Bioenergetic Profiling of Lymphocytes in Patients With Visceral Leishmaniasis (VL) and Post Kala-Azar Dermal...

Studies pertaining to Visceral leishmaniasis (VL) and its dermal sequel, Post Kala-azar Dermal Leishmaniasis (PKDL) are usually restricted to their immunopathogenesis, but the role, if any, regarding metabolic dysfunction of lymphocytes remains unanswered, and was the focus of this study. To delineate and correlate the functional and bioenergetic status of lymphocytes in patients with VL and PKDL. In Peripheral blood of patients with VL (n = 11) or PKDL (n = 18), along with healthy controls (n = 10), the T lymphocyte subsets (CD4⁺ and CD8⁺), their activation (CD69) and exhaustion (CD279) status were determined by flow cytometry. Oxidative phosphorylation (OXPHOS) and glycolysis were measured concomitantly in an extracellular flux analyser, whilst the status of mitochondrial respiration and glycolysis related genes was measured by qPCR. In comparison to healthy controls, the activation status remained unchanged in VL and PKDL cases but the frequency of exhausted T cells was significantly raised. These exhausted T cells showed an increased expression of OXPHOS in terms of signalling markers (SMAD3 and CPT1A) and oxygen consumption rate (OCR), along with an increased expression of mitochondrial respiration genes, which correlated positively with CD279⁺ T cells, whereas glycolysis remained unchanged. Patients with VL and PKDL demonstrated increased expression of CD279/Programmed cell death protein 1 (PD-1). This PD-1 signalling possibly activated SMAD3 and mitochondrial CPT1A, which led to increased mitochondrial respiration. This metabolic adaptation possibly facilitated sustenance of the exhausted T cell phenotype and contributed to disease progression. Targeting immunometabolism could well be a therapeutic approach worthy of future pharmacological consideration.