Stimulator of IFN Gene Is Critical for Induction of IFN-β during Chlamydia muridarum Infection

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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-β are unclear. Previous studies have demonstrated no role for TLR4 and a partial role for MyD88 in chlamydial-induced IFN-β. In this study, we demonstrate that mouse macrophages lacking TLR3, TRIF, TLR7, or TLR9 individually or both TLR4 and MyD88, still induce IFN-β 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-β. 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-β mRNA expression, suggesting a critical role for STING in chlamydial-induced IFN-β 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-β depended on the downstream transcription IFN regulatory factor 3, and on activation of NF-κB 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-β 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-κB, and p38 MAPK.