PPARγ-Mediated Increase in Glucose Availability Sustains Chronic Brucella abortus Infection in Alternatively Activated Macrophages

•B. abortus is associated with AAMs during chronic infection in mice•AAMs support high levels of intracellular B. abortus replication•PPARγ activation contributes to increased persistence of B. abortus in vivo•Elevated glucose in AAMs promotes increased intracellular replication of B. abortus

SummaryEradication of persistent intracellular bacterial pathogens with antibiotic therapy is often slow or incomplete. However, strategies to augment antibiotics are hampered by our poor understanding of the nutritional environment that sustains chronic infection. Here we show that the intracellular pathogen Brucella abortus survives and replicates preferentially in alternatively activated macrophages (AAMs), which are more abundant during chronic infection. A metabolic shift induced by peroxisome proliferator-activated receptor γ (PPARγ), which increases intracellular glucose availability, is identified as a causal mechanism promoting enhanced bacterial survival in AAMs. Glucose uptake was crucial for increased replication of B. abortus in AAMs, and for chronic infection, as inactivation of the bacterial glucose transporter gluP reduced both intracellular survival in AAMs and persistence in mice. Thus, a shift in intracellular nutrient availability induced by PPARγ promotes chronic persistence of B. abortus within AAMs, and targeting this pathway may aid in eradicating chronic infection.