Decoding the sand fly–Leishmania interaction: from biological insights to disease control

Leishmaniasis persists as a major yet under-controlled vector-borne disease, maintained by a highly specialized and dynamic interaction between Leishmania parasites and their sand fly vectors. Understanding how vector competence emerges from the integration of molecular, immunological, and microbiome-driven processes is critical for identifying novel intervention points to reduce disease incidence. We share our perspective on this multilayered biological dialogue shaped by molecular interactions, innate immune signaling, and microbiota ecology. Rather than a non-reactive host, the sand fly regulates digestion, immunity, and the resident microbial gut communities. In parallel, Leishmania deploys virulence strategies that can manipulate gut physiology, immune responses, and even vector behavior to ensure its survival and transmission. The outcomes depend on timing and, eventually, species-specific compatibility. We further explore how antiviral defenses, bacterial symbionts, and metabolic context intersect with parasite development, revealing layers of complexity that extend beyond basic parasite–vector models. We point out new opportunities for intervention, ranging from transmission-blocking approaches to microbiome-based control that can disrupt disease transmission at its source.