Reprogramming of host glutamine metabolism duringChlamydia trachomatisinfection and its key role in peptidoglycan synthesis

Obligate intracellular bacteria such asChlamydia trachomatisundergo 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. AsChlamydiafail 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 inChlamydiareplication. 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 ofChlamydia. Intriguingly,Chlamydiafailed 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. This study describes the mechanism by whichChlamydia trachomatisreprogrammes host glutamine metabolism in a c-Myc-dependent manner. The authors show that glutamine uptake via the SLC15A transporter and glutaminolysis are crucial for peptidoglycan synthesis andChlamydiareplication.