Control of lipid droplet homeostasis by Chlamydia

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PROJECT SUMMARY. C. trachomatis, the most common agent of bacterial sexually-transmitted infections, is an obligate intracellular pathogen that replicates inside a parasitic vacuole called the inclusion. The nascent inclusion is derived from the host plasma membrane and serves as a platform from which Chlamydia controls interactions with the host microenvironment. To survive inside the host cell, Chlamydia scavenges for nutrients and lipids by recruiting and fusing with various cellular compartments. Notably, C. trachomatis utilizes host fatty acids (FA) to promote its growth. In eukaryotic cells, lipid droplets (LDs) are the primary compartment for FA storage and they are involved in the intracellular development of Chlamydia. C. trachomatis acquires resources from the host using multiple strategies, including vesicle fusion, which is mediated by SNARE proteins [Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) Receptor]. The assembly of a specific vesicular SNARE (v-SNARE) with its cognate target SNARE (t-SNARE) complex into a stable four-helix bundle provides the energy necessary to disrupt and merge lipid bilayers during membrane fusion. Chlamydia has been shown to co-opt specific SNARE-mediated pathways to control lipid acquisition. We have recently shown that two SNARE proteins, SNAP23, and Syntaxin4, are involved in LD homeostasis during Chlamydia infection. Interestingly, knocking down SNAP23 or Syntaxin4 further increases the number of Chlamydia-induced LDs, but correlates with inhibition of Chlamydia replication. Since oleic acid (OA)-generated LDs in wild-type cells do not impair Chlamydia replication, these results suggest that a mere increase in LD number is not responsible for inhibiting Chlamydia progeny development. Instead, it suggests that a distinct subset of LDs is generated during infection, which is SNARE-dependent, and that loss of this LD subset and/or the presence of a different subset of LDs impacts Chlamydia progeny. Here, we propose to test the hypothesis that host and chlamydial proteins control the homeostasis of specific LDs during infection, which contributes to Chlamydia replication. Ultimately, this information will have a broad scientific impact as it will provide new insights (i) into the mechanisms used by Chlamydia to induce and co-opt host LDs and (ii) into the potential molecular mechanisms used by other pathogens to co-opt these organelles. Our results will shed light on this critical understudied pathway that is widely used by human pathogens.
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