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Published on: August 5, 2016
Utilization of Host Polyamines in Alternatively Activated Macrophages Promotes Chronic Infection by Brucella abortus
Tobias Kerrinnes1,2, Maria G Winter3, Briana M Young1
1Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, USA.
Abstract:
Treatment of intracellular bacterial pathogens with antibiotic therapy often requires a long course of multiple drugs. A barrier to developing strategies that enhance antibiotic efficacy against these pathogens is our poor understanding of the intracellular nutritional environment that maintains bacterial persistence. The intracellular pathogen Brucella abortus survives and replicates preferentially in alternatively activated macrophages (AAMs); however, knowledge of the metabolic adaptations promoting exploitation of this niche is limited. Here we show that one mechanism promoting enhanced survival in AAMs is a shift in macrophage arginine utilization from production of nitric oxide (NO) to biosynthesis of polyamines, induced by interleukin 4 (IL-4)/IL-13 treatment. Production of polyamines by infected AAMs promoted both intracellular survival of B. abortus and chronic infection in mice, as inhibition of macrophage polyamine synthesis or inactivation of the putative putrescine transporter encoded by potIHGF reduced both intracellular survival in AAMs and persistence in mice. These results demonstrate that increased intracellular availability of polyamines induced by arginase-1 expression in IL-4/IL-13-induced AAMs promotes chronic persistence of B. abortus within this niche and suggest that targeting of this pathway may aid in eradicating chronic infection.
Insights
Macrophages utilize arginine for polyamine synthesis, aiding intracellular bacteria like Brucella abortus survival. Targeting this metabolic shift offers a potential strategy for treating chronic Brucella infections.
Area of Science:
- Immunology
- Microbiology
- Metabolic pathways
Background:
- Intracellular bacterial pathogens require long antibiotic treatments.
- Understanding the intracellular environment is key to enhancing antibiotic efficacy.
- Brucella abortus thrives in alternatively activated macrophages (AAMs), but its metabolic adaptations are poorly understood.
Purpose of the Study:
- To investigate the metabolic adaptations of Brucella abortus within alternatively activated macrophages.
- To identify mechanisms promoting bacterial survival and persistence in the AAM niche.
- To explore potential therapeutic targets for chronic Brucella infections.
Main Methods:
- Analyzing macrophage arginine utilization shifts induced by interleukin-4 (IL-4)/interleukin-13 (IL-13) treatment.
- Investigating the role of polyamine biosynthesis in Brucella abortus intracellular survival.
- Assessing the impact of inhibiting polyamine synthesis or a specific transporter (potIHGF) on bacterial persistence.
Main Results:
- IL-4/IL-13 treatment shifts macrophage arginine metabolism from nitric oxide (NO) production to polyamine biosynthesis.
- Increased polyamine production in infected AAMs enhances Brucella abortus intracellular survival and promotes chronic infection in mice.
- Inhibiting polyamine synthesis or the potIHGF transporter reduces Brucella abortus survival in AAMs and persistence in vivo.
Conclusions:
- Macrophage polyamine biosynthesis, induced by IL-4/IL-13 via arginase-1, promotes chronic Brucella abortus persistence.
- Targeting the macrophage polyamine pathway may be a novel strategy for eradicating chronic Brucella infections.
