Reduced IP6K levels impair life-cycle transitions and intracellular development of Trypanosoma cruzi within human cardiomyocytes

Abstract

Trypanosoma cruzi is the etiological agent of Chagas disease (CD). During its life cycle, T. cruzi undergoes several key differentiation processes that are essential for its survival. The precise mechanisms that regulate these processes remain elusive, and any interference in this cycle would represent a breakthrough in the development of effective therapy against CD. Here we show that key differentiation processes of T. cruzi (metacyclogenesis, amastigogenesis and trypomastigogenesis) are profoundly impaired in response to low inositol hexakisphosphate kinase (IP6K) levels. Epimastigote forms of IP6K-deficient T. cruzi exhibit morphological alterations and reduced metacyclogenesis. IP6K-deficient metacyclic forms show reduced infective potential in human cardiomyocytes. IP6K-deficient amastigote forms present impaired ability to transform into trypomastigotes, with most of the population egressing from human cardiomyocytes without completing trypomastigogenesis. Although IP6K catalyzes the formation of inositol pyrophosphates (IP7), the levels of this metabolite do not undergo significant reduction in response to low IP6K levels, suggesting that this kinase sustains the T. cruzi life cycle through non-canonical functions. Since total depletion of IP6K is lethal and the primary structure of IP6K shares only ~25% similarity with its human homolog, this kinase emerges as a promising target for drug development against CD. In response to low IP6K levels, the parasite Trypanosoma cruzi - the etiological agent of Chagas disease - exhibits impaired differentiation processes, suggesting that this kinase is fundamental to its life cycle.