Survival of the fittest: How Leishmania evades drug therapy

Leishmaniasis, caused by vector-borne Leishmania spp., continues to cause a significant burden of disease around the world. These sand fly-transmitted protozoan parasites, of which numerous species exist, are responsible for cutaneous (CL), mucocutaneous (MCL), and visceral leishmaniasis (VL) - diseases which can be debilitating or even fatal, especially in immunocompromised individuals. In many areas, dogs serve as a reservoir for Leishmania. Treatment of leishmaniasis relies on a minute arsenal of chemotherapeutic drugs that are toxic, costly, or difficult to source. Meanwhile, an effective vaccine formula remains elusive, although vaccines for the prevention of canine leishmaniasis (CanL) have been in use for decades. Treatment failure (TF) is an important concern for leishmaniasis. Incomplete cure or relapse is relatively common in cases of VL and CL. When it comes to CanL, TF or relapse is typical; host immunity and drug characteristics play a major role. Meanwhile, drug resistance (DR) has also become a major issue in some regions and may play an important role in TF. Leishmania parasites possess an impressively plastic genome and utilize copy number variations (CNVs) and single-nucleotide polymorphisms (SNPs) to escape drug pressure. Futhermore, studies have shown that they deploy extracellular vesicles (EVs) with a variety of key molecules as cargo, contributing not only to host-pathogen interaction & pathogenesis, but also to spread of DR. TF and DR are discussed here in detail, as well as the current state of vaccine development and available and prospective therapies for CL, MCL, VL, and CanL. Variables affecting the course of disease are addressed. Finally, the role of dogs as a reservoir for Leishmania parasites, as well as their potential to contribute to the spread of DR parasites, is considered.