Sequestration of host metabolism by an intracellular pathogen

Abstract

For intracellular pathogens, residence in a vacuole provides a shelter against cytosolic host defense to the cost of limited access to nutrients. The human pathogen Chlamydia trachomatis grows in a glycogen-rich vacuole. How this large polymer accumulates there is unknown. We reveal that host glycogen stores shift to the vacuole through two pathways: bulk uptake from the cytoplasmic pool, and de novo synthesis. We provide evidence that bacterial glycogen metabolism enzymes are secreted into the vacuole lumen through type 3 secretion. Our data bring strong support to the following scenario: bacteria co-opt the host transporter SLC35D2 to import UDP-glucose into the vacuole, where it serves as substrate for de novo glycogen synthesis, through a remarkable adaptation of the bacterial glycogen synthase. Based on these findings we propose that parasitophorous vacuoles not only offer protection but also provide a microorganism-controlled metabolically active compartment essential for redirecting host resources to the pathogens.DOI: http://dx.doi.org/10.7554/eLife.12552.001

Chlamydial Plasmid-Dependent Pathogenicity

“…Many mucosal microbiota species both synthesize and consume glycogen and glycogen is known to promote microbiota fitness [132]. Fortunately, glgA mutants have been produced by the Nelson group [133], which can be used to dissect the roles of the pGP4-dependent chlamydial glycogen synthesis versus lytic exit in chlamydial pathogenicity in mice. Collaborative efforts are underway to address this.…”

Infection‐driven activation of transglutaminase 2 boosts glucose uptake and hexosamine biosynthesis in epithelial cells

“…We have recently shown that C. trachomatis acts as a glucose sink (Gehre et al , ). The host cell responds to glucose demand by increasing glucose uptake through overexpression of plasma membrane glucose transporters (Ojcius et al , ; Wang et al , ).…”

“…Since O ‐GlcNAcylation directly depends on UDP‐GlcNAc concentration, this observation suggests that UDP‐GlcNAc levels in the cytoplasm are not significantly increased in infected cells. We have previously demonstrated that C. trachomatis co‐opts SLC35D2, a host antiporter transporting UDP‐GlcNAc, UDP‐glucose, and GDP‐mannose to import these metabolites into the vacuole in which the bacteria develop (Gehre et al , ). We reasoned that UDP‐GlcNAc might not accumulate in the cytoplasm in infected cells because it was relocated to the inclusion lumen.…”

“…AbdelRahman & Belland, ). This obligate intracellular bacterium depends on the host to supply several essential metabolites, and in particular glucose (Stephens et al , ; Gehre et al , ). Epithelial cells respond to the infection with the secretion of proinflammatory cytokines such as interleukin‐6 (IL‐6) and IL‐8 (Rasmussen et al , ).…”

Biotic interactions as drivers of algal origin and evolution

“…Both glaucophytes and red algae store carbohydrates in their cytosol, suggesting that the glycogen/starch pool may have provided an opportunity to buffer the unsynchronized demand and supply of carbon of the cyanobiont and its host. Several observations support this idea: (1) enzymes involved in the manipulation of host carbohydrate metabolism are pathogen effectors secreted by the type‐III secretion system (Gehre et al ., ); (2) pathogenic Chlamydiae synthesize extracellular storage carbohydrates within parasitophorous vacuoles using analogous nucleotide‐sugars and nucleotide‐sugar transporters (Gehre et al ., ); (3) nucleotide‐sugar transporters of host origin are evolutionary ancestors of plastid carbon exporters in red and green algae, as well as in plastids of secondary or tertiary endosymbiotic origin (Moog et al ., ); and (4) analysis of the tryptophan biosynthesis pathway in Archaeplastida shows that one‐half (4/8) of the genes encoding proteins in this pathway are putatively of chlamydial origin, as are the Escherichia coli tyr/mtr (tyrosine/tryptophan) transporter genes (Cenci et al ., , ).…”