Opportunities for Host-targeted Therapies for Malaria

Abstract

Despite the recent successes of artemisinin-based antimalarial drugs, many still die from severe malaria, and eradication efforts are hindered by the limited drugs currently available to target transmissible gametocyte parasites and liver-resident dormant Plasmodium vivax hypnozoites. Host-targeted therapy is a new direction for infectious disease drug development and aims to interfere with host molecules, pathways, or networks that are required for infection or that contribute to disease. Recent advances in our understanding of host pathways involved in parasite development and pathogenic mechanisms in severe malaria could facilitate the development of host-targeted interventions against Plasmodium infection and malaria disease. This review discusses new opportunities for host-targeted therapeutics for malaria and the potential to harness drug polypharmacology to simultaneously target multiple host pathways using a single drug intervention.

Keywords: cerebral malaria; drug discovery; host–parasite interactions; liver; malaria; polyphamacology.

Figure 1.. The complexity of the malaria parasite life cycle and opportunities for host-targeted therapies.

The Plasmodium parasite undergoes extensive cell biological changes throughout its life cycle within the human host, accompanied by expansions and contractions in parasite numbers starting from (A) the small number of parasites that are initially deposited in the dermis by the bite of an Anopheles mosquito. Within the dermis most parasites are eliminated, but a small number cross into a blood vessel and then are carried within the blood circulation to (B) the liver where they traverse the sinusoidal endothelium to invade hepatocytes. Both P. falciparum and P. vivax undergo LS schizogony, in which parasites asexually replicate within the hepatocyte to produce upwards of 20,000 merozoite parasite forms over 7–10 days. Some species of parasites (e.g. P. vivax) also form dormant parasite forms, called hypnozoites, which can reactivate later. Once parasites complete LS development, the merozoites reenter the bloodstream to infect erythrocytes and undergo repeated cycles of asexual development. (C) During the asexual blood stage of P. falciparum, infected erythrocytes exit the blood circulation by cytoadhering to vascular endothelium, using members of a clonally variant gene family called PfEMP1, expressed on the surface of the erythrocyte. The site of endothelial cytoadhesion is associated with organ-specific disease complications, most prominently in cerebral malaria. (D) During intraerythrocytic replication, parasites can also differentiate into sexual forms, called gametocytes, which sequester in bone marrow to complete their maturation before remerging as stage V forms that are transmissible to mosquitoes. Opportunities for host-targeted intervention can be envisioned at multiple points within the malaria life cycle, either as prophylaxis, treatment, or adjunctive therapies.

Figure 2.. Exploiting polypharmacology and drug repurposing for host-targeted therapies in malaria.

Polypharmacology and repurposing of drugs have the potential to reduce the time, cost, and failure rate of production of malaria therapeutics, as well as create new options for host-targeted therapies. Calculations for de novo cancer therapeutic development estimate 10–17 years for de novo drug development with a 10% success rate, while drug repurposing requires 3–12 years, with a 30% success rate and only 50–60% of the cost [159, 160]. Potential compounds for repurposing can include those that are FDA approved, still within the development pipeline, or discarded for reasons other than safety. Many drugs exhibit polypharmacology, targeting more than one protein or process within a cell, and the ability to target multiple pathways may be what makes them efficacious in the context of malaria treatment. Therefore, rejected drugs, or drug derivatives, that passed human safety trials but were not carried forward could be effective against Plasmodium infection through a mode of action other than that for which they were originally developed.

Figure 3.. Proposed host-targeted interventions to reverse the major pathogenetic processes in cerebral malaria.

(A) IEs accumulate in cerebral microvasculature by PfEMP1 binding to specific receptors on endothelial cells. The depicted PfEMP1 variant is a dual EPCR-ICAM-1 binder. De-sequestration strategies include host receptor biologics such as anti-EPCR antibodies and modified soluble EPCR variants [117], both of which have yet to be demonstrated as de-sequestration therapies. Sevuparin, a modified heparin analog, caused transient de-sequestration of IEs in uncomplicated malaria patients [122]. (B) Parasite factors including PfHRP2 and histones, released during IE rupture, as well as host factors including Ang-2 released from activated endothelial cells and the soluble plasma protein thrombin, are believed to contribute to endothelial barrier disruption. EPCR-binding IEs block binding of APC to EPCR and impair the cytoprotective properties of endothelial cells, contributing to barrier disruption and a pro-coagulant and pro-thrombotic state. Host-targeted therapeutics include barrier-strengthening exogenous factors such as Ang-1 and APC, and small molecule modulators of host-signaling pathways. (C) Elevated levels of pro-inflammatory cytokines and chemokines (TNFα, CXCL10) contribute to excessive pro-inflammatory signaling, which exacerbates endothelial dysfunction. Immunomodulators such as rosiglitazone [150], may neutralize cytokines, boost anti-inflammatory mechanisms, and reduce pro-thrombotic signaling. This, in turn, may reduce endothelial cell activation and dysfunction, as well as the continual recruitment of platelet and monocytes in brain microvasculature. Abbreviations: IEs, infected erythrocytes; ICAM-1, intercellular adhesion molecule 1; EPCR, endothelial protein C receptor; PfHRP2, Plasmodium falciparum histidine-rich protein 2; Ang-2, angiopoietin-2; APC, activated protein C; TNFα, tumor necrosis factor alpha.

Figure I.

Kinase inhibitors (A and B) have varying and overlapping specificities for host kinases (1, 2 and 3) and have different effects on LS infection: inhibitor B reduces LS infection while inhibitor A does not. Kinase 3 is therefore identified as important for maintenance of LS infection. Inhibitor C can then be predicted to reduce LS infection based on its known activity against kinase 3. In this schematic the importance of 3 host kinases in maintaining LS infection are probed using only 2 inhibitors. Scaled up, kinase regression uses roughly 30 kinase inhibitors to predict the role of 300 kinases and the effect of 178 inhibitors on LS infection.