BACKGROUND: The present study investigates implications of a sub-chromosomal deletion in Leishmania infantum strains, 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, impacting parasite virulence, pathogenicity, and drug susceptibility. The factors favoring prevalence and the widespread geographic distribution of these deleted mutant parasites (DEL) in the NW (NW) are discussed under the generated data. METHODS: We conducted phenotypic assessments of the sub-chromosomal deletion through in vitro assays with axenic parasites and experimental infections in both in vitro and in vivo models of vertebrate and invertebrate hosts using geographically diverse mutant field isolates. RESULTS: Despite reduced pathogenicity, the DEL strains efficiently infect vertebrate hosts and exhibit relevant differences, including enhanced metacyclogenesis and colonization rates in sand flies, potentially facilitating transmission. This combination may represent a more effective way to maintain and disperse the transmission cycle of DEL strains. CONCLUSIONS: Phenotypic assessments reveal altered parasite fitness, with potential enhanced transmissibility at the population level. Reduced susceptibility of DEL strains to miltefosine, a key drug in VL treatment, further complicates control efforts. The study underscores the importance of typing parasite genomes for surveillance and control, advocating for the sub-chromosomal deletion as a molecular marker in AVL management.

Department of Parasitology Faculty of Science Charles University Prague Czech Republic

Institut Pasteur Univerisité Paris Cité INSERM U1201 Unité de Parasitologie Moléculaire et Signalisation Paris France

Instituto de Bioquímica Médica Leopoldo de Meis Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil

Instituto Nacional de Ciência e tecnologia EpiAMO Porto Velho Brazil

Laboratório de Biologia Molecular de Parasitas e Vetores Instituto Oswaldo Cruz Rio de Janeiro Brazil

Laboratório de Imunologia das Leishmanioses Instituto de Microbiologia Paulo de Góes Centro de Ciências da Saúde Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil

Laboratório de Pesquisa em Leishmanioses Instituto Oswaldo Cruz FIOCRUZ Rio de Janeiro Brazil

Laboratório de Pesquisa em Malaria Instituto Oswaldo Cruz FIOCRUZ Rio de Janeiro Brazil

Laboratory of Molecular Virology and Parasitology Instituto Oswaldo Cruz FIOCRUZ Rio de Janeiro Brazil

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