Stimulation of the cytosolic receptor for peptidoglycan, Nod1, by infection with Chlamydia trachomatis or Chlamydia muridarum

Abstract

SummaryInfection of epithelial cells by the intracellular pathogen, Chlamydia trachomatis , leads to activation of NFk B and secretion of pro-inflammatory cytokines. We find that overexpression of a dominant-negative Nod1 or depletion of Nod1 by RNA interference inhibits partially the activation of NF-k B during chlamydial infection in vitro , suggesting that Nod1 can detect the presence of Chlamydia . In parallel, there is a larger increase in the expression of pro-inflammatory genes following Chlamydia infection when primary fibroblasts are isolated from wild-type mice than from Nod1 -deficient mice. The Chlamydia genome encodes all the putative enzymes required for proteoglycan synthesis, but proteoglycan from Chlamydia has never been detected biochemically. Since Nod1 is a ubiquitous cytosolic receptor for peptidoglycan from Gram-negative bacteria, our results suggest that C. trachomatis and C. muridarum do in fact produce at least the rudimentary proteoglycan motif recognized by Nod1. Nonetheless, Nod1 deficiency has no effect on the efficiency of infection, the intensity of cytokine secretion, or pathology in vaginally infected mice, compared with wild-type controls. Similarly, Rip2, a downstream mediator of Nod1, Toll-like receptor (TLR)-2, and TLR4, increases only slightly the intensity of chlamydial infection in vivo and has a very mild effect on the immune response and pathology.Thus, Chlamydia may not produce sufficient peptidoglycan to stimulate Nod1-dependent pathways efficiently in infected animals, or other receptors of the innate immune system may compensate for the absence of Nod1 during Chlamydia infection in vivo .

Innate immunity and disorders of the female reproductive tract

“…Studies in mice also suggest that NOD1 does not play a major role in the genital tract response to chlamydial infection. While the presence of a dominant negative mutant of NOD1 partially inhibited NFKB activation as a result of chlamydial infection of the cervical epithelial HeLa cell line, proinflammatory mediator expression in the genital tracts of NOD1-deficient mice after chlamydial infection was comparable with that in wild-type mice (Welter-Stahl et al 2006). However, these data may not be representative of infection with C. trachomatis as the pathology of infection has been reported to differ between C. muridarum and C. trachomatis (Morre et al 2000).…”

Colonization of second-trimester placenta parenchyma

“…Both groups of microorganisms have cell wall constituents, such as peptidoglycan and lipoteichoic acid that are considered highly immunogenic. [33][34][35] Small amounts of these cell wall constituents have the potential to promote maturation of the fetal immune system during pregnancy. Since much of the developing neonatal immune system is provoked by GI microflora following birth, 36 might placenta bacteria play a role in immune development before birth?…”

Chlamydial Intracellular Survival Strategies

“…RNAi-mediated knockdown of NOD1, or its downstream adaptor RIP2, in infected epithelial and endothelial cells ablates expression of inflammatory cytokines (Opitz et al 2005;Welter-Stahl et al 2006;Buchholz and Stephens 2008). Similarly, Nod1 2/2 and Rip2 2/2 mice show significantly delayed clearance of C. pneumoniae from their lungs ).…”