Acquisition of nutrients by Chlamydiae: unique challenges of living in an intracellular compartment

Abstract

The Chlamydiae are obligate intracellular pathogens that replicate within a membrane-bound vacuole, termed the 'inclusion'. From this compartment, bacteria acquire essential nutrients by selectively redirecting transport vesicles and hijacking intracellular organelles. Rerouting is achieved by several mechanisms including proteolysis-mediated fragmentation of the Golgi apparatus, recruitment of Rab GTPases and SNAREs, and translocation of cytoplasmic organelles into the inclusion lumen. Given Chlamydiae's extended coevolution with eukaryotic cells, it is likely that co-option of multiple cellular pathways is a strategy to provide redundancy in the acquisition of essential nutrients from the host and has contributed to the success of these highly adapted pathogens.

Figure 1

Schematic representation of host cell pathways exploited by Chlamydiae to acquire nutrients. (A) Golgin-84 is proteolytically processed during infection through activation of host caspases, calpains and potentially by bacterial protease(s). This leads to Golgi fragmentation into ribbon-like structures in a process mediated by Rab-6 and Rab-11. These Golgi ministacks are recruited around the inclusion. Formation of Golgi-ministacks is necessary for chlamydial uptake of host sphingolipids and replication. Golgi-derived exocytic vesicles containing sphingolipids and cholesterol fuse with the inclusion. (B) GPI-anchored plasma membrane protein CD59 is trafficked to the inner face of the inclusion in a Golgi-independent manner. (C) Infection leads to increased phosphorylation of extracellular signal-regulated map kinase (ERK) which, in turn, activates calcium-dependent cytosolic phospholipase A2 (cPLA2). cPLA2 removes straight chain fatty acids from the sn2 position of host glycerophospholipids to generate lyso-phospholipids (Lyso-PL). Chlamydia-derived branched fatty acids (b-FA) are incorporated into Lyso-PL to generate Chlamydia-modified phospholipids (Chl-PL). (D) Chlamydia targets multivesicular bodies (MVB) to sequester required nutrients like sphingolipids and cholesterol. (E) Lipid droplets, the main store of neutral lipids, are targeted by Chlamydia lipid droplet-associated proteins (Lda) and translocated into the inclusion. (F) Pan-species recruitment of Rab-1, Rab-4, and Rab-11, whereas Rab-6 and Rab-10 are recruited to C. trachomatis and C. pneumoniae inclusions, respectively. Candidate bacterial recruitment factors have been identified (Cpn0585 and CT229). (G) SNARE proteins Vamp-3, 7 and 8 are recruited to the inclusion, possibly by chlamydial proteins containing SNARE-like motifs (like incA and CT813) in the inclusion membrane.