Insights into Divergent Leishmaniasis Pathogenesis: A Quantitative Flagellar Proteomic Comparison of L. mexicana, L. amazonensis, and L. infantum

Leishmaniasis, a neglected tropical disease endemic to 98 countries, affects more than 300 million people worldwide. The disease is transmitted through the bite of infected female phlebotomine sand flies harboring Leishmania parasites. Although infection initiates at the cutaneous inoculation site, Leishmania species exhibit distinct tissue tropisms, resulting in three primary clinical manifestations: cutaneous (CL), mucocutaneous (MCL), and visceral leishmaniasis (VL). The initial stage of infection involves the engulfment of metacyclic promastigotes (MPs) by host phagocytes, a process mediated by early interactions between the MP flagellum and the host cell surface. This study investigates how species-specific MP-flagellar proteomic profiles dictate unique interactions with host cell populations, thereby driving divergent pathogenic outcomes. To address this, we conducted a comparative quantitative proteomic analysis of flagella from Leishmania species representing each clinical form. Our analysis revealed distinct flagellar proteomic signatures that differentiate the VL-causing species, L. infantum, from others. Notably, we identified five virulence factor families that were differentially expressed: amastins, cysteine peptidases, heat shock proteins, promastigote surface antigens, and leishmanolysins. These findings link flagellar surface composition to species-specific pathogenicity, providing molecular insights into early infection dynamics and identifying potential antigenic targets for developing species-specific vaccines and therapeutics.