Ablation of telomerase reverse transcriptase in Leishmania major results in a senescent-like phenotype and loss of infectivity

Abstract

Abstract The lack of efficient human vaccines and effective nontoxic drugs for leishmaniasis necessitates a search for new therapeutic targets. The telomere environment could provide potential targets against leishmaniasis. TERT, the telomerase reverse transcriptase component, has been on the radar for new therapeutic options against several diseases for more than two decades. In this study, we constructed a full deletion ( Lm TERT-/-) and an ORF disruption ( Lm N420) of the gene encoding the TERT component of Leishmania major . Lm TERT-/- and Lm N420 parasites showed replicative and proliferative defects, growth impairment, cell cycle alterations, increased DNA damage, and progressive telomere shortening. Blockage of parasite altruism and the presence of autophagosomes characteristic of a senescent-like phenotype were also detected. Lm TERT-/- and Lm N420 parasites caused either micro lesion development or no visible lesions in mouse footpads and reduced infectivity in macrophages. While our checks to see if telomere erosion had reached the SCG genes involved in lipophosphoglycan modification showed no changes, our proteomic assessment revealed a downregulation of a metacyclic-associated protein. Complementation of the knockout lineages using the WT Lm TERT restored some of the lost phenotypes. Therefore, we speculate that the pleiotropic effects of the loss of Lm TERT advance the case for using it as a drug target against the parasite.