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

SANMARCO, LILIANA MARÍA; QUEBRADA PALACIO, LUZ PIEDAD; MINGUEZ, ÁNGEL RAMÓN; MORELLI, LAURA; BERGERO, GASTÓN; VISCONTI, LAURA MARINA; SILVA, EUGENIO ANTONIO CARRERA; AOKI, MARIA PILAR; EBERHARDT, NATALIA; ADAMI, PAMELA MARTINO; HERNÁNDEZ-VASQUEZ, YOLANDA; POSTAN, MIRIAM

JCI Insight

American Society for Clinical Investigation

Lugar: Michigan; Año: 2019 vol. 4 p. 1 - 16

Chagas disease is a lifelong pathology resulting from Trypanosoma cruzi infection. It representsone of the most frequent causes of heart failure and sudden death in Latin America. Herein, weprovide 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 withchronic Chagas disease. Monocytes from patients exhibited a higher frequency of hypoxia-induciblefactor 1α and increased expression of its target genes/proteins. Nonclassical monocytes areexpanded in patients? peripheral blood and represent an important source of NO. Monocytes entailCD8+ T cell surface nitration because both the frequency of nonclassical monocytes and that ofNO-producing monocytes positively correlated with the percentage of TN+ lymphocytes. Inhibitionof glycolysis in in vitro?infected peripheral blood mononuclear cells decreased the inflammatoryproperties of monocytes/macrophages, diminishing the frequency of IL-1β? and NO-producingcells. In agreement, glycolysis inhibition reduced the percentage of TN+CD8+ T cells, improvingtheir functionality. Altogether, these results clearly show that glycolysis governs oxidative stresson monocytes and modulates monocyte?T cell interplay in human chronic Chagas disease.Understanding the pathological immune mechanisms that sustain an inflammatory environment inhuman pathology is key to designing improved therapies.