Date Published: July 24, 2017
Publisher: Public Library of Science
Author(s): Sokhna Keita Alassane, Marie-Laure Nicolau-Travers, Sandie Menard, Olivier Andreoletti, Jean-Pierre Cambus, Noémie Gaudre, Myriam Wlodarczyk, Nicolas Blanchard, Antoine Berry, Sarah Abbes, David Colongo, Babacar Faye, Jean-Michel Augereau, Caroline Lacroux, Xavier Iriart, Françoise Benoit-Vical, Leonardo Jose de Moura Carvalho.
Cerebral malaria (CM) is the most severe manifestation of human malaria yet is still poorly understood. Mouse models have been developed to address the subject. However, their relevance to mimic human pathogenesis is largely debated. Here we study an alternative cerebral malaria model with an experimental Plasmodium berghei Keyberg 173 (K173) infection in Sprague Dawley rats. As in Human, not all infected subjects showed cerebral malaria, with 45% of the rats exhibiting Experimental Cerebral Malaria (ECM) symptoms while the majority (55%) of the remaining rats developed severe anemia and hyperparasitemia (NoECM). These results allow, within the same population, a comparison of the noxious effects of the infection between ECM and severe malaria without ECM. Among the ECM rats, 77.8% died between day 5 and day 12 post-infection, while the remaining rats were spontaneously cured of neurological signs within 24–48 hours. The clinical ECM signs observed were paresis quickly evolving to limb paralysis, global paralysis associated with respiratory distress, and coma. The red blood cell (RBC) count remained normal but a drastic decrease of platelet count and an increase of white blood cell numbers were noted. ECM rats also showed a decrease of glucose and total CO2 levels and an increase of creatinine levels compared to control rats or rats with no ECM. Assessment of the blood-brain barrier revealed loss of integrity, and interestingly histopathological analysis highlighted cyto-adherence and sequestration of infected RBCs in brain vessels from ECM rats only. Overall, this ECM rat model showed numerous clinical and histopathological features similar to Human CM and appears to be a promising model to achieve further understanding the CM pathophysiology in Humans and to evaluate the activity of specific antimalarial drugs in avoiding/limiting cerebral damages from malaria.
Malaria remains a “major killer of children” in one of its more severe aspects, Cerebral Malaria (CM), with a fatality rate of 15–25% in African children despite effective antimalarial chemotherapy . CM causes 78% of all malaria deaths. It is caused by the apicomplexan parasite Plasmodium falciparum, affecting not only children under the age of 5, but also pregnant women and non-immune patients such as tourists in endemic areas [2–4]. This pathology is an acute encephalopathy characterized by fever, vomiting, headache, seizure, respiratory distress, malarial retinopathy, impaired consciousness and/or coma [2,5–7].
The present experimental model of cerebral malaria in young Sprague Dawley rats infected by K173, appears as a particularly relevant model regarding the histological, physiological and biochemical parameters compared to those observed in Human CM. The most remarkable point is the sequestration of iRBCs in brain micro-vessels in all ECM rats like in Human CM whereas this phenomenon is debated in the mouse model [13,93]. In this rat model, hematological parameters susceptible to be predictive of the ECM progression were also determined. The parameters most affected in the ECM group were platelets and white blood cells with regenerative thrombocytopenia and leukocytosis as observed in Human CM while RBC count remained normal. It would be of great interest to determine whether the RBCs associated with hematocrit and hemoglobin, during the hospitalization of patients affected by malaria could be used to predict severe outcomes. In Human CM, it is urgent to stop and to reverse the development of symptoms, as quickly as possible, because of the high risk of neurological sequels. Even though artemisinin-based therapies decrease parasitemia rapidly, the neuropathology also needs to be treated, perhaps by an adjunct therapy associated to the antiparasitic compound. For the moment none of the compounds tested (for instance: protein C, ADAMTS 13 protease activator, nitric oxide, angiotensin-II inhibitor, erythropoietin) has a real protective action against the deleterious effects of Human CM . The present ECM rat model is thus an interesting tool in the search for such molecules in a relevant pharmacological approach.