Monocyte glycolysis determines CD8+ T cell functionality in human Chagas disease

JCI Insight. 2019 Sep 19;4(18):e123490. doi: 10.1172/jci.insight.123490.


Chagas disease is a lifelong pathology resulting from Trypanosoma cruzi infection. It represents one of the most frequent causes of heart failure and sudden death in Latin America. Herein, we provide evidence that aerobic glycolytic pathway activation in monocytes drives nitric oxide (NO) production, triggering tyrosine nitration (TN) on CD8+ T cells and dysfunction in patients with chronic Chagas disease. Monocytes from patients exhibited a higher frequency of hypoxia-inducible factor 1α and increased expression of its target genes/proteins. Nonclassical monocytes are expanded in patients' peripheral blood and represent an important source of NO. Monocytes entail CD8+ T cell surface nitration because both the frequency of nonclassical monocytes and that of NO-producing monocytes positively correlated with the percentage of TN+ lymphocytes. Inhibition of glycolysis in in vitro-infected peripheral blood mononuclear cells decreased the inflammatory properties of monocytes/macrophages, diminishing the frequency of IL-1β- and NO-producing cells. In agreement, glycolysis inhibition reduced the percentage of TN+CD8+ T cells, improving their functionality. Altogether, these results clearly show that glycolysis governs oxidative stress on monocytes and modulates monocyte-T cell interplay in human chronic Chagas disease. Understanding the pathological immune mechanisms that sustain an inflammatory environment in human pathology is key to designing improved therapies.

Keywords: Cardiovascular disease; Glucose metabolism; Immunology; Metabolism; Monocytes.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Case-Control Studies
  • Cell Communication / drug effects
  • Cell Communication / immunology*
  • Chagas Disease / blood
  • Chagas Disease / drug therapy
  • Chagas Disease / immunology*
  • Chlorocebus aethiops
  • Coculture Techniques
  • Female
  • Glycolysis / drug effects
  • Glycolysis / immunology*
  • Humans
  • Lymphocyte Activation / drug effects
  • Male
  • Middle Aged
  • Monocytes / drug effects
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Nitric Oxide / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / immunology
  • Primary Cell Culture
  • Protozoan Proteins / immunology
  • Trypanosoma cruzi / immunology*
  • Tyrosine / metabolism
  • Vero Cells
  • Young Adult


  • Protozoan Proteins
  • Nitric Oxide
  • Tyrosine