Centuries have passed since quinine was established as an effective treatment for malaria, and yet today’s therapeutic arsenal against the four Plasmodium species that infect humans—P. falciparum, vivax, ovale and malariae—remains severely limited.
Malarial parasites have a complex, multi-stage life cycle (Fig. 1). Mosquitoes transmit ‘sporozoites’, which target and infect liver cells. Within liver cells called hepatocytes, the sporozoites undergo a single round of division to yield ‘merozoites’ (Fig. 2), which—after days or weeks—get released into the bloodstream, where they repeatedly infect red blood cells. For P. ovale and P. vivax, residency in the liver can be especially protracted, with parasites spending months or years as latent ‘hypnozoites’.
Missing the target
Most therapeutic approaches target the parasite in its symptomatic, blood-borne stage (Fig. 3). Laurent Rénia of the A*STAR Singapore Immunology Network and Georges Snounou and Dominique Mazier of the Université Pierre et Marie Curie in Paris, however, now argue that by failing to target the parasite in the pre-pathological liver stage, scientists are missing a key opportunity to constrain, and perhaps eventually eradicate, malaria. In a recent Perspectives article in Nature Reviews Drug Discovery, these veteran malaria researchers—Rénia has over 20 years experience in studying liver-stage infection—explore gaps in our understanding of the Plasmodium life cycle, and describe some technical innovations needed to help drive development of better therapeutics.
Need for new models
Lack of experimental models is a major challenge. Standard mouse models have proved useful for characterizing liver-stage infection, but the Plasmodium species that infect these animals fail to undergo the hypnozoite stage. Primate studies can remedy this problem, but these carry substantial cost and regulatory burdens. The authors suggest that new hope may lie in the use of mice that contain human blood cells or hepatocytes, and are thus susceptible to human-infective species. These mice should, in principle, also help to advance our understanding of the Plasmodium life cycle.
Initial discovery of promising drug candidates, however, requires the identification of suitable cell-culture models. “[It is a priority] to obtain easily cultured hepatocyte cell lines that are highly susceptible to malaria infection,” explains Rénia, “because this will make it possible to undertake high-throughput screening.” Currently, there is a shortage of in vitro platforms that usefully recapitulate liver-stage infection—access to healthy primary hepatocytes is limited, and even with immortalized cell lines amenable to infection, the efficiency of parasitic invasion may be too low.
Furthermore, each species has its own target cell preferences, and the key determinants remain unclear. “The four species that infect humans are biologically, immunologically and clinically distinct,” says Rénia.
Some existing drugs, which target both blood- and liver-stage parasites, greatly increase the risk of emergence of drug-resistant parasites. However, future drugs should offer greater selectivity. Better characterization of the metabolic interplay between parasite and liver cell, made possible through the ongoing development of increasingly sophisticated tools for genomic and proteomic analysis, should assist these efforts.
Rénia acknowledges the difficulties ahead, but also the importance of perseverance. “The liver stages should not be neglected as an important target for drug development despite the technical challenges,” he says. His group is now involved in a drug-screening collaboration with the Novartis Institute for Tropical Disease.
The A*STAR-affiliated authors in this feature are from the Singapore Immunology Network.