title: Plasmodium coatneyi in rhesus macaques replicates the multisystemic dysfunction of severe malaria in humans.
abstract: Severe malaria, a leading cause of mortality among children and nonimmune adults, is a multisystemic disorder characterized by complex clinical syndromes that are mechanistically poorly understood. The interplay of various parasite and host factors is critical in the pathophysiology of severe malaria. However, knowledge regarding the pathophysiological mechanisms and pathways leading to the multisystemic disorders of severe malaria in humans is limited. Here, we systematically investigate infections with Plasmodium coatneyi, a simian malaria parasite that closely mimics the biological characteristics of P. falciparum, and develop baseline data and protocols for studying erythrocyte turnover and severe malaria in greater depth. We show that rhesus macaques (Macaca mulatta) experimentally infected with P. coatneyi develop anemia, coagulopathy, and renal and metabolic dysfunction. The clinical course of acute infections required suppressive antimalaria chemotherapy, fluid support, and whole-blood transfusion, mimicking the standard of care for the management of severe malaria cases in humans. Subsequent infections in the same animals progressed with a mild illness in comparison, suggesting that immunity played a role in reducing the severity of the disease. Our results demonstrate that P. coatneyi infection in rhesus macaques can serve as a highly relevant model to investigate the physiological pathways and molecular mechanisms of malaria pathogenesis in naïve and immune individuals. Together with high-throughput postgenomic technologies, such investigations hold promise for the identification of new clinical interventions and adjunctive therapies.
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA. alberto.moreno@emory.edu
authors.forename: Alberto
authors.initials: A
authors.lastname: Moreno
authors.forename: Monica
authors.initials: M
authors.lastname: Cabrera-Mora
authors.forename: Anapatricia
authors.initials: A
authors.lastname: Garcia
authors.forename: Jack
authors.initials: J
authors.lastname: Orkin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Strobert
authors.forename: John W
authors.initials: JW
authors.lastname: Barnwell
authors.forename: Mary R
authors.initials: MR
authors.lastname: Galinski
mesh_terms: D000740:Anemia / Q000276:immunology / Q000469:parasitology / Q000662:veterinary; D000818:Animals; D001777:Blood Coagulation; D001855:Bone Marrow Diseases / Q000097:blood / Q000469:parasitology / Q000662:veterinary; D004195:Disease Models, Animal; D004920:Erythropoiesis; D004921:Erythropoietin / Q000097:blood; D008253:Macaca mulatta / Q000469:parasitology*; D008288:Malaria / Q000097:blood / Q000276:immunology / Q000469:parasitology / Q000662:veterinary*; D008297:Male; D008992:Monkey Diseases / Q000097:blood* / Q000276:immunology / Q000469:parasitology; D010961:Plasmodium / Q000145:classification*; D011897:Random Allocation; D013997:Time Factors
chemical_list: D004921:Erythropoietin