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Deprecated: Implicit conversion from float 261.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Immunol 2014 ; 193 (5): 2394-404 Nephropedia Template TP
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The DNA sensor, cyclic GMP-AMP synthase (cGAS) is essential for induction of IFN beta during Chlamydia trachomatis infection1 #MMPMID25070851
J Immunol 2014[Sep]; 193 (5): 2394-404 PMID25070851show ga
IFN? has been implicated as an effector of oviduct pathology resulting from genital chlamydial infection in the mouse model. In this study, we investigated the role of cytosolic DNA and engagement of DNA sensors in IFN? expression during chlamydial infection. We determined that TREX-1, a host 3?to 5? exonuclease, reduced IFN? expression significantly during chlamydial infection using siRNA and gene knock out fibroblasts, implicating cytosolic DNA as a ligand for this response. The DNA sensor cGAS has been shown to bind cytosolic DNA to generate cGAMP, which binds to the signaling adaptor STING to induce IFN? expression. We determined that cGAS is required for IFN? expression during chlamydial infection in multiple cell types. Interestingly, although infected cells deficient for STING or cGAS alone failed to induce IFN?, co-culture of cells depleted for either STING or cGAS rescued IFN? expression. These data demonstrate that cGAMP produced in infected cGAS+STING? cells can migrate into adjacent cells via gap junctions to function in trans in cGAS?STING+ cells. Further, we observed cGAS localized in punctate regions on the cytosolic side of the chlamydial inclusion membrane in association with STING, indicating that chlamydial DNA is likely recognized outside the inclusion as infection progresses. These novel findings provide evidence that cGAS-mediated-DNA sensing directs IFN? expression during C.trachomatis infection and suggests that effectors from infected cells can directly upregulate IFN? expression in adjacent uninfected cells during in vivo infection, contributing to pathogenesis.