Plasmodium coatneyi in Rhesus Macaques Replicates the Multisystemic Dysfunction of Severe Malaria in Humans 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 Journal Title: Infection and Immunity Volume: Volume 81, Number 6 Publisher: American Society for Microbiology | 2013-06-01, Pages 1889-1904 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1128/IAI.00027-13 Permanent URL: https://pid.emory.edu/ark:/25593/s78xt Final published version: http://dx.doi.org/10.1128/IAI.00027-13 Copyright information: © 2013, American Society for Microbiology. All Rights Reserved. Accessed October 6, 2021 3:29 PM EDT Plasmodium coatneyi in Rhesus Macaques Replicates the Multisystemic Dysfunction of Severe Malaria in Humans Alberto Moreno,a,b Monica Cabrera-Mora,a AnaPatricia Garcia,c,d Jack Orkin,e Elizabeth Strobert,e John W. Barnwell,f Mary R. Galinskia,b Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USAa; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USAb; Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USAc; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Emory University Hospital, Atlanta, Georgia, USAd; Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USAe; Malaria Branch, Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, Georgia, USAf 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 crit- ical 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 ma- caques (Macaca mulatta) experimentally infected with P. coatneyi develop anemia, coagulopathy, and renal and metabolic dys- function. 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 inves- tigate the physiological pathways and molecular mechanisms of malaria pathogenesis in naïve and immune individuals. To- gether with high-throughput postgenomic technologies, such investigations hold promise for the identification of new clinical interventions and adjunctive therapies. alaria is the most prevalent parasitic disease globally, with tions of malaria parasites with other pathogens, are also con- Mthe World Health Organization (WHO) recent estimates founding factors, constituting another level of parasite-host dy- showing 216 million or more clinical episodes annually, resulting namics that is not well understood. in 655,000 deaths (1). Children under 5 years of age, pregnant The World Health Organization has established clinical crite- women, and nonimmune adults are particularly susceptible to ria to define severe malaria cases and facilitate the comparison of developing severe disease (2). Although the large dimension of the data obtained from ecologically diverse areas of the world with problem is well known, knowledge concerning the molecular different patterns of transmission (5). The WHO has defined life- mechanisms involved in the physiopathology of severe malaria is threatening clinical syndromes that are frequently associated with limited. patients infected with P. falciparum as follows: severe anemia, Severe malaria has been traditionally associated with Plasmo- neurological syndrome, thrombocytopenia accompanied by co- dium falciparum infections; however, there is mounting evidence agulation disorders, respiratory distress or pulmonary edema, indicating that P. vivax can also be responsible for severe and acute renal failure, circulatory collapse, and severe metabolic sometimes lethal cases of malaria (3, 4). While both species can complications. Recently, Lanca and colleagues have summarized cause severe disease, with various commonalities, the clinical clinical and epidemiological data indicating that some similar syn- spectrum is known to differ in a number of respects. Cerebral dromes can also define severe malaria caused by P. vivax (6). malaria with coma is a common complication of P. falciparum Experimental model systems are needed to investigate the un- severe malaria. This contrasts with the frequent presentation of derlying mechanism and pathophysiology of severe malaria in hu- respiratory distress in severe malaria caused by P. vivax infections. mans in order to facilitate the development of biological or phar- Severe anemia, multiorgan dysfunction, and thrombocytopenia macological tools for clinical intervention. Rodent malaria models are complications noted with either species. Sequestration of P. falciparum-infected erythrocytes (RBCs) bound to the endothe- lium of small vessels in various tissues and organs, particularly in Received 11 January 2013 Returned for modification 14 February 2013 the brain, has been associated with cerebral malaria and other Accepted 6 March 2013 disorders of severe malaria, although it has not been determined if Published ahead of print 18 March 2013 disease results from the sequestration of infected erythrocytes or if Editor: J. H. Adams infected erythrocyte adhesion is enhanced by the pathophysiolog- Address correspondence to Alberto Moreno, [email protected]. ical state. P. vivax-infected erythrocytes circulate and largely are Copyright © 2013, American Society for Microbiology. All Rights Reserved. not adhesive and do not sequester in the vasculature of particular doi:10.1128/IAI.00027-13 organs. P. falciparum and P. vivax coinfections, as well as coinfec- June 2013 Volume 81 Number 6 Infection and Immunity p. 1889–1904 iai.asm.org 1889 Moreno et al. of cerebral malaria and severe anemia have been studied and the TABLE 1 Rhesus physiological score system (RPSS) immune-pathological pathways of causation dissected exten- Score sively. However, new effective clinical interventions have not come from this body of work, and it has been questioned if these Variable 01 2 rodent malaria models are relevant to human malaria (7, 8). Non- Dehydration None Mild Moderate to human primate (NHP) models of malaria infection are available, marked although certainly underutilized, to study malaria disease states Respiratory rate Normal Tachypnea Dyspnea (8–10). The potential of infections of various simian malaria par- Activity Good Fair (malaise) Poor (lethargy) Appetite Good Fair (malaise) Poor (lethargy) asites in macaques to identify mechanisms of pathogenesis com- Hemoglobin (g/dl) Ͼ14 10–14 Ͻ10 mon to human malaria has been studied to a limited extent (8– Platelets (no. of cells/␮l) Ͼ300,000 100,000–300,000 Ͻ100,000 10). P. coatneyi and P. falciparum, although not particularly close Parasitemiaa (no. of 0 0.1–1,000 1,000–10,000 phylogenetically, do closely share a number of nearly identical parasites/␮l) phenotypic characteristics. Both species are characterized by a 48- a For parasitemia levels, additional scores were assigned: 3, 10,000 to 20,000/␮l; 4, hour intraerythrocytic developmental cycle, electron-dense knob 20,000 to 40,000/␮l; 5, 40,000 to 60,000/␮l; 6, 60,000 to 80,000/␮l; 7, 80,000 to 100,000/ protrusions on the surface of their infected host cells, and pro- ␮l; 8, Ͼ100,000/␮l. found deep vasculature sequestration of trophozoite- and schi- zont-infected erythrocytes. The primary sites of infected erythro- cyte adhesion to endothelium for P. coatneyi were in the vessels of National Primate Research Center were assigned to this study. Procedures the heart, fatty tissues, omentum, intestines, and musculature, used were approved by Emory University’s Institutional Animal Care and very similar to tissue sites for P. falciparum in human malaria Use Committee and followed accordingly. The Hackeri strain of P. coat- (11–13). In this regard, infection with P. coatneyi has been pro- neyi used in these studies came from archived stocks maintained by cryo- posed as an optimal primate model for human cerebral malaria preservation at the Centers for Disease Control and Prevention (21). (13–16). Although these particular studies have shown histologi- Twenty animals were randomized into four groups of 5 animals; and two cal findings with sequestration of infected erythrocytes in cerebral of these groups were exposed to P. coatneyi at two different time points. vasculature, the multisystemic clinical data collected during the Ten animals