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

Abstract

Obligate intracellular bacteria like Chlamydia trachomatis undergo a complex developmental cycle between infectious non-replicative (EBs) and non-infectious replicative (RBs) forms. EBs shortly after entering a host cell transform to RBs, a crucial process in infection, initiating chlamydial replication. As Chlamydia fail to replicate outside the host cell it is currently unknown how the replicative part of the developmental cycle is initiated. Here we show in a cell-free approach in axenic media that 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 limited 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-infective strategies.

Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of Chlamydia trachomatis during Treatment with β-Lactam Antimicrobials

“…In host cells, 2-oxoglutarate is an important intermediate in the mitochondrial TCA cycle, and glutamine is one of the important carbon sources to be catabolized to 2oxoglutarate (22)(23)(24). The first process of glutamine metabolism involves its conversion to glutamate by the mitochondrial matrix-localized phosphate-dependent glutaminase (55).…”

“…In C. trachomatis infection, glutamine is rapidly utilized via glutaminolysis and the TCA cycle in order to generate glutamate and other metabolites such as 2-oxoglutarate (24). Since citrate synthase, aconitate hydratase, and isocitrate dehydrogenase are lacking in the chlamydial TCA cycle (22,23), C. trachomatis has to acquire host cell-derived 2-oxoglutarate using the porin PorB or glutamine/glutamate that can be catabolized to 2-oxoglutarate to fuel its own TCA cycle (23,24,56). Therefore, we suggest that mitochondrial activation via PTPs-STAT3 plays a key role in the generation of ATP as well as the enhancement of glutamine metabolism to compensate for the truncated chlamydial TCA cycle in productive C. trachomatis infection.…”

c-Myc plays a key role in IFN-γ induced persistence ofChlamydia trachomatis

“…c-Myc is an important regulator of host cell metabolism and is indispensable for chlamydial acute infection and progeny formation 46 . Since Chlamydia obtain all nutrients from the host cell and it has been shown that several environmental conditions affecting host cell metabolism like iron and amino acid starvation also induce chlamydial persistence 51,52 , we investigated the role of c-Myc in chlamydial persistence.…”

“…Since Chlamydia obtain all nutrients from the host cell and it has been shown that several environmental conditions affecting host cell metabolism like iron and amino acid starvation also induce chlamydial persistence 51,52 , we investigated the role of c-Myc in chlamydial persistence. From our previous study, it was known that ablation of c-Myc expression interfered with chlamydial development and progeny formation 46 . To investigate if Chlamydia enter a persistence state in c-Myc depleted cells, we infected a HeLa 229 cell line with an anhydrotetracycline (AHT)-inducible short hairpin RNA (shRNA) for c-Myc in the absence and presence of the inducer.…”

“…In pyrimidine biosynthesis, the rate-limiting step is catalysed by carbamoyl aspartate dehydratase (CAD) 42 , which is also regulated by c-Myc as a response to growth stimulatory signals, such as activation of EGFR/RAS/MAP kinase 43 , Hif 1/2 α 44 or estrogen receptor/Sp1 45 pathways. We recently identified a central role of c-Myc in the control of the metabolism in Chlamydia-infected cells 46 . Chlamydia has a reduced genome and only very limited metabolic capacity.…”