Identification of a novel bicarbonate transporter critical for Leishmania virulence

Leishmania parasites must regulate the intracellular pH to survive in acidic phagolysosomes of host macrophages. Yet, the precise mechanism remains unclear. While carbonic anhydrases are well-established in cytoplasmic buffering, their function alone is incomplete without an associated bicarbonate transporter. To date, no such transporter has been identified in Leishmania or other protozoans. Using pharmacological inhibition and ¹³ C-bicarbonate uptake assay, we demonstrate active bicarbonate uptake in Leishmania , implicating transmembrane transport. We report the identification of SLC26A homolog in the parasite, namely LmSLC26A, as the first bicarbonate transporter in Leishmania . Its localization to the plasma membrane is confirmed via immunofluorescence. Reduced Bicarbonate uptake and intracellular acidosis were observed in heterozygous knockout (LmSLC26A⁺/⁻) parasites, leading to reduced growth and cell viability, which are rescued by exogenous bicarbonate. Furthermore, LmSLC26A⁺/⁻ parasites showed reduced infectivity in both the macrophage and murine models. Together with its role in pH homeostasis and survival in host environments, LmLSC26A is revealed to be a critical regulator of Leishmania pH homeostasis, essential for survival and virulence. Its role in bicarbonate transport presents a promising therapeutic target for combating Leishmania infections.