Understanding and modulating macrophage metabolism for improving inflammatory functions against Trypanosoma cruzi infection
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This dissertation aims to illuminate how metabolism regulates the pro-inflammatory functions in macrophages for improving the clearance of Trypanosoma cruzi infection. T. cruzi is the etiologic agent of Chagas disease, which affects over 8 million people and current therapy has limited efficacy. Macrophages are one of the first sentinels to T. cruzi infection yet are susceptible to infection. Prior research indicated that glycolysis and broken Krebs cycle support pro-inflammatory functions of macrophages. This study advances our understanding of how T. cruzi infection shifts the metabolism of macrophages and suppress accumulation of oxidative mediators. The first is to evaluate the pro-inflammatory macrophage response to T. cruzi with respect to production of pro-inflammatory mediators and metabolic state. The second is to modulate the macrophage metabolism during infection and evaluate the functional outcome, with the focus on a lipid metabolism transcription factor, peroxisome proliferator-activated receptor-α (PPAR-α), and oxidative species generation. This study tested two hypotheses: that macrophages infected with T. cruzi fail to metabolically and phenotypically shift to the pro-inflammatory phenotype, and that modulating PPAR-α is a strategy to improve macrophage function against T. cruzi. The findings of this research demonstrate that macrophages infected with T. cruzi poorly accumulate reactive oxygen species and nitric oxide, in which the shunt to the pentose phosphate pathway is important for oxidative species generation and suppressing T. cruzi survival and replication. Contrary to our expectations, inhibition of PPAR-α and mitochondrial pyruvate transport moderately suppressed oxidative species levels. Supplying macrophages with IFN-γ during infection succeeded in shifting metabolism to glycolysis and enhancing oxidative species levels. We conclude that the pentose phosphate pathway is vital in the T. cruzi clearing response of macrophages and could serve as a novel basis for a strategy to improve the innate immune response to T. cruzi infection and prevent Chagas disease progression.