title: Plasmodium cynomolgi infections in rhesus macaques display clinical and parasitological features pertinent to modelling vivax malaria pathology and relapse infections.
abstract: Plasmodium vivax infections in humans or in new world monkeys pose research challenges that necessitate the use of alternative model systems. Plasmodium cynomolgi is a closely related species that shares genetic and biological characteristics with P. vivax, including relapses. Here, the haematological dynamics and clinical presentation of sporozoite-initiated P. cynomolgi infections in Macaca mulatta (rhesus macaques) are evaluated over a 100-day period.
  
  
  
  Five M. mulatta were inoculated with 2000 P. cynomolgi B strain sporozoites. Parasitological and haematological data were collected daily to study the clinical presentations of primary infections and relapses. Peripheral blood and bone marrow aspirates were collected at specific time points during infection for future and retrospective systems biology analyses.
  
  
  
  Patent infections were observed between days 10 and 12, and the acute, primary infection consisted of parasitaemias ranging from 269,962 to 1,214,842 parasites/µl (4.42-19.5 % parasitaemia). All animals presented with anaemia, ranging from moderate (7-10 g/dl) to severe (<7 g/dl), based on peripheral haemoglobin concentrations. Minimum haemoglobin levels coincided with the clearance of parasites and peripheral reticulocytosis was evident at this time. Mild thrombocytopaenia (<150,000 platelets/µl) was observed in all animals, but unlike haemoglobin, platelets were lowest whenever peripheral parasitaemia peaked. The animals' conditions were classified as non-severe, severe or lethal (in one case) based upon their clinical presentation. The lethal phenotype presented uniquely with an exceptionally high parasitaemia (19.5 %) and lack of a modest reticulocyte release, which was observed in the other animals prior to acute manifestations. One or two relapses were observed in the four surviving animals, and these were characterized by significantly lower parasitaemias and minimal changes in clinical parameters compared to pre-infection values.
  
  
  
  Rhesus macaque infections initiated by P. cynomolgi B strain sporozoites recapitulated pathology of human malaria, including anaemia and thrombocytopaenia, with inter-individual differences in disease severity. Importantly, this study provides an in-depth assessment of clinical and parasitological data, and shows that unlike the primary infections, the relapses did not cause clinical malaria. Notably, this body of research has provided experimental plans, large accessible datasets, and blood and bone marrow samples pertinent for ongoing and iterative systems biology investigations.
authors: International Center for Malaria Research, Education and Development, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA, 30329, USA.|Malaria Host-Pathogen Interaction Center, Atlanta, GA, USA.
authors: Chester
authors: C
authors: Joyner
authors: International Center for Malaria Research, Education and Development, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA, 30329, USA.|Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA, USA.|Malaria Host-Pathogen Interaction Center, Atlanta, GA, USA.
authors: Alberto
authors: A
authors: Moreno
authors: International Center for Malaria Research, Education and Development, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA, 30329, USA.|Malaria Host-Pathogen Interaction Center, Atlanta, GA, USA.
authors: Esmeralda V S
authors: EV
authors: Meyer
authors: International Center for Malaria Research, Education and Development, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA, 30329, USA.|Malaria Host-Pathogen Interaction Center, Atlanta, GA, USA.
authors: Monica
authors: M
authors: Cabrera-Mora
authors: Department of Genetics, Institute of Bioinformatics, Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA.|Malaria Host-Pathogen Interaction Center, Atlanta, GA, USA.
authors: Jessica C
authors: JC
authors: Kissinger
authors: Malaria Branch, Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, GA, USA.|Malaria Host-Pathogen Interaction Center, Atlanta, GA, USA.
authors: John W
authors: JW
authors: Barnwell
authors: International Center for Malaria Research, Education and Development, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA, 30329, USA. mary.galinski@emory.edu.|Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA, USA. mary.galinski@emory.edu.|Malaria Host-Pathogen Interaction Center, Atlanta, GA, USA. mary.galinski@emory.edu.
authors: Mary R
authors: MR
authors: Galinski
mesh_terms: D000740:Anemia / Q000209:etiology / Q000473:pathology; D000818:Animals; D005260:Female; D008253:Macaca mulatta; D008288:Malaria / Q000150:complications / Q000469:parasitology / Q000473:pathology / Q000662:veterinary*; D008297:Male; D016789:Plasmodium cynomolgi / Q000302:isolation & purification*; D012008:Recurrence; D013921:Thrombocytopenia / Q000209:etiology / Q000473:pathology
keywords: Anaemia; Animal models; Host-pathogen interactions; Malaria; Non-human primates; Plasmodium vivax; Rhesus; Systems biology; Thrombocytopaenia