Plasmodium coatneyi in Rhesus Macaques Replicates the Multisystemic Dysfunction of Severe Malaria in Humans

• Type of Material: Article
• Authors: Alberto Moreno, Emory University; Monica Cabrera-Mora, Emory University; Anapatricia Garcia, Emory University; Jack Orkin, Emory University; Elizabeth Strobert, Emory University; John W. Barnwell, Centers for Disease Control and Prevention; Mary R Galinski, Emory University
• Language: English
• Date: 2013-06-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2013, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/IAI.00027-13
• Title of Journal or Parent Work: Infection and Immunity
• ISSN: 0019-9567
• Volume: 81
• Issue: 6
• Start Page: 1889
• End Page: 1904
• Grant/Funding Information: This research was supported by NIH/NHLBI grant number 1P01 HL078826 (original project 3 led by M.R.G. and A.M.) and NIH/NIAID grants R01-AI064766; and R01-AI024710.; The Yerkes National Primate Research Center received support from the National Center for Research Resources P51RR000165, and it is currently supported by the Office of Research Infrastructure Programs/OD P51OD011132.
• Keywords: Immunology; RED-CELLS; Life Sciences & Biomedicine; Infectious Diseases; HUMAN CEREBRAL MALARIA; Science & Technology; PAPUA-NEW-GUINEA; MACACA-MULATTA; TUMOR-NECROSIS-FACTOR; SEVERE FALCIPARUM-MALARIA; FACTOR-ALPHA; PRIMATE MODEL; SERUM-LEVELS; INTERFERON-GAMMA
• Research Categories: Health Sciences, Public Health; Biology, Microbiology

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.