Abstract
BACKGROUND: Leishmania is a neglected tropical parasite that may affect millions of people worldwide, causing infections that range from subclinical to life-threatening in many animal species, including humans. The four subgenera described (i.e., Leishmania, Mundinia, Sauroleishmania and Viannia) exhibit distinct biological and ecological characteristics. The genus likely originated during the Mesozoic era, with hypotheses suggesting a Palearctic, Neotropical, or Supercontinent origin. Understanding the evolutionary history of Leishmania parasites may clarify host specificity, geographic distribution, and vector associations across subgenera. METHODOLOGY AND KEY FINDINGS: In this study, we analyzed Leishmania evolutionary associations with vertebrate hosts as well as sand fly vectors using a combination of cophylogenetic and maximum parsimony approaches. A significant phylogenetic congruence was found between Leishmania and its vertebrate hosts using PACo (p = 0.0001, m2XY=0.5419) and ParaFit (p = 0.0034, ParaFit Global statistic = 0.012), with several host-switching and duplication events (p = 0.0298), particularly involving Leishmania-humans associations. A cospeciation event was also predicted at a higher taxonomic level, corresponding to the divergence of mammals from reptiles and the subsequent separation of the Leishmania, Viannia and Mundinia subgenera from Sauroleishmania. Similarly, significant cophylogenetic signals were observed between Leishmania and sand fly hosts using PACo (m2XY=1.3988, p = 0.0001) and ParaFit (ParaFit Global = 0.062, p = 0.0001) functions. Cospeciation events were again predicted at higher taxonomic levels in the divergence of New World and Old World sand flies, with Viannia species and Leishmania, Sauroleishmania and Mundinia species associated with the latter (p = 0.01). CONCLUSIONS: Our findings support the Supercontinent hypothesis and emphasize the relevance of the historical biogeography in Leishmania diversification. This comprehensive cophylogenetic analysis enhances our understanding of Leishmania origins and diversification, offering insights into host specificity, vector adaptation, and the long-term maintenance of its digenetic life cycle.