Defects in triacylglycerol synthesis correlate with an increased Type I interferon response to Chlamydia trachomatis infection

SAKA, HA; JOEL T. HAAS; ROBERT V. FARESE JR; RAPHAEL VALDIVIA

San Antonio, Texas

Encuentro; CBRS 2013: 6th Biennial Meeting of the Chlamydia Basic Research Society; 2013

Chlamydia Basic Research Society

Defects in triacylglycerol synthesis correlate with an increased Type I interferon response to Chlamydia trachomatis infection Hector Alex Saka1, Joel T. Haas2, Robert V. Farese Jr.2 and Raphael Valdivia1 1 Dept. of Molecular Genetics and Microbiology, Duke University  Medical Center, Durham, NC, 27710; 2 Gladstone Institute for Cardiovascular Disease, University of California , San Francisco, CA 94158. Presenting author is underlined.   Lipid droplets (LDs) are ER-derived organelles consisting of a core of neutral lipids, mainly triacylglycerols and sterol-esters surrounded by a phospholipid monolayer. LDs accumulate in the vicinity of the inclusion in Chlamydia trachomatis-infected cells, leading to the eventual translocation of the whole organelle into the inclusion. To better understand the role that LDs play in Chlamydia infection, we used mouse embryo fibroblasts (MEF) derived from animals deficient for the diacylglycerol-acyltransferases (DGAT1 and DGAT2, responsible for triacylglycerol synthesis), which are devoid of LDs.  We found that C. trachomatis replication, as assessed by yield of infectious units, was severely impaired in DGAT1/2 knockout.  In contrast, the replication of the closely related species Chlamydia muridarum was not affected, suggesting that the reduction in C. trachomatis replication may not be related to nutritional stress.  We provide evidence that the ability of DGAT1/2 deficient MEFs to control C. trachomatis replication is linked to their capacity to engage a robust and sustained Type I interferon response to Chlamydia-derived nucleic acid ligands and other stimuli including synthetic analogs of dsDNA and dsRNA. This enhanced response correlated with an altered localization of STING (Stimulator of interferon genes), which predominantly localized to the Golgi apparatus instead of cytoplasmic punctate structures upon stimulation with exogenous cyclic dinucleotides or Chlamydia infection. Our results suggest that altered lipid homeostasis may be linked to innate immunity signaling by regulating the proper localization of proteins like STING which are required for the initiation and maintenance of interferon responses.