Host HDL biogenesis machinery is recruited to the inclusion ofChlamydia trachomatis-infected cells and regulates chlamydial growth

Abstract

SUMMARY Chlamydia trachomatis is an obligate intracellular bacterial pathogen that is the most common cause of sexually transmitted bacterial infections and is the etiological agent of trachoma, the leading cause of preventable blindness. The organism infects epithelial cells of the genital tract and eyelid resulting in a damaging inflammatory response. C. trachomatis grows within a vacuole termed the inclusion, and its growth depends on numerous host factors, including lipids. Although a variety of mechanisms are involved in the acquisition of host cell cholesterol and glycosphingolipids by C. trachomatis, none of the previously documented pathways for lipid acquisition are absolutely required for growth. Here we demonstrate that multiple components of the host high density lipoprotein (HDL) biogenesis machinery including the lipid effluxers, ABCA1 and CLA 1, and their extracellular lipid acceptor, apoA-1, are recruited to the inclusion of C. trachomatis-infected cells. Furthermore, the apoA-1 that accumulates within the inclusion co-localizes with pools of phosphatidylcholine. Knockdown of ABCA1, which mediates the cellular efflux of cholesterol and phospholipids to initiate the formation of HDL in the serum, prevents the growth of C. trachomatis in infected HeLa cells. In addition, drugs that inhibit the lipid transport activities of ABCA1 and CLA 1 also inhibit the recruitment of phospholipids to the inclusion and prevent chlamydial growth. These results strongly suggest that C. trachomatis co-opts the host cell lipid transport system involved in the formation of HDL to acquire lipids, such as phosphatidylcholine, that are necessary for growth.

Mycobacterium marinum Degrades Both Triacylglycerols and Phospholipids from Its Dictyostelium Host to Synthesise Its Own Triacylglycerols and Generate Lipid Inclusions

“…Interestingly, a similar observation was reported during infection of HeLa cells with Chlamydia trachomatis [40]. The authors showed that Bodipy-PC is first enriched at the membrane of the inclusion and finally gets incorporated into the bacteria themselves [40]. By TLC, we observed that the label of host phospholipids decreased during the first hours of infection, whereas fluorescently-labelled TAGs increased in the isolated lipid fraction from the bacteria, leading to the conclusion that host phospholipids of wild type and dgat1&2 DKO cells were successfully used as FA source (Figs 7 and 9C).…”

“…Interestingly, a similar observation was reported during infection of HeLa cells with Chlamydia trachomatis [40]. The authors showed that Bodipy-PC is first enriched at the membrane of the inclusion and finally gets incorporated into the bacteria themselves [40].…”

Chlamydia trachomatis Relies on Autonomous Phospholipid Synthesis for Membrane Biogenesis

“…PC, cholesterol, and SM are trafficked to the chlamydial inclusion to construct this specialized membrane (19,23,24,26). The lower yields of infectious C. trachomatis EB observed when host lipid synthesis/trafficking are inhibited illustrate the importance of host lipid metabolism to maximizing the yield of C. trachomatis (17,19,23,26). The effect of SM inhibitors shows that blocking SM synthesis does not stop C. trachomatis replication but leads to the premature rupture of the inclusion membrane releasing C. trachomatis into the host cytoplasm (23).…”

“…Second, C. trachomatis co-opts host trafficking pathways to mobilize host cell membrane lipids (PC, cholesterol, and sphingomyelin (SM)) from cellular organelles to assemble the inclusion and bacterial membrane systems. SM and cholesterol are trafficked from the Golgi (15,16,19,(23)(24)(25), and components of the host high density lipoprotein biogenesis machinery are recruited to the inclusion membrane to facilitate the translocation of PC (26). Lipid transfer is facilitated by the close association of the C. trachomatis inclusion with host organelles such as the endoplasmic reticulum (23,(27)(28)(29)(30) and multivesicular bodies (31)(32)(33).…”

Chlamydia cell biology and pathogenesis

“…61), dynamin 71 and FYN kinase 21 . Non-vesicular mechanisms involve lipid transporters, including the ceramide endoplasmic reticulum transport protein (CERT; also known as COL4α3BP) 73,74 , which directly binds to IncD (also known as CT115) 74,75 , and members of the high-density lipoprotein (HDL) biogenesis machinery, which deliver host phosphatidylcholine 76 . The acquisition of glycerophospholipids requires the activation of phospholipase A2 and mitogen-activated protein kinase (MAPK; also known as ERK) 21 .…”