Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi

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.

Dynamic Control Balancing Cell Proliferation and Inflammation is Crucial for an Effective Immune Response to Malaria

“…In previous work, we had established crucial differences in the transcriptomics of the two hosts that ultimately determines the outcome in terms of susceptibility and resilience (Gupta et al, 2021). As also noted in the clinical assessment by Peterson et al (Peterson et al, 2021), transcriptomics analysis showed that Mf detects the pathogen earlier than Mm, and even though both host species mount a similar immune response, Mf starts controlling inflammation as early as the log phase of infection (Gupta et al, 2021). Subsequently, Mf switches the immune response towards cell proliferation pathways, which presumably aids recovery (Gupta et al, 2021).…”

“…Our analysis is based on data that were obtained with an experimental design ( Supplementary Figure S18 ) recently detailed in ( Peterson et al, 2021 ) and ( Gupta et al, 2021 ). In this longitudinal study of P. knowlesi infections in Mm and Mf, peripheral blood and bone marrow samples were collected at various time points (TPs), including baseline (before infection), pre-patent (TP3 or 3 days post inoculation; dpi), log-phase (TP4 or eight dpi) and peak-phase (TP5 or 10 dpi).…”

“…A deeper knowledge of the details of P. knowlesi infections can be expected to provide a crucial basis for understanding the immune responses in general and for comparing resilient and severe malarial responses in particular. As a zoonotic species, P. knowlesi has the advantage that it can be studied in different NHP species ( Pasini et al, 2018 ; Peterson et al, 2021 ). Among these NHP models, Macaca mulatta (Mm) and M. fascicularis (Mf) provide unique advantages specifically for comparing P. knowlesi infections with different disease progression.…”

“…Among these NHP models, Macaca mulatta (Mm) and M. fascicularis (Mf) provide unique advantages specifically for comparing P. knowlesi infections with different disease progression. Namely, even though Mm and Mf are evolutionarily very close, Mm, once infected, suffers from increasing parasitemia, which is in almost all cases fatal if not treated, whereas Mf controls parasitemia and escapes death without treatment ( Knowles and Gupta, 1932 ; Napier and Campbell, 1932 ; Peterson et al, 2021 ). These dramatic differences provide unparalleled opportunities to study the details of host physiology and immune responses in the context of host-parasite interactions and explore mechanisms of resilience in human malaria, and to potentially relate the findings to other diseases that may also show drastically different possible outcomes.…”

“…The authors are very grateful to Regina Joice Cordy for generating the Biocrates targeted metabolomics data and performing initial analyses that provided insights into the role of kynurenine in the host response to malaria. They also acknowledge Luis L. Fonseca and other members of the Malaria Host-Pathogen Interaction Center (MaHPIC) Consortium ( http://systemsbiology.emory.edu ) for insightful discussions and for the NHP longitudinal infection and data management work on which this analysis is based ( Peterson et al, 2021 ). The authors would also like to thank the Yerkes National Primate Research Center’s Genomics Core for sequencing services.…”