Host-directed therapy, an untapped opportunity for antimalarial intervention

Abstract

Host-directed therapy (HDT) is gaining traction as a strategy to combat infectious diseases caused by viruses and intracellular bacteria, but its implementation in the context of parasitic diseases has received less attention. Here, we provide a brief overview of this field and advocate HDT as a promising strategy for antimalarial intervention based on untapped targets. HDT provides a basis from which repurposed drugs could be rapidly deployed and is likely to strongly limit the emergence of resistance. This strategy can be applied to any intracellular pathogen and is particularly well placed in situations in which rapid identification of treatments is needed, such as emerging infections and pandemics, as starkly illustrated by the current COVID-19 crisis.

Keywords: Host-directed therapy; antimalarial drug discovery; malaria.

Graphical abstract

Figure 1

The life cycle of malaria parasites offers opportunities for HDT Plasmodium-infected Anopheles mosquitoes inject sporozoites into human hosts during blood meals. Sporozoites migrate to the liver and mature into schizonts within hepatocytes, which then rupture and release merozoites into the bloodstream. For P. vivax and P. ovale, parasites can also undergo a dormant stage by forming hypnozoites in hepatocytes, which can reactivate to cause relapsing disease up to several years after the initial infection. The merozoites produced during hepatocytic schizogony access the bloodstream and undergo cyclical asexual multiplication in erythrocytes. Merozoites infect red blood cells and mature from trophozoites into schizonts, which rupture and release merozoites. In the case of P. falciparum, infected erythrocytes can adhere to the vascular endothelium, which causes endothelial barrier dysfunction. Some blood-stage parasites differentiate into sexual erythrocytic stages in the bone marrow and release gametocytes into the bloodstream after maturation. Anopheles mosquitoes ingest gametocytes during blood meals; they mature in the mosquito midgut into male gametes (microgametes) and female gametes (macrogametes) that fuse to form zygotes, which then develop into motile and elongated ookinetes. The ookinetes invade the mosquito midgut wall, where they develop into oocysts, rupture, and release sporozoites. These sporozoites then migrate to the salivary glands of the mosquito. Inoculation of sporozoites from salivary glands into new human hosts continues during the next blood meal. HDT can be implemented at both the liver and blood stages of this life cycle; potential strategies are listed in the boxes to the right (see text for details). Adapted from Nilsson et al.