The enemy within: Targeting host-parasite interaction for antileishmanial drug discovery

Abstract

The state of antileishmanial chemotherapy is strongly compromised by the emergence of drug-resistant Leishmania. The evolution of drug-resistant phenotypes has been linked to the parasites' intrinsic genome instability, with frequent gene and chromosome amplifications causing fitness gains that are directly selected by environmental factors, including the presence of antileishmanial drugs. Thus, even though the unique eukaryotic biology of Leishmania and its dependence on parasite-specific virulence factors provide valid opportunities for chemotherapeutical intervention, all strategies that target the parasite in a direct fashion are likely prone to select for resistance. Here, we review the current state of antileishmanial chemotherapy and discuss the limitations of ongoing drug discovery efforts. We finally propose new strategies that target Leishmania viability indirectly via mechanisms of host-parasite interaction, including parasite-released ectokinases and host epigenetic regulation, which modulate host cell signaling and transcriptional regulation, respectively, to establish permissive conditions for intracellular Leishmania survival.

Fig 1. Different aspects of macrophage–Leishmania interaction.

Leishmania responds to the intramacrophagic environment by adaptive differentiation (left panel) and hijacks vital macrophage functions via release of parasite ectoproteins (such as the ectokinase casein kinase 1 isoform 2 [CK1.2]), which affect host defense mechanisms, causing immune subversion (middle panel), and modulate host metabolic pathways, promoting parasite growth (right panel).

Fig 2. Targeting host–parasite interaction as a new venue for antileishmanial drug discovery.

Exosomal or secreted parasite factors released into the host cell likely modulate the macrophage epigenome, causing phenotypic changes that favor parasite survival, including suppression of immune functions, prolongation of host cell survival, and metabolic changes necessary for parasite proliferation. Interfering with parasite factors that act in trans on the host cell or restoration of the normal host cell epigenome will likely interfere with intracellular parasite survival and may thus be exploited for antileishmanial drug discovery.