Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
Emory Vaccine Center, Emory University, Atlanta, GA, USA.
Malar J. 2021 Dec 30;20(1):486. doi: 10.1186/s12936-021-03925-6.
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.
食蟹猴（Macaca fascicularis）是疟原虫 knowlesi 的天然宿主，能控制这种寄生虫引起的寄生虫血症，且无需治疗即可存活。了解食蟹猴感染疟原虫的疾病进展和恢复能力将有助于有效利用该物种来研究对疟疾的恢复能力的机制。本纵向研究旨在确定感染疟原虫 knowlesi 的食蟹猴的临床、生理和病理变化，这些变化可以解释它们的恢复表型。
通过静脉内感染冷冻保存的疟原虫 knowlesi 孢子来感染食蟹猴（n=15，雄性，年轻成年），并每天监测寄生虫血症。在感染前（n=7）获取完整的血细胞计数、网织红细胞计数、血液化学和生理遥测数据，并在接种后每天获取，最多达 50 天。在特定时间点采集骨髓抽吸物、血浆样本和 22 个组织样本，以评估急性和慢性感染期间疟原虫感染的纵向临床、生理和病理影响。
正如预期的那样，食蟹猴控制了急性感染，并且在没有抗疟干预的情况下，保持低水平的持续寄生虫血症。出乎意料的是，在感染早期，会出现发热，最终恢复到基线水平，同时还伴有轻度至中度血小板减少症和中度至重度贫血。数学建模和网织红细胞生成指数表明，贫血主要是由于去除了未感染的红细胞，而不是红细胞生成受损所致。观察到轻度组织损伤，并且组织寄生虫负荷与组织损伤相关，尽管组织中的寄生虫积累通常较低。
实验感染疟原虫 knowlesi 孢子的食蟹猴表现出多种疟疾临床症状，个体之间的严重程度不同。总体而言，这些动物具有共同的恢复能力机制，其特征是在出现血症后 3-5 天控制寄生虫血症，控制发热，并伴有生理和骨髓反应来补偿贫血。这些反应共同最大限度地减少了组织损伤，同时支持慢性感染的建立，这对于自然流行地区的传播可能很重要。这些结果为食蟹猴疟疾发病机制和恢复能力提供了新的基础见解，可能有助于提高对人类感染的认识。
