The immunological, environmental, and phylogenetic perpetrators of metastatic leishmaniasis

•Cutaneous leishmaniasis (CL) is spreading with the expanding borders of climate change.•The many forms of metastatic leishmaniasis are difficult to predict and treat.•Risk is based on factors in the environment, parasite, and host immune response.•In all forms, timing and potency of the innate response is especially important.

Cutaneous leishmaniases have persisted for centuries as chronically disfiguring parasitic infections affecting millions of people across the subtropics. Symptoms range from the more prevalent single, self-healing cutaneous lesion to a persistent, metastatic disease, where ulcerations and granulomatous nodules can affect multiple secondary sites of the skin and delicate facial mucosa, even sometimes diffusing throughout the cutaneous system as a papular rash. The basis for such diverse pathologies is multifactorial, ranging from parasite phylogeny to host immunocompetence and various environmental factors. Although complex, these pathologies often prey on weaknesses in the innate immune system and its pattern recognition receptors. This review explores the observed and potential associations among the multifactorial perpetrators of infectious metastasis and components of the innate immune system.