Platelets as pathogenetic effectors and killer cells in cerebral malaria

KEYWORDS:

• Plasmodium falciparum
• platelets
• cerebral malaria

Plasmodium falciparum malaria is a major cause of morbidity and mortality worldwide. Neurological complications are common in falciparum malaria, but cerebral malaria (CM) is the most severe. This complex and multifactorial syndrome leads to a mortality rate of approximately 15–25% even when appropriate treatment and intensive care are provided [1]. The fundamental pathogenesis of fatal CM is still not well understood. However, several hypotheses have been suggested, including mechanical obstruction of microvessels by P. falciparum-parasitized red blood cells (PRBCs), excessive release of immunomodulators by the immune system of the host, and critical hematological dysfunctions [2].

Platelets, which lie at the intersection between hemostasis and innate immune response [3], have recently emerged as key effectors in the pathogenesis of CM. Paradoxically, they can also act as antiparasitic agents, potentially keeping malaria infection under control. Understanding the precise balance of pathogenetic versus protective effects of platelets in CM could provide the key to boost their microbicidal effect against P. falciparum and/or specifically inhibit the mechanisms by which they contribute to the cerebral pathology.

Platelets have been shown to have a detrimental effect on the host in CM pathology over two decades ago. Indeed, in the P. berghei ANKA murine model of CM, platelets accumulate in the organs prior to the development of lesions, a phenomenon that can be prevented by anti-integrin antibodies. Furthermore, induction of thrombocytopenia prevents CM [4,5]. In patients with CM, platelets had been first detected by electron microscopy in brain microvessels, suggesting a similar pathogenetic role in the human disease [6]. More recently, platelet accretion has been demonstrated and quantitated using immunohistochemistry [7,8]. In addition, this accumulation may be responsible for the transfer of CD36 on brain endothelium, potentially providing new receptors for PRBC cytoadherence [7]. Indeed brain endothelium, at variance with endothelial cells elsewhere in the body, expresses little or no CD36 [7].

Such an accumulation of platelets is not due to disseminated intravascular coagulation, as reviewed in [9], which is consistent with previous results in the mouse model [10]. Rather, the very early steps of platelet binding involve the release of ultra-large von Willebrand factor strings by endothelial cells [11], a process required for the development of the neurological syndrome in vivo [12].

In addition to these in vivo data, platelets have been found to significantly stimulate brain endothelial cells in vitro, resulting in the upregulation of genes controlling inflammation and apoptosis [13]. These results expanded the concept that platelets can potentiate brain endothelial alterations induced by PRBCs [14]. Furthermore, PRBC clumping can be induced by platelets, which in turn contribute to the severity of sequestration [15,16]. Aside from their direct involvement, platelets can be indirectly pathogenetic, that is, via their released elements: these include membrane microparticles [17,18] and preformed chemokines such as platelet factor 4 [19]. The platelet content in immune mediators – such as chemokines, cytokines, prostaglandins, and amines – allows them to contribute to inflammation in CM [4]. Beyond CM, platelets are clearly linked to disease pathogenesis via immune mechanisms, notably in experimental arthritis, systemic lupus erythematosus [20], and T-cell-induced liver damage [21]. More widely, the role of platelets as immunomodulators has been documented [22].

Thrombocytopenia often accompanies malarial infection [23]. It is recognized as a risk factor, in mice [24] and in patients, both in Africa [25] and in Southeast Asia [26]. The indirect correlation between parasitemia and platelet counts [16] suggests that thrombocytopenia might be a protective maneuver of the infected host to defend itself. This is in line with the long known potential of platelets to kill rodent [27] and human [28] malaria parasites. These observations were expanded by McMorran et al. who showed that platelets may be protective against CM [29,30]. This effect might be indirect as well, notably through the induction of the acute phase response by platelets in vivo [31]. Such a role for platelets in defense mechanisms has been described in other infectious contexts [3].

Defining the precise involvement of platelets and their microparticles in disease severity may help identify new potential targets for both antiparasitic and adjunct therapies in CM. Indeed, a rigorous screening of the molecules and pathways responsible for the reported protective effect of platelets may open new therapeutic avenues against P. falciparum, which may be used in a broader context than in CM only. Alternatively, a better comprehension of the pathogenetic role of platelets during CM may inform adjunct therapies aimed at dampening such deleterious effects for the host. Lastly, the identification of plasma marker profiles – involving platelets and microparticles – during the different stages of infection in CM patients could help understanding the kinetics and factors influencing the potential switch from protective to pathogenetic.

In conclusion, the complexity of CM pathogenesis and the duality of platelet involvement in this syndrome warrant further studies and highlight the need to better delineate whether platelets should be the target of new adjunct therapies. As previously suggested, platelets can be protective in the early stages of infection and pathogenetic in the latest stages of brain complications [32]; therefore, an interesting aim for the malaria research community could be to determine how interfering with platelet accumulation or activation can help reduce morbidity in CM.

Financial & competing interests disclosure

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, as well as by the National Health and Medical Research Council and the Australian Research Council (Australia). G Grau received a research grant from Novartis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. SC Wassmer discloses National Institute of Allergy and Infectious Diseases of the National Institutes of Health (USA) award number U19AI089676. GER G discloses National Health and Medical Research Council and the Australian Research Council (Australia), research grant from Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.