Update displayed reversal of their symptoms similar to many patients diagnosed with HCM. Other CM features shared by HCM patients and P. berghei ANKA-infected mice include platelet activation and coagulopathy, implicated in vascular damage and organ dysfunction in malaria [6,7]. A correlation between sequestered parasite biomass and disease severity evident in HCM has also been demonstrated in CM susceptible mice [1,8]. Similar to variability in CM pathology in P. berghei ANKA-infected mice, there appears to be variability in pathology among HCM patients [4]. However, accurate diagnosis of severe malaria in African children may be compromised due to a high incidence of HIV, bacterial infections and malnutrition [9]. The basis of variation in pathology in HCM is currently unclear, but genetic variability in the host as well as the parasite probably contributes to the etiology of HCM [10]. The authors also question the validity of the P. berghei ANKA mouse model in providing evidence supporting an immunological basis for the pathology of HCM. Other malaria researchers would argue that studies in the experimental CM model provide important clues for understanding HCM in which the role of the immune response remains unclear. Epidemiological studies and investigation of cytokine profiles in humans with severe malaria indicate the host immune response contributes to the pathogenesis of HCM and other severe consequences of malaria infection [4]. Due to limitations in performing well-controlled and ethical studies in human populations, particularly in young African children who are extremely vulnerable to HCM, it is difficult if not impossible to systematically investigate the potential of immune mechanisms for mediating disease in HCM [4]. White et al. conclude their paper by stating that due to the considerable differences between murine CM and HCM, in pathology and susceptibility to treatment with adjunctive interventions, it is legitimate to question the relevance and thus the utility of this mouse model [1]. As highlighted therein, there is an urgent need for adjunctive therapies for treatment of severe falciparum malaria especially for treatment of children with HCM in subSaharan Africa [1]. Despite the fact that the malaria research community, both those pursuing human studies
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in the field and those carrying out laboratory-based investigations in mouse malaria models, are unanimous in recognizing this urgent need, disagreement continues as to the usefulness or relevance of mouse models to understanding human malaria. Nevertheless, experimental models are invaluable for elucidating the pathogenesis of human diseases, particularly infectious diseases [11]. In view of the overwhelming malaria problem the world is facing, better understanding and more openness must flourish between the human and mouse proponents. Only such a cooperative spirit will foster the mutual goal of confronting the devastation inflicted by the Plasmodium parasite on the human host. References 1 White, N.J. et al. (2010) The murine cerebral malaria phenomenon. Trends Parasitol. 26, 11–15 2 Hunt, N.H. et al. (2006) Immunopathogenesis of cerebral malarial. Int. J. Parasitol. 36, 569–582 3 Sanni, L. et al. (2004) Cerebral edema and cerebral hemorrhages in interleukin-10-deficient mice infected with Plasmodium chabaudi. Infect. Immun. 72, 3054–3058 4 De Souza, B. et al. (2009) Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease. Parasitol. DOI:10.1017/S00311182009991715. 5 Hearn, J. et al. (2000) Immunopathology of cerebral malaria: morphological evidence of parasite sequestration in murine brain microvasculature. Infect. Immun. 26, 5364–5376 6 Francischetti, I.M.B. (2008) Does activation of the blood coagulation cascade have a role in malaria pathogenesis? Trends Parasitol. 24, 258–263 7 Cox, D. and McConkey, S. (2010) The role of platelets in the pathogenesis of cerebral malaria. Cell. Mol. Life Sci. 67, 557–568 8 Amante, F.H. et al. (2007) A role for natural regulatory T cells in the pathogensis of experimental cerebral malaria. Am. J. Pathol. 171, 548– 559 9 Gwer, S. (2007) Over-diagnosis and co-morbidity of severe malaria in African children: a guide for clinicians. Am. J. Trop. Med. Hyg. 77 (S6), 6–13 10 Bongfen, S.E. et al. (2009) Genetic and genomic analyses of host– pathogen interactions in malaria. Trends Parasitol. 25, 417–421 11 Drescher, K.M. and Sosnowska, D. (2008) Being a mouse in a man’s world: what TMEV has taught us about human disease. Front. Biosci. 13, 3775–3785
1471-4922/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2010.03.008 Trends in Parasitology 26 (2010) 274–275
Letters
Cerebral malaria: in praise of epistemes Laurent Re´nia1, Anne Charlotte Gru¨ner1 and Georges Snounou1,2,3,4 1
Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, Singapore 2 INSERM UMR S 945, Paris F-75013, France 3 Universite´ Pierre & Marie Curie, Faculte´ de Me´decine Pitie´-Salpeˆtrie`re, Paris F-75013, France 4 Department of Microbiology, National University of Singapore, Singapore
In a recent Opinion article, Nick White and colleagues highlight the surge in studies on the cerebral pathogenesis observed in mice infected with Plasmodium berghei ANKA, Corresponding author: Snounou, G. (
[email protected]).
and argue that differences in the histopathological picture in humans and mice are such that the experimental model provides little relevance to investigations of cerebral malaria in humans. We address some of the epistemological points raised by this critique. 275
Update Of all the severe clinical manifestations of malaria infections, cerebral malaria, considered specific to falciparum malaria, is dreaded the most because it often declares without warning and has high case fatality (15–20% under optimal medical care). The inordinate accumulation of parasites in the brain vasculature was first proposed to explain comatose pernicious malaria by Laveran in the early 1880’s [1]. Soon after, similar observations from Councilman, Marchiafava and Bignami, to those recently of White and Taylor, confirm the view that sequestration of Plasmodium falciparum-infected red blood cells is most often seen in brain necropsies from cerebral malaria [2]. Rapid reduction of parasite loads contributes to improved prognosis, but it is unlikely that drugs acting faster than artemisinins will be found. At present we simply do not know which pathological changes lead to death in cerebral malaria, or how and when these are specifically triggered. Experimental investigations of these processes in humans are not an option. Adjunct treatments that counteract the pathological processes leading to cerebral malaria death might well be the only clinical avenue to improve case fatality. However, the choice of an adjunct treatment that would justify costly clinical trials remains largely a matter of conjecture, however inspired or educated. Scientists constantly seek animal models that could help them confirm, refine or exclude hypotheses. Malaria infections leading to death associated with neurological signs have been only been observed in some inbred mouse strains infected by defined parasite lines: P. yoelii 17X Lethal [3] or P. berghei K173 or ANKA [4–6]. The P. berghei ANKA model is the most investigated. The fact that brain pathology and clear neurological signs are observed justifies the term cerebral malaria, whereas the clear histopathological differences between mice and human post-mortem samples must be acknowledged by adding murine or experimental to cerebral malaria (MCM or ECM) to distinguish it from human cerebral malaria (HCM). White and colleagues [7] argue that these differences are so fundamental that data from the murine model is of no relevance to HCM and further charge that MCM investigations ‘developed into an independent and self-sustaining episteme’ generating data of little utility. It might well be that the pathogenic mechanisms in MCM are completely distinct from those in HCM, though there is no evidence that this is the most probable scenario. The scepticism of those investigating HCM is understandable because the working hypothesis is that substantial parasite sequestration in the brain is the primary cause of HCM. Data from two self-sustaining epistemes, HCM post-mortem histopathology and in vitro cytoadherence of P. falciparum-infected erythrocytes, are supportive but by no means sufficient to justify the elevation of this hypothesis into a dogma. HCM pathogenesis is less clear-cut than some suppose. First, it is not understood why high levels of intracerebral parasite sequestration, supposedly necessary for HCM development, occur in only a very small minority of untreated P. falciparum infections. Perhaps this is due to a particular combination of parasite/host genotypes, as is the case in MCM. Second, it has been proposed by some that HCM differs between non-immune 276
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Thai adults and semi-immune African children [8], and that in these children different pathologies lead to unrousable coma [9]. Thus, there might be more than one pathogenic path leading to HCM. Third, in a careful histopathological study of fatal HCM in African children, parasite sequestration was absent in 7 out of 31 brains examined [2]. The authors concluded that these children had, therefore, died of causes unrelated to the malaria infection, an interpretation not devoid of circularity. If 22% of the strictly clinically defined HCM cases are in fact due to overdiagnosis, it becomes imperative to reassess conclusions from all past HCM investigations, where the same clinical definition was adopted. We contend that an alternative but equally plausible conclusion is that HCM death sometimes occurs despite minimal parasite sequestration in the brain. Fourth, conclusions from postmortem-based HCM are limited de facto, because for obvious ethical reasons, the spatial and temporal evolution of the parasitological and pathological processes that lead to death, HCM or otherwise, in untreated or treated patients cannot be investigated. Finally, a recent description of severe vivax malaria challenges in equal parts the notions that sequestration is the preserve of P. falciparum or that it is the root cause of severe malaria. The pathogeneses of severe malaria in general and HCM in particular are yet to be unravelled. From the scientific and editorial points of view, critiques akin to those of White et al. [7], biased as some might consider them, are to be encouraged and promoted. Open debate is invariably preferable to intellectual isolation. The Opinion piece raised a further point that deserves comment: should an experimental model’s putative lack of direct relevance to humans be sufficient grounds to deny it funding or dissemination in the scientific press? We contend that to do so would substantially impoverish fundamental research. The malaria research community, today as 130 years ago, encompasses a broad diversity of approaches that compete for resources apportioned according to the varied prevalent opinions and prejudices. History tells us that major breakthroughs arose equally from epistemes with a clear potential to help reduce malaria, as from others for which the committees of wise men and women could not perceive any utility. The phenomenon of MCM exists, and investigations of its pathogenesis need no further justification. The parasites of malaria still cause untold misery principally because of the adaptability inherent to their diversity, and we assert that the scientific community should respond with epistemes of matching diversity. The duty of researchers is to imbue the investigations in their respective epistemes with areˆte. Techne will surely follow. References 1 Laveran, C.L.A. (1884) Traite´ des Fie`vres Palustres avec la Description des Microbes du Paludisme, Octave Doin 2 Taylor, T.E. et al. (2004) Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat. Med. 10, 143–145 3 Yoeli, M. and Hargreaves, B.J. (1974) Brain capillary blockage produced by a virulent strain of rodent malaria. Science 184, 572–573 4 Mackey, L.J. et al. (1980) Immunopathological aspects of Plasmodium berghei infection in five strains of mice. II. Immunopathology of cerebral and other tissue lesions during the infection. Clin. Exp. Immunol. 42, 412–420
Update 5 Polder, T.W. et al. (1983) Topographical distribution of the cerebral lesions in mice infected with Plasmodium berghei. Tropenmed. Parasitol. 34, 235–243 6 Rest, J.R. (1982) Cerebral malaria in inbred mice. I. A new model and its pathology. Trans. R. Soc. Trop. Med. Hyg. 76, 410–415 7 White, N.J. et al. (2010) The murine cerebral malaria phenomenon. Trends Parasitol. 26, 11–15
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8 Warrell, D.A. (1997) Cerebral malaria: clinical features, pathophysiology and treatment. Ann. Trop. Med. Parasitol. 91, 875–884 9 Marsh, K. et al. (1995) Indicators of life-threatening malaria in African children. N. Engl. J. Med. 332, 1399–1404 1471-4922/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2010.03.005 Trends in Parasitology 26 (2010) 275–277
Letters
Neuropathogenesis of human and murine malaria Eleanor M. Riley1, Kevin N. Couper1, Helena Helmby1, Julius C.R. Hafalla1, J. Brian de Souza2, Jean Langhorne3, W. (Bill) Jarra3 and Fidel Zavala4 1
London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK University College London Medical School, London W1T 4JF, UK 3 National Institute for Medical Research, Mill Hill London NW7 1AA, UK 4 Bloomberg School of Public Health, Johns Hopkins University, Baltimore MD 21205, USA 2
White et al. [1] make some important points cautioning the extrapolation of findings from animal models to human cerebral malaria (CM). However, in doing so they overlook a substantial body of research that offers a rather different interpretation of the literature than the one they put forward. There is a danger that their article may create an unnecessary and potentially detrimental divide between clinicians and basic biomedical researchers. In the opinion of White et al., the study of the Plasmodium berghei ANKA (PbA) model of CM has limited value in the quest to understand the pathogenesis of human CM. They base this opinion on their claim, first, that experimental CM (ECM) is predominantly an immune-driven syndrome with little or no parasite sequestration within the brain and, second, that human CM results from mechanical obstruction of brain microvessels by adhesion of parasitised red blood cells (pRBCs) to cerebral endothelial cells with little involvement of the immune response. In both cases we feel that they have taken a polarised view of the evidence. Although vascular occlusion due solely to pRBC sequestration is infrequently observed in ECM, there is plenty of evidence for accumulation of PbA-infected erythrocytes in brains of mice displaying acute neurological signs, and there is a clear overlap in the histopathological features of the human and murine syndromes, including microvascular pathology and haemorrhage [2,3] (Figure 1). Moreover, as in humans, parasite biomass is significantly greater in mice developing ECM than in mice without ECM (reviewed in Ref. [2]). Importantly, and as briefly mentioned by White et al., there is an ongoing debate within both research communities as to whether cerebral pathology results simply from mechanical obstruction of blood flow by sequestered pRBCs and/or from pRBC-induced cerebral inflammation and consequent disruption of the blood brain barrier. Contrary to the impression given by White et al., many scientists working on the PbA model of CM would completely agree with the authors that the proximal cause of CM is accumulation of Corresponding author: Riley, E.M. (
[email protected]).
pRBCs in brain microvessels, but more research is required, in both systems, to understand both the causes and the consequences of pRBC sequestration. White et al. do not discuss why pRBCs are sequestered in the brain. High affinity interactions between pRBCs and brain endothelial cells require both the expression of sequestration ligands on pRBCs and of specific receptors such as ICAM-1, VCAM-1 and E-selectin on brain endothelial cells [3]. These receptors are not expressed at high
Figure 1. Neuropathology of P. falciparum and P. berghei ANKA infections. (a,b) perivascular haemorrhage; (c,d) accumulation of pRBC within brain microvessels by (c) haematoxylin and eosin staining or (d) immunofluorescence with PbAspecific IgG; (e,f) retinal vascular occlusion. Arrows in (c) point to pRBC adhering to vascular endothelium. Image adapted from Refs [3,12,13] and Couper et al. (unpublished).
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