Investigating the Pathogenesis of Severe Malaria: A Multidisciplinary and Cross-Geographical Approach

Abstract

More than a century after the discovery of Plasmodium spp. parasites, the pathogenesis of severe malaria is still not well understood. The majority of malaria cases are caused by Plasmodium falciparum and Plasmodium vivax, which differ in virulence, red blood cell tropism, cytoadhesion of infected erythrocytes, and dormant liver hypnozoite stages. Cerebral malaria coma is one of the most severe manifestations of P. falciparum infection. Insights into its complex pathophysiology are emerging through a combination of autopsy, neuroimaging, parasite binding, and endothelial characterizations. Nevertheless, important questions remain regarding why some patients develop life-threatening conditions while the majority of P. falciparum-infected individuals do not, and why clinical presentations differ between children and adults. For P. vivax, there is renewed recognition of severe malaria, but an understanding of the factors influencing disease severity is limited and remains an important research topic. Shedding light on the underlying disease mechanisms will be necessary to implement effective diagnostic tools for identifying and classifying severe malaria syndromes and developing new therapeutic approaches for severe disease. This review highlights progress and outstanding questions in severe malaria pathophysiology and summarizes key areas of pathogenesis research within the International Centers of Excellence for Malaria Research program.

Figure 1.

The major clinical complications associated with adult and pediatric severe malaria. Clinically severe malaria is a multisystem disorder that can affect different organs and differs in presentation between children and adults. The major clinical complications in children are cerebral malaria, severe malaria anemia, and metabolic acidosis. In adults, cerebral malaria is frequently accompanied by multiorgan system complications, including metabolic acidosis, acute kidney failure, jaundice, and acute respiratory distress (ARDS).

Figure 2.

Schematic representation of the pathological differences between cerebral malaria CM1 and CM2. Autopsy studies in children have divided CM cases into two groups based on histological features, CM1 cases have infected erythrocyte sequestration in the cerebral microvasculature and no associated vascular pathology. CM2 cases are defined by cerebral sequestration plus intra- and perivascular pathology, including ring hemorrhages, fibrin-platelet thrombi, and intravascular monocytes. In the CM2 group, infected erythrocyte (IE) sequestration is frequently associated with fibrin-platelet thrombi in both capillaries and postcapillary venules. Insets provide examples of pathological features observed in CM2 cases described in Dorovini-Zis and others. Inset (A) shows a small branching capillary in which the upstream region is filled with sequestered IEs and one of the branches is occluded by a thrombus. This event is associated with a ring hemorrhage in which the microvessel is partially denuded of endothelial cells and is surrounded by a zone of necrosis and a ring of uninfected red blood cells in the white matter. Inset (B) shows a small vessel packed with sequestered IEs and surrounded by extravasated fibrinogen indicating increased permeability of the blood–brain barrier. Inset (C) shows a micovessel filled with monocytes containing phagocytosed hemozoin pigment. Intravascular pigmented monocytes are found adherent to the microvessel wall, but do not transverse across the blood–brain barrier. The molecular mechanisms driving the CM1 and CM2 pathophysiology are incompletely understood. Intercellular adhesion molecule 1 (ICAM-1) and endothelial protein C receptor (EPCR) are candidate brain endothelial receptors,, but it is not known if the same parasite adhesion types are associated with CM1, CM2, and adult CM (not pictured). Recent studies reported that binding of IE to EPCR was associated with the development of severe malaria and that decreased EPCR staining on endothelial cells and increased fibrin deposition occurred at the site of IE adhesion in cerebral microvessels during fatal pediatric CM. This association suggests there may be causal links between cytoadhesion and microvascular pathophysiology. However, fibrin deposition is not found in CM1 and is less prominent in adult CM, highlighting gaps in our understanding of CM pathophysiology.

Figure 3.

Proposed influence of the host endothelial responsiveness to tumor necrosis factor (TNF) on the severity of malaria infection. Low endothelial TNF responders are less prone to upregulate receptors involved in the sequestration of infected erythrocyte (IE) and platelets than high responders. This leads to a minimal adhesion of IE and host cells and a lower pro-apoptotic signal for the endothelial cells, which might account for the absence of pathology. High responders, however, are over-activated in the presence of TNF, leading to high adhesion of IE and a strong pro-apoptotic signal, possibly resulting in the breakdown of the blood–brain barrier and, ultimately, to vasogenic edema (A). Potential clinical benefits offered by angiopoietin (Ang)-1 as a quiescence agent for high TNF-responding endothelial cells during cerebral malaria (CM) (B).