Reprogramming of host glutamine metabolism during Chlamydia trachomatis infection and its key role in peptidoglycan synthesis

Nat Microbiol. 2020 Nov;5(11):1390-1402. doi: 10.1038/s41564-020-0762-5. Epub 2020 Aug 3.

Abstract

Obligate intracellular bacteria such as Chlamydia trachomatis undergo a complex developmental cycle between infectious, non-replicative elementary-body and non-infectious, replicative reticulate-body forms. Elementary bodies transform to reticulate bodies shortly after entering a host cell, a crucial process in infection, initiating chlamydial replication. As Chlamydia fail to replicate outside the host cell, it is unknown how the replicative part of the developmental cycle is initiated. Here we show, using a cell-free approach in axenic media, that the uptake of glutamine by the bacteria is crucial for peptidoglycan synthesis, which has a role in Chlamydia replication. The increased requirement for glutamine in infected cells is satisfied by reprogramming the glutamine metabolism in a c-Myc-dependent manner. Glutamine is effectively taken up by the glutamine transporter SLC1A5 and metabolized via glutaminase. Interference with this metabolic reprogramming limits the growth of Chlamydia. Intriguingly, Chlamydia failed to produce progeny in SLC1A5-knockout organoids and mice. Thus, we report on the central role of glutamine for the development of an obligate intracellular pathogenic bacterium and the reprogramming of host glutamine metabolism, which may provide a basis for innovative anti-infection strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System ASC / genetics
  • Amino Acid Transport System ASC / metabolism
  • Animals
  • Cell Line
  • Chlamydia Infections / metabolism*
  • Chlamydia Infections / microbiology
  • Chlamydia trachomatis / growth & development
  • Chlamydia trachomatis / metabolism
  • Chlamydia trachomatis / physiology*
  • Gene Expression Regulation
  • Glutamine / metabolism*
  • Host-Pathogen Interactions
  • Humans
  • Mice
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Peptidoglycan / biosynthesis*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction

Substances

  • Amino Acid Transport System ASC
  • Minor Histocompatibility Antigens
  • Peptidoglycan
  • Proto-Oncogene Proteins c-myc
  • Slc1a5 protein, mouse
  • Glutamine
  • Mitogen-Activated Protein Kinase Kinases