Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi.
Anaemia
Bone marrow
Cynomolgus monkeys
Fever
Histopathology
Infectious diseases resilience
Malaria
Nonhuman primate models
Telemetry
Thrombocytopenia
Journal
Malaria journal
ISSN: 1475-2875
Titre abrégé: Malar J
Pays: England
ID NLM: 101139802
Informations de publication
Date de publication:
30 Dec 2021
30 Dec 2021
Historique:
received:
18
06
2021
accepted:
24
09
2021
entrez:
31
12
2021
pubmed:
1
1
2022
medline:
12
1
2022
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 34969401
doi: 10.1186/s12936-021-03925-6
pii: 10.1186/s12936-021-03925-6
pmc: PMC8719393
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
486Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM008169
Pays : United States
Organisme : NIH HHS
ID : P51 OD011132
Pays : United States
Organisme : NIAID NIH HHS
ID : HHSN272201200031C
Pays : United States
Organisme : CLC NIH HHS
ID : C0000008
Pays : United States
Organisme : defense advanced research projects agency
ID : W911NF16C0008
Organisme : nih office of research infrastructure programs
ID : P51OD011132
Investigateurs
Dave C Anderson
(DC)
Ferhat Ay
(F)
Cristiana F A Brito
(CFA)
John W Barnwell
(JW)
Megan DeBarry
(M)
Steven E Bosinger
(SE)
Jung-Ting Chien
(JT)
Jinho Choi
(J)
Anuj Gupta
(A)
Chris Ibegbu
(C)
Xuntian Jiang
(X)
Dean P Jones
(DP)
Nicolas Lackman
(N)
Tracey J Lamb
(TJ)
Frances E-H Lee
(FE)
Karine Gaelle Le Roche
(KG)
Shuzhao Li
(S)
Esmeralda V S Meyer
(EVS)
Diego M Moncada-Giraldo
(DM)
Dan Ory
(D)
Jan Pohl
(J)
Saeid Safaei
(S)
Igñacio Sanz
(I)
Maren Smith
(M)
Gregory Tharp
(G)
ViLinh Tran
(V)
Elizabeth D Trippe
(ED)
Karan Uppal
(K)
Susanne Warrenfeltz
(S)
Tyrone Williams
(T)
Zerotti L Woods
(ZL)
Informations de copyright
© 2021. The Author(s).
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