Journal Article

Sequestration of host metabolism by an intracellular pathogen

Perrinet, Stéphanie, Nelson, David E, Gehre, Lena, Prevost, Marie-Christine, Subtil, Agathe, Gorgette, Olivier, Giebel, Amanda M, Ducatez, Mathieu, Ball, Steven G

2016

Overview

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. Chlamydia trachomatis is the most common sexually transmitted bacteria that causes disease. Infections often do not produce any obvious symptoms, but can lead to infertility or other severe problems if left untreated. This microbe is also the leading cause of blindness by an infectious agent.The bacteria grow in the human body by infecting host cells. Inside these cells, the bacteria are found inside compartments known as inclusions, which protect them from the host’s defense responses and enable them to create a comfortable environment for themselves. However, this comes at a cost because the bacteria lose immediate access to the nutrients in the rest of the host cell. Thus, C.trachomatis has developed ways to import these nutrients into inclusions, and, more generally, to take the control of its interactions with the host cell. The inclusions built up by C. trachomatis contain a high amount of glycogen, a carbohydrate that generally acts as an energy storage molecule. Although this observation was made many decades ago, the molecular mechanism by which such a large molecule accumulates in the inclusion has not been clarified. Gehre et al. have now used a variety of cell biology techniques to address this question. The experiments show that there are two different pathways through which glycogen accumulates within the inclusion. Some glycogen is transported in bulk from the interior of the host cell into the inclusion. However, the bacteria also make new glycogen in the inclusion from a building block molecule called UDP-glucose. To do this, the bacteria recruit a host transport molecule to the membrane that surrounds the inclusion. This transport molecule brings UDP-glucose into the inclusion, where an enzyme called glycogen synthase – which is released by the bacteria – uses the UDP-glucose to make glycogen. The C. trachomatis glycogen synthase is unusual because most other bacteria can only make glycogen from another type of glucose. By using both pathways, C. trachomatis is able to trap most of the glycogen stores of the infected cell within the inclusion so that they are inaccessible to the host but ready for the bacteria to use. Previous work has shown that C. trachomatis is much better at accumulating glycogen than other Chlamydia bacteria are. Therefore, a future challenge will be to find out exactly how this helps C. trachomatis survive inside human cells.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publication,eLife Sciences Publications, Ltd
• Subject: Animals / Bacteria / Bacterial glycogen synthase / Bacterial Proteins - metabolism / Bacteriology / Biological Transport / Biosynthesis / Cell Behavior / Cell Biology / Cell Line / Cellular Biology / Chlamydia / chlamydia trachomatis / Chlamydia trachomatis - growth & development / Chlamydia trachomatis - metabolism / Chlamydiae / Enzymes / Genetics / Genomes / Glycogen / Glycogen - metabolism / Glycogen synthase / Glycogen Synthase - metabolism / Host-parasite relationships / Host-Pathogen Interactions / Human genetics / Human health and pathology / Humans / Infections / Infectious diseases / Intracellular / intracellular parasites / Iodine / Life Sciences / Metabolism / Microbiology and Infectious Disease / Microbiology and Parasitology / Mutation / Nucleotide Transport Proteins - metabolism / Nutrients / Observations / Pathogens / Potassium / Pulmonology and respiratory tract / Secretion / Shelters / Shigella / Stains & staining / Uridine Diphosphate Glucose - metabolism / Vacuoles / Vacuoles - chemistry / Vacuoles - microbiology