Abstract
Malaria is a major cause of morbidity and mortality with an annual death toll exceeding one million. Severe malaria is a complex multisystem disorder, including one or more of the following complications: cerebral malaria, anemia, acidosis, jaundice, respiratory distress, renal insufficiency, coagulation anomalies, and hyperparasitemia. Using a combined in vivo/in vitro metabolic-based approach, we investigated the putative pathogenic effects of Plasmodium berghei ANKA on brain, in a mouse strain developing malaria but resistant to cerebral malaria. The purpose was to determine whether the infection could cause a brain dysfunction distinct from the classic cerebral syndrome. Mice resistant to cerebral malaria were infected with P. berghei ANKA and explored during both the symptomless and the severe stage of the disease by using in vivo brain magnetic resonance imaging and spectroscopy. The infected mice did not present the lesional and metabolic hallmarks of cerebral malaria. However, brain dysfunction caused by anemia, parasite burden, and hepatic damage was evidenced. We report an increase in cerebral blood flow, a process allowing temporary maintenance of oxygen supply to brain despite anemia. Besides, we document metabolic anomalies affecting choline-derived compounds, myo-inositol, glutamine, glycine, and alanine. The choline decrease appears related to parasite proliferation. Glutamine, myo-inositol, glycine, and alanine variations together indicate a hepatic encephalopathy, a finding in agreement with the liver damage detected in mice, which is also a feature of the human disease. These results reveal the vulnerability of brain to malaria infection at the severe stage of the disease even in the absence of cerebral malaria.
Highlights
P. berghei ANKA (PbA) is a widely recognized experimental model of malaria
We previously performed the first characterization of the experimental cerebral syndrome using in vivo magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) techniques [13]
The purpose was to test the hypothesis that PbA infection could elicit brain dysfunction, despite the absence of experimental cerebral malaria (CM), and by mechanisms different from those involved in CM
Summary
Thirty female BALB/c mice from Charles River Laboratories (l’Arbresle, France) (8 –10 week old, 20 –25 g body weight) were maintained at 23–25 °C with a 12-h light/12-h dark cycle and had free access to food and water. Animal studies were in agreement with the French guidelines for animal care and approved by the local Committee on Ethics. Twenty mice were infected with PbA by intraperitoneal injection of 106 parasitized red blood cells. Parasitemia was determined on Giemsa-stained blood smears and was expressed as the percentage of parasitized red blood cells. Total red blood cell counts and hemoglobin levels were determined from heparinized blood. Hemoglobin levels were assessed in blood collected from healthy BALB/c and infected mice at 8 or 15 days post-infection. Hemoglobin level in blood was calculated using standard curves (Randox Kit, Mauguio, France)
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