Silent Survivors: The Role of Persister Cells in Leishmaniasis and Therapeutic Failure

Abstract

Leishmania spp., the causative agents of leishmaniasis, exhibit complex evolved mechanisms that allow long-term survival within the host despite antileishmanial treatment. This ability is closely associated with the presence of persister-like parasite populations that are phenotypically distinct from actively replicating forms. These subpopulations are capable of reversible drug tolerance without genetic resistance, which allows them to tolerate drug exposure and evade immune mechanisms. Persister-like parasites have been reported in multiple clinical manifestations such as visceral, cutaneous, and post-kala-azar dermal leishmaniasis. These persister-like parasites undergo metabolic slowdown, altered gene expression, and increased stress tolerance. These parasite-intrinsic changes are reinforced by host-parasite interactions within immune-regulated niches, where cytokine signaling, macrophage deactivation, and tissue-specific environments limit effective parasite elimination. Several molecular pathways, such as stress-activated kinases and dormancy-associated regulators, including phosphatases and L. donovani Zeta-toxin (Ld_ζ1) proteins, contribute to the maintenance of this persistent state. This review summarizes the current understanding of Leishmania persistence by integrating mechanistic insights, experimental and clinical observations, methodological challenges, and emerging molecular approaches. It also discusses implications for drug discovery and the limitations of conventional therapies that fail to target nonreplicating forms. Understanding persistence as a biological survival strategy is essential for interpreting treatment failure, relapse, and ongoing transmission and paves the way for more targeted and effective therapeutic interventions.