Invited ReviewSevere malaria: what’s new on the pathogenesis front?
Graphical abstract
Introduction
Malaria is still a leading cause of morbidity and mortality in the developing world. The virulence of Plasmodium falciparum is caused by several factors including parasite proteins on the surface of infected erythrocytes (IE). These allow the binding of these cells to the microvascular endothelium of various organs and tissues during infection. Proteins of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family mediate this adhesion through specific binding to multiple cell receptors. These include intercellular adhesion molecule-1 (ICAM-1), CD36, E-selectin, neural cell adhesion molecule (NCAM) and CD31 (PECAM-1) for endothelial beds, as well as chondroitin sulfate A (CSA) for placental syncytiotrophoblasts. Binding to endothelium results in widespread sequestration of IE, which can lead to lead to endothelial activation as well as pro-inflammatory and pro-coagulant responses.
Severe falciparum malaria encompasses a broad range of diseases, the development of which may be influenced by age, exposure and immune status (Wassmer et al., 2015). It includes complications that affect specific organs such as the brain in cerebral malaria (CM) or the placenta in malaria in pregnancy (MiP). Histopathology and laboratory studies allowed investigators to establish a causal link between placenta-specific sequestration of P. falciparum and MiP. Indeed, the ability of PfEMP1 variants to target different receptors, the expression of which varies depending on the organ, could explain why some patients with malaria develop organ-specific syndromes. Researchers have speculated that a specific PfEMP1 variant could bind receptors that are preferentially expressed in cerebral microvasculature, and could account for the focal manifestations observed in CM, the most lethal complication of P. falciparum infection. Two recent reports simultaneously shed new light on the pathogenetic mechanisms leading to CM. First, endothelial protein C receptor (EPCR) was identified as a binding partner for PfEMP1. Second, normally low levels of EPCR in brain microvessels were shown to be further down-regulated in CM, with a loss of EPCR and thrombomodulin at sites of IE sequestration. These studies provided new clues towards parasite and host cell interactions leading to CM, and connected for the first time brain-specific sequestration of EPCR-binding parasites to the loss of the protein C anti-coagulant function and endothelial cytoprotective pathways (Aird et al., 2014).
While the relative frequency of severe malaria is low, its reported case fatality rate has not substantially changed over decades, especially for CM (Manning et al., 2014). Due to the lack of specific neuro- and vasculoprotective therapies, treatments for CM are currently still precariously limited to antimalarial drugs and emergency supportive care. The former are quickly dwindling, as the resistance of P. falciparum malaria against artemisinin combination treatments, the recommended first-line therapy for infected patients, is on the rise in southeastern Asia. Multi-drug-resistant falciparum malaria is increasingly difficult to treat and new antimalarials are not expected to become available within the next few years. This underlines the necessity for molecular markers for surveillance of partner drug resistance, in conjunction with the implementation of new biomarkers for early diagnosis and outcome prediction, as well as effective adjunct therapies.
Here we review some recent data with a focus on newly developed research approaches aimed at a better understanding of the pathogenetic mechanisms of severe malaria in general and CM in particular.
Section snippets
Parasite-brain microvasculature specificity in CM: a virulence factor?
The severity of P. falciparum is linked to sequestration of IEs within the microvasculature of various organs including the brain. This sequestration is driven both by the expressed var gene in the parasite, leading to the expression of a specific variant of PfEMP-1, and the presence of its associated receptors on microvascular walls (Hviid and Jensen, 2015). Since there are considerable variations in both adhesion molecule expression and functional properties of endothelial cells depending on
Microvascular endothelial dysfunction: new causes and repercussions
In the recent years, convincing evidence has been presented to support the role of both endothelial cell activation and platelets in modulating the pathogenesis of severe P. falciparum malaria. Thrombin, a common factor in both processes, is now thought to be a driver of pathology in CM. The relative contribution of EPCR-binding parasites versus loss of EPCR from the endothelial surface in mediating CM is not known, although both are associated with disease in clinical studies (Turner et al.,
Rosetting and clumping: consequences for sequestration and microvascular obstruction
Parasite adhesion interactions in severe falciparum malaria are not restricted to the endothelium. Indeed, IEs can bind uninfected erythrocytes to form rosettes (Handunnetti et al., 1989), or platelets to form clumps (Pain et al., 2001). Both processes have been associated with severe malaria (Rowe et al., 1995, Pain et al., 2001) and CM (Carlson et al., 1990, Wassmer et al., 2008).
In this context, recent advances have been made in elucidating the molecular mechanisms underlying rosetting, with
Clinical consequences of BBB opening in CM: vasogenic oedema and brain swelling
Following the report by Seydel et al. (2015), a study was initiated to investigate the different mechanisms potentially responsible for brain swelling in both pediatric and adult CM patients in India (Wassmer et al., 2015). Brain swelling was identified by MRI in over 50% of patients enrolled in the ongoing study, irrespective of their age group. The frequent occurrence of brain swelling in CM has been previously reported in separate studies on Indian adults using computed tomography (CT) (
New adjunct therapies and critical care approaches in severe malaria
Even under optimal conditions, the case–fatality rate in severe malaria treated with either artemisinin derivatives or quinine remains high. In addition, multi-drug-resistant falciparum malaria is increasingly difficult to treat and new effective antimalarial agents are not expected to become available within the next few years. In an effort to reduce malaria-related mortality, numerous adjunctive therapies that may alter severe malaria-induced physiological abnormalities are being evaluated,
Novel parasite factors involved in malarial pathogenesis and possible therapeutic targets
In parallel to the development of adjunct therapies, a growing effort in the search for new and effective pharmacotherapies has been triggered by the emergence of multi-drug resistance in P. falciparum. While still in their infancy, these approaches are promising and provide a wide range of new therapeutic targets. Several new parasite factors were recently identified and have emerged as potential drug target candidates. Among those, G-quadruplex (G4) DNA motifs and RecQ helicases are newly
Pathologies other than CM: MiP
Plasmodium falciparum infection during pregnancy can result in a pathology caused by the accumulation of IEs in the placental intervillous space and the infiltration of maternal monocytes/macrophages (Rogerson et al., 2003), with detrimental outcomes for both the mother and the foetus. Expression of PfEMP1-var2csa at the surface of IEs mediates their adhesion to the placenta. Adaptive immunity is progressively acquired during sequential malaria infections in pregnancy and is mediated by the
New investigative tools and experimental models
A vast array of new tools and models has recently become available to facilitate the investigation of severe malaria pathogenesis, with a particular focus on CM. These are detailed elsewhere (Sahu et al., 2015). Further to this, the rise of the ‘omic’ era during the past decade has provided the malaria research community with unprecedented approaches and technologies to better understand the biology, evolution and pathogenesis of different Plasmodium spp. The Malaria Host-Pathogen Interaction
Conclusions and future perspectives
Despite the recent leap in our understanding of pathogenetic mechanisms leading to severe malaria, the translational outputs to improve the clinical outcome of patients remain meager. Collaborative and multidisciplinary approaches using clinical samples from field sites in endemic areas, in vitro and ex vivo models, as well as animal models of the disease, are crucial to allow global advances in the fight not only against severe falciparum malaria, but also emerging public health issues such as
Acknowledgements
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (USA) under Award Number U19AI089676-01S1, as well as by the National Health and Medical Research Council (Australia), the Rebecca L. Cooper Foundation (Australia) and the Australian Research Council (Australia).
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