cells, TLR2 and TLR4 are expressed at low level. [65][66][67][68] The differential expression of PRRs at different sites may be related to the different microenvironments and the different roles of PRRs.…”

The Lip Lipoprotein from Neisseria gonorrhoeae Stimulates Cytokine Release and NF-κB Activation in Epithelial Cells in a Toll-like Receptor 2-dependent Manner

“…Treatments of the End/E6E7 cells were in keratinocyte serum-free growth medium. Soluble CD14, at a concentration of 500 ng/ml, was added to the medium when indicated (41). Treatments for the HEK 293 cells were in medium supplemented with 10% fetal bovine serum.…”