Cutaneous and Mucocutaneous Leishmaniasis: Perspectives on Immunity, Virulence, and Treatment

Leishmaniasis, a neglected tropical disease caused by protozoa of the genus <i>Leishmania</i>, presents a wide clinical spectrum from self-healing cutaneous lesions to life-threatening visceral disease. Its epidemiology and severity vary by geography and species (Old vs. New World), vector biology, and host factors. Pathogenesis reflects a tripartite interplay among parasite, host, and sand fly saliva. Parasite virulence determinants-including lipophosphoglycan, GP63, proteophosphoglycans, and GPI-anchored antigens-facilitate complement evasion, macrophage entry, and suppression of microbicidal pathways. Innate defenses (complement, neutrophils, dendritic cells, NK cells) and PRR signaling (TLRs/NLRs) shape early outcomes, while the balance between Th1-mediated macrophage activation and Th2/regulatory responses dictates clearance versus persistence. Clinically, most infections remain cutaneous; a minority disseminate to mucosa, driven by immunopathology and species traits. Management must be individualized by <i>Leishmania</i> species, lesion burden/site, immune status, geographic region and drug availability. Local therapies (intralesional antimonials, cryo-/thermotherapy) are suitable for limited disease, whereas systemic agents (antimonials, amphotericin B, miltefosine, pentamidine, azoles) are reserved for complex, mucosal, disseminated, or immunosuppressed cases. Drug resistance-via altered uptake/efflux, metabolic rewiring, and genomic plasticity-increased toxicity and treatment failure. Targeting parasite virulence and unique metabolic pathways, improving species-specific diagnostics, and integrating host-directed strategies are priorities to shorten therapy and improve clinical outcomes.