Gene deletion as a possible strategy adopted by New WorldLeishmania infantumto maximize geographic dispersion

Abstract

AbstractBackgroundThe present study investigates implications of a sub-chromosomal deletion inLeishmania infantumstrains, the causative agent of American Visceral Leishmaniasis (AVL). Primarily found in New World strains, the deletion leads to the absence of the ecto-3’-nucleotidase/nuclease enzyme (3’NU/NT), impacting parasite virulence, pathogenicity, and drug susceptibility. The potential factors favoring prevalence and the widespread geographic distribution of these deleted mutant parasites (DEL) in the New World (NW) are discussed under the generated data.MethodsWe conducted phenotypic analyses of the parasites showing the sub- chromosomal deletion by applyingin vitroassays of 3’NU/NT activity, metacyclic enrichment, and relative quantitation of transcripts abundance on axenic parasites. We further performed experimental infections in bothin vitroandin vivomodels of vertebrate and invertebrate hosts using geographically diverse mutant field isolates.ResultsVirulence assays, poorer ability to survive neutrophil traps (NETs) and murine model infection revealed reduced pathogenicity in vertebrate hosts by the DEL strains. Conversely, these parasites exhibit enhanced metacyclogenesis and colonization rates in sand flies, potentially facilitating transmission. This combination may represent a more efficient way to maintain and disperse the transmission cycle of DEL strains.ConclusionsPhenotypic assessments reveal altered parasite fitness, with enhanced transmissibility at the population level. Reduced susceptibility of DEL strains to miltefosine, a key drug in VL treatment, further complicates control efforts. Our study underscores the importance of typing parasite genomes for surveillance and control and proposes the sub-chromosomal deletion as a molecular marker in AVL management.