PT  - JOURNAL ARTICLE
AU  - Daniel M. Czyż
AU  - Jonathan Willett
AU  - Sean Crosson
TI  - <em>Brucella abortus</em> induces a Warburg shift in host metabolism that enhances intracellular replication of the pathogen
AID  - 10.1101/120527
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 120527
4099  - http://biorxiv.org/content/early/2017/03/25/120527.short
4100  - http://biorxiv.org/content/early/2017/03/25/120527.full
AB  - Intracellular bacterial pathogens exploit host cell resources to replicate and survive inside the host. Targeting these host systems is one promising approach to developing novel antimicrobials for intracellular infections. We show that human macrophage-like cells infected with Brucella abortus undergo a metabolic shift characterized by attenuated tricarboxylic acid cycle metabolism, altered mitochondrial morphology and increased lactate production. This shift to an aerobic glycolytic state resembles the Warburg effect, a change in energy production that is well-described in cancer cells, and also occurs in activated inflammatory cells. B. abortus efficiently uses lactic acid as a carbon and energy source and requires the ability to metabolize lactate for normal replication in human macrophage-like cells. We further demonstrate that chemical inhibitors of host glycolysis and lactate production do not affect in vitro growth of B. abortus in axenic culture, but decrease its replication in the intracellular niche. Our data support a model in which infection shifts host metabolism to a Warburg-like state, and B. abortus uses this change in metabolism to promote intracellular replication. Pharmacological perturbation of these features of host cell metabolism may be a useful strategy to inhibit infection by intracellular pathogens.IMPORTANCE Brucella spp. are intracellular pathogens that cause disease in a range of mammals, including livestock. Transmission from livestock to humans is common and can lead to chronic human disease. Human macrophage-like cells infected with Brucella abortus undergo a Warburg-like metabolic shift to an aerobic glycolytic state that produces lactic acid, which B. abortus can use as a carbon and energy source to promote its growth. We provide evidence that the pathogen exploits this change in host metabolism to replicate in the intracellular niche. Drugs that target this feature of host cell metabolism inhibit intracellular replication of B. abortus and may be broadly useful therapeutics for intracellular infections.