Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi

• Authors: Mariko S Peterson, Emory University; Chester J Joyner, Emory University; Jessica A Brady, University of Georgia; Jennifer Wood, Emory University; Monica Cabrera-Mora, Emory University; Celia L Saney, Emory University; Luis L Fonseca, Georgia Institute of Technology; Wayne T Cheng, University of Georgia; Jianlin Jiang, Emory University; Stacey A Lapp, Emory University; Stephanie R Soderberg, Emory University; Mustafa Nural, University of Georgia; Jay C Humphrey, University of Georgia; Allison Hankus, Emory University; Deepa Machiah, Yerkes National Primate Research Center; Ebru Karpuzoglu, Emory University; Jeremy D DeBarry, University of Georgia; Jessica C Kissinger, University of Georgia; Alberto Moreno, Emory University; Sanjeev Gumber, Emory University; Eberhard Voit, Emory University; Juan B Gutiérrez, University of Georgia; Rehina Joice Cordy, Emory University; Mary R Galinski, Emory University
• Journal Title: MALARIA JOURNAL
• Volume: Volume 20, Number 1
• Publisher: BMC | 2021-12-30, Pages 486-486
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s12936-021-03925-6
• Subjects: Health Sciences, Immunology; Engineering, Biomedical
• Keywords: Science & Technology; Life Sciences & Biomedicine; Infectious Diseases; Parasitology; Tropical Medicine; Malaria; Nonhuman primate models; Cynomolgus monkeys; Infectious diseases resilience; Telemetry; Fever; Anaemia; Thrombocytopenia; Bone marrow; Histopathology; SEVERE MALARIAL ANEMIA; ANTIGENIC VARIATION; SABAH; PARASITE; IMMUNITY; MONKEYS; CYNOMOLGI; MALAYSIA; COATNEYI; MULATTA

Abstract

Background: Kra monkeys (Macaca fascicularis), a natural host of Plasmodium knowlesi, control parasitaemia caused by this parasite species and escape death without treatment. Knowledge of the disease progression and resilience in kra monkeys will aid the effective use of this species to study mechanisms of resilience to malaria. This longitudinal study aimed to define clinical, physiological and pathological changes in kra monkeys infected with P. knowlesi, which could explain their resilient phenotype. Methods: Kra monkeys (n = 15, male, young adults) were infected intravenously with cryopreserved P. knowlesi sporozoites and the resulting parasitaemias were monitored daily. Complete blood counts, reticulocyte counts, blood chemistry and physiological telemetry data (n = 7) were acquired as described prior to infection to establish baseline values and then daily after inoculation for up to 50 days. Bone marrow aspirates, plasma samples, and 22 tissue samples were collected at specific time points to evaluate longitudinal clinical, physiological and pathological effects of P. knowlesi infections during acute and chronic infections. Results: As expected, the kra monkeys controlled acute infections and remained with low-level, persistent parasitaemias without anti-malarial intervention. Unexpectedly, early in the infection, fevers developed, which ultimately returned to baseline, as well as mild to moderate thrombocytopenia, and moderate to severe anaemia. Mathematical modelling and the reticulocyte production index indicated that the anaemia was largely due to the removal of uninfected erythrocytes and not impaired production of erythrocytes. Mild tissue damage was observed, and tissue parasite load was associated with tissue damage even though parasite accumulation in the tissues was generally low. Conclusions: Kra monkeys experimentally infected with P. knowlesi sporozoites presented with multiple clinical signs of malaria that varied in severity among individuals. Overall, the animals shared common mechanisms of resilience characterized by controlling parasitaemia 3–5 days after patency, and controlling fever, coupled with physiological and bone marrow responses to compensate for anaemia. Together, these responses likely minimized tissue damage while supporting the establishment of chronic infections, which may be important for transmission in natural endemic settings. These results provide new foundational insights into malaria pathogenesis and resilience in kra monkeys, which may improve understanding of human infections.