RRC ID 11806
Author Prantner D, Darville T, Nagarajan UM.
Title Stimulator of IFN gene is critical for induction of IFN-beta during Chlamydia muridarum infection.
Journal J Immunol
Abstract Type I IFN signaling has recently been shown to be detrimental to the host during infection with Chlamydia muridarum in both mouse lung and female genital tract. However, the pattern recognition receptor and the signaling pathways involved in chlamydial-induced IFN-beta are unclear. Previous studies have demonstrated no role for TLR4 and a partial role for MyD88 in chlamydial-induced IFN-beta. In this study, we demonstrate that mouse macrophages lacking TLR3, TRIF, TLR7, or TLR9 individually or both TLR4 and MyD88, still induce IFN-beta equivalent to wild type controls, leading to the hypothesis that TLR-independent cytosolic pathogen receptor pathways are crucial for this response. Silencing nucleotide-binding oligomerization domain 1 in HeLa cells partially decreased chlamydial-induced IFN-beta. Independently, small interfering RNA-mediated knockdown of the stimulator of IFN gene (STING) protein in HeLa cells and mouse oviduct epithelial cells significantly decreased IFN-beta mRNA expression, suggesting a critical role for STING in chlamydial-induced IFN-beta induction. Conversely, silencing of mitochondria-associated antiviral signaling proteins and the Rig-I-like receptors, RIG-I, and melanoma differentiation associated protein 5, had no effect. In addition, induction of IFN-beta depended on the downstream transcription IFN regulatory factor 3, and on activation of NF-kappaB and MAPK p38. Finally, STING, an endoplasmic reticulum-resident protein, was found to localize in close proximity to the chlamydial inclusion membrane during infection. These results indicate that C. muridarum induces IFN-beta via stimulation of nucleotide-binding oligomerization domain 1 pathway, and TLR- and Rig-I-like receptor-independent pathways that require STING, culminating in activation of IFN regulatory factor 3, NF-kappaB, and p38 MAPK.
Volume 184(5)
Pages 2551-60
Published 2010-3-1
DOI 10.4049/jimmunol.0903704
PII jimmunol.0903704
PMID 20107183
PMC PMC2863030
MeSH Adaptor Proteins, Vesicular Transport / deficiency Adaptor Proteins, Vesicular Transport / genetics Animals Cell Line Cells, Cultured Chlamydia muridarum / genetics* Chlamydia muridarum / physiology Female HeLa Cells Host-Pathogen Interactions Humans Interferon-beta / genetics Interferon-beta / metabolism* Macrophages, Peritoneal / cytology Macrophages, Peritoneal / metabolism* Macrophages, Peritoneal / microbiology Male Membrane Glycoproteins / deficiency Membrane Glycoproteins / genetics Membrane Proteins / genetics Membrane Proteins / metabolism* Mice Mice, Inbred C57BL Mice, Inbred Strains Mice, Knockout Myeloid Differentiation Factor 88 / deficiency Myeloid Differentiation Factor 88 / genetics RNA Interference Toll-Like Receptor 3 / deficiency Toll-Like Receptor 3 / genetics Toll-Like Receptor 4 / deficiency Toll-Like Receptor 4 / genetics Toll-Like Receptor 7 / deficiency Toll-Like Receptor 7 / genetics Toll-Like Receptor 9 / deficiency Toll-Like Receptor 9 / genetics
IF 4.886
Times Cited 71
WOS Category IMMUNOLOGY
Resource
Mice RBRC00858 RBRC01420