New insights into microvascular injury to inform enhanced diagnostics and therapeutics for severe malaria

Abstract

Severe malaria (SM) has high mortality and morbidity rates despite treatment with potent antimalarials. Disease onset and outcome is dependent upon both parasite and host factors. Infected erythrocytes bind to host endothelium contributing to microvascular occlusion and dysregulated inflammatory and immune host responses, resulting in endothelial activation and microvascular damage. This review focuses on the mechanisms of host endothelial and microvascular injury. Only a small percentage of malaria infections (≤1%) progress to SM. Early recognition and treatment of SM can improve outcome, but we lack triage tools to identify SM early in the course of infection. Current point-of-care pathogen-based rapid diagnostic tests do not address this critical barrier. Immune and endothelial activation have been implicated in the pathobiology of SM. We hypothesize that measuring circulating mediators of these pathways at first clinical presentation will enable early triage and treatment of SM. Moreover, that host-based interventions that modulate these pathways will stabilize the microvasculature and improve clinical outcome over that of antimalarial therapy alone.

Keywords: Severe malaria (SM); adjunctive therapy; host innate response; microvascular injury; risk-stratification; severity markers.

Figure 1.

Severe malaria pathogenesis: Both host and parasite factors contribute to the pathogenesis of severe malaria (SM). Key mechanisms include, sequestration of infected erythrocytes in the microvasculature of vital organs, hemolysis, inflammation, coagulopathy, endothelial activation, and microvascular injury. Each of these mechanisms may amplify another, leading to multi-organ failure and death.

Figure 2.

Schematic of mechanisms underlying SM pathology that represent potential sites for therapeutic intervention (highlighted in yellow): During quiescence, Ang-1 via Tie-2, and possibly Slit-2 via Robo4, promote endothelial integrity by stabilizing junctional proteins. During severe infections Weibel-Palade bodies (WPB) in the endothelial cell, stimulated by inflammatory responses, release Ang-2 and vWF. Ang-2 displaces Ang-1 and inhibits Tie-2 endothelial stabilizing effects. The expression of cell adhesion molecules, such as ICAM-1, are increased, leading to enhanced sequestration, and vWF released from WPB, promoting a pro-coagulatory state. These pathological mechanisms may interact and exacerbate each other (green arrows), leading to microvascular dysfunction. Circulating levels of Ang-2 and sTREM-1 are good prognostic markers of disease severity and outcome. Rosiglitazone is a promising putative adjunctive therapeutic as it acts upon several of the pathological mechanisms linked to the development of SM.