A Review of <i>Plasmodium coatneyi</i>–Macaque Models of Severe Malaria

Lombardini, Eric; Gettayacamin, Montip; Turner, Gareth D. H.; Brown, Arthur E.

doi:10.1177/0300985815583098

Cited by 12 publications

(30 citation statements)

References 110 publications

(175 reference statements)

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“…This number may have been higher if the animals had not been cured as a group after the fifth specimen collection. Nevertheless, the observed relapse patterns reported here are similar to what would be expected with P. vivax infections with tropical strains of this parasite [7, 66, 67]. A follow-up, iterative experiment was designed to monitor the natural relapse patterns, without such treatment plans, and to monitor gametocytes during the relapse periods more carefully.…”

Section: Discussionsupporting

confidence: 75%

Plasmodium cynomolgi infections in rhesus macaques display clinical and parasitological features pertinent to modelling vivax malaria pathology and relapse infections

Joyner

Moreno

Meyer

et al. 2016

Malar J

101

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Background: 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.Methods: 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.Results: 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 preinfection values.Conclusions: 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

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Section: Discussionsupporting

confidence: 75%

Plasmodium cynomolgi infections in rhesus macaques display clinical and parasitological features pertinent to modelling vivax malaria pathology and relapse infections

Joyner

Moreno

Meyer

et al. 2016

Malar J

101

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“…Here, histological changes in the liver, lungs, kidneys, and the gastrointestinal tract were identified, but consistent with kra monkeys being a resilient host, the tissue lesions observed were relatively mild (Supplementary Table 2). These results can be contrasted with the severe tissue damage previously reported from P. knowlesi , P. coatneyi or P. cynomolgi infections in rhesus macaques [45, 77–80].…”

Section: Discussioncontrasting

confidence: 81%

Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi

Ms¹,

Joyner²,

Ja³

et al. 2021

Preprint

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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. Results As expected, the kra monkeys controlled parasitaemia and remained with low-level, persistent parasitaemias without antimalarial intervention. Unexpectedly, early in the infection, fevers developed, which ultimately returned to baseline, as well as mild to moderate thrombocytopaenia, and moderate to severe anaemia. Mathematical modeling 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.

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“…Our investigations yielded a large collection of datasets and analyses from over 30 macaque infections and controls, including frequent samplings of blood and bone marrow 34 , 36 – 43 . The first two simian malaria parasite species are excellent models of corresponding human infections by the parasites P. falciparum and P. vivax , respectively 28 , 44 , while P. knowlesi reflects aspects of both, depending on the question 29 , 45 . Plasmodium cynomolgi and P. knowlesi infect both humans and NHPs and constitute zoonotic public health concerns in Southeast Asia, where humans and macaque species coexist 7 , 46 – 49 .…”

Section: Introductionmentioning

confidence: 99%

Dramatic transcriptomic differences in Macaca mulatta and Macaca fascicularis with Plasmodium knowlesi infections

Gupta

Styczynski

Galinski

et al. 2021

Sci Rep

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Plasmodium knowlesi, a model malaria parasite, is responsible for a significant portion of zoonotic malaria cases in Southeast Asia and must be controlled to avoid disease severity and fatalities. However, little is known about the host-parasite interactions and molecular mechanisms in play during the course of P. knowlesi malaria infections, which also may be relevant across Plasmodium species. Here we contrast P. knowlesi sporozoite-initiated infections in Macaca mulatta and Macaca fascicularis using whole blood RNA-sequencing and transcriptomic analysis. These macaque hosts are evolutionarily close, yet malaria-naïve M. mulatta will succumb to blood-stage infection without treatment, whereas malaria-naïve M. fascicularis controls parasitemia without treatment. This comparative analysis reveals transcriptomic differences as early as the liver phase of infection, in the form of signaling pathways that are activated in M. fascicularis, but not M. mulatta. Additionally, while most immune responses are initially similar during the acute stage of the blood infection, significant differences arise subsequently. The observed differences point to prolonged inflammation and anti-inflammatory effects of IL10 in M. mulatta, while M. fascicularis undergoes a transcriptional makeover towards cell proliferation, consistent with its recovery. Together, these findings suggest that timely detection of P. knowlesi in M. fascicularis, coupled with control of inflammation while initiating the replenishment of key cell populations, helps contain the infection. Overall, this study points to specific genes and pathways that could be investigated as a basis for new drug targets that support recovery from acute malaria.

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A Review of Plasmodium coatneyi–Macaque Models of Severe Malaria

Cited by 12 publications

References 110 publications

Plasmodium cynomolgi infections in rhesus macaques display clinical and parasitological features pertinent to modelling vivax malaria pathology and relapse infections

Plasmodium cynomolgi infections in rhesus macaques display clinical and parasitological features pertinent to modelling vivax malaria pathology and relapse infections

Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi

Dramatic transcriptomic differences in Macaca mulatta and Macaca fascicularis with Plasmodium knowlesi infections

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