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

Abstract

SUMMARY Eradication 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 (AAM), 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 AAM. Glucose uptake was crucial for increased replication of B. abortus in AAM, and chronic infection, as inactivation of the bacterial glucose transporter gluP reduced both intracellular survival in AAM and persistence in mice. Thus, a shift in intracellular nutrient availability induced by PPARγ promotes chronic persistence of B. abortus within AAM and targeting this pathway may aid in eradicating chronic infection.

Brucella abortus Depends on Pyruvate Phosphate Dikinase and Malic Enzyme but Not on Fbp and GlpX Fructose-1,6-Bisphosphatases for Full Virulence in Laboratory Models

“…First, a B. abortus 2308 (and B. suis 1330) GluP (glucose/galactose transporter) mutant has been identified as attenuated in signature-tagged experiments (15,20,20). Second, it was reported recently that the multiplication of B. abortus in alternatively activated macrophages increases when the intracellular glucose levels are artificially increased (60). Based on these observations, an almost opposite model proposes a main role for 6 C sugars in the replicative niche (and 5 C sugars if we assume that the evidence obtained in B. melitensis also applies to B. abortus; see the introduction).…”

Vibrio vulnificus Secretes an Insulin-degrading Enzyme That Promotes Bacterial Proliferation in Vivo

“…Intracellular Salmonellae have been shown to relay on host intracellular glucose (41). Intracellular Brucella abortus also needs glucose for chronic infection (42). However, little is known about how extracellular bacterial pathogens access host metabolites (43).…”

Polarizing the T helper 17 response inCitrobacter rodentiuminfection via expression of resistin-like molecule α

“…First, compared with CAMacs, AAMacs exhibit a vastly different metabolic profile, resulting in a glucose-rich intracellular environment conducive for bacterial growth. 30,32 Additionally, AAMacs have deficient autophagy responses that are necessary for intracellular bacterial killing. 31 AAMacs may also impair bacterial clearance via cell-extrinsic mechanisms such as the inhibition of T cell activation or antibacterial CAMac responses.…”

“…[29][30][31][32] CAMacs differentiate in response to toll-like receptor ligands such as LPS and Th1 cytokines, and promote bacterial killing through the production of proinflammatory cytokines and microbicidal products. In contrast, AAMacs that differentiate in response to Th2 cytokines are considered antiinflammatory and express regulatory molecules such as Transforming Growth Factor β and arginase1.…”