Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi

Peterson, M. S.; Joyner, C. J.; Brady, J. A.; Wood, J. S.; Cabrera-Mora, M.; Saney, C. L.; Fonseca, L. L.; Cheng, W. T.; Jang, J.; Lapp, S. A.; Soderberg, S. R.; Nural, M. V.; Humphrey, J. C.; Hankus, A.; Machiah, D.; Karpuzoglu, E.; DeBarry, J. D.; MaHPIC-Consortium,; Tirouvanziam, R.; Kissinger, J. C.; Moreno, A.; Gumber, S.; Voit, E. O.; Gutierrez, J. B.; Cordy, R. J.; Galinski, M. R.

doi:10.1101/2021.06.28.448877

Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.06.28.448877

Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi

View original source ↗Export metadata ↓

Abstract

BackgroundKra 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. MethodsKra 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. ResultsAs 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. ConclusionsKra 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.

Source connections

Published article ↗

Explore related subjects

pathology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Peterson, M. S., Joyner, C. J., Brady, J. A., Wood, J. S., Cabrera-Mora, M., Saney, C. L., Fonseca, L. L., Cheng, W. T., Jang, J., Lapp, S. A., Soderberg, S. R., Nural, M. V., Humphrey, J. C., Hankus, A., Machiah, D., Karpuzoglu, E., DeBarry, J. D., MaHPIC-Consortium,, Tirouvanziam, R., Kissinger, J. C., Moreno, A., Gumber, S., Voit, E. O., Gutierrez, J. B., Cordy, R. J., Galinski, M. R.. 2021-06-28. Clinical recovery of Macaca fascicularis infected with Plasmodium knowlesi. https://doi.org/10.1101/2021.06.28.448877

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Midlife nonlinearities across scale in Biondi body amyloid formation in the human choroid plexus

Human choroid plexus epithelial cells (CPECs), which produce cerebrospinal fluid and form the blood-cerebrospinal fluid barrier, accumulate discrete intracellular amyloid inclusions called Biondi bodies (BBs). Using systematic manual and machine learning approaches on the choroid plexus glomus, we determined the percentages of CPECs containing thioflavin S-stained BBs as well as BB load and spatial distributions in whole slide images from 77 cases across the human lifespan. On average, BB prevalence was near zero until age 40, rose steeply in the 5th and 6th decades, and exceeded 50% after age 70. As prevalence plateaued, BB load continued to rise with age. Accelerated BB accumulation was seen in two cases of diabetic ketoacidosis, including a 16-year-old, while an 85-year-old with the relatively rare APOE2/E2 genotype had fewer BBs than expected. BB prevalence in the choroid plexus glomus was not associated with Alzheimer's disease, but was lower in females than males. Notably, spatial clustering of BBs was universal across cases while nearest-neighbor analyses suggested cell-to-cell, prion-like BB spread that can account for the nonlinearities seen at tissue and population scales. The abrupt, nonlinear BB accumulation during midlife coincides with or precedes other common aging-associated neuropathologies of the human brain, consistent with broad BB and choroid plexus contributions to brain aging and disease.

pathology↗

bioRxiv2026

Elevated precontractile calcium set point is sustained by limited PMCA1 export in dystrophic muscle

Duchenne muscular dystrophy is caused by loss of dystrophin and marked by elevated muscle calcium, usually attributed to contraction-induced membrane damage. Whether calcium rises before muscle can contract, and what sustains it, is unresolved. In Caenorhabditis elegans embryos and patient-derived human myoblasts, dystrophic muscle carries an elevated resting calcium set point before contraction is possible. Embryonic calcium is elevated 400 minutes after fertilization, before movement is detectable or the neuromuscular junction forms. Silencing the plasma membrane calcium pump gene mca-1 raises calcium in wild-type but not dystrophic animals, whereas silencing its paralogue raises it in both: the limitation is specific to that export route. Dystrophic human myoblasts have less pump; pump inhibition or silencing increases calcium preferentially in healthy cells, and raising pump expression lowers calcium most in dystrophic cells. Constrained calcium export is an early, continuing determinant of the dystrophic set point.

pathology↗

bioRxiv2026

Systematic comparison of gliflozins identifies a selective anti-calcifying effect of canagliflozin beyond canonical SGLT2 inhibition

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) provide important cardiorenal benefits in chronic kidney disease (CKD), but their effects on vascular calcification remain conflicting. Whether potential anti-calcifying effects are shared across gliflozins or involve mechanisms beyond canonical SGLT2 inhibition is unknown. Methods: We systematically compared canagliflozin, dapagliflozin and empagliflozin in a high-phosphate diet-induced mouse model of vascular calcification and complementary ex vivo and in vitro models, including rodent and human vascular tissues and vascular smooth muscle cells (VSMCs). Aortic transcriptional response was investigated by RNA sequencing. VSMC calcification, proliferation, migration, viability, glucose uptake and bioenergetics were investigated using complementary cellular assays, including OsteoSense staining, Annexin V/propidium iodide staining, radiolabeled 2-deoxyglucose uptake and Seahorse ATP rate analysis. SGLT2/1 expression was examined by RT-qPCR, Western blotting and immunofluorescence. We also evaluated sotagliflozin, a dual SGLT1/2 inhibitor, and mizagliflozin, a selective SGLT1 inhibitor. Results: Among the three gliflozins, only canagliflozin significantly reduced aortic calcification in vivo. Its anti-calcifying effect was also observed in rodent aortic rings, human vascular explants, cultured VSMCs and aortic rings from diabetic db/db mice. Aortic RNA-seq revealed that canagliflozin partially reversed HPD-induced transcriptional alterations, including changes in pro-calcific signaling and cellular metabolism, while some endothelial and inflammatory responses were shared among gliflozins. In mouse VSMCs, canagliflozin reduced calcification across all tested concentrations, dose-dependently decreased osteogenic marker expression, and reduced proliferation and migration. Increased apoptotic and damaged cell fractions were observed at higher concentrations, but not at lower concentrations. Canagliflozin also reduced glucose uptake and mitochondrial ATP production, without significantly affecting glycolytic ATP production. Neither dapagliflozin nor empagliflozin reproduced these cellular and metabolic effects at any of the concentrations tested. SGLT2 and SGLT1 expression was low or undetectable in vascular tissues and cells, and neither sotagliflozin nor mizagliflozin reproduced the anti-calcifying effect of canagliflozin in vivo or in vitro. Conclusions: Canagliflozin exhibits a selective anti-calcifying profile among the gliflozins tested, associated with changes in VSMC responses and cellular metabolism. These findings suggest that its vascular protective effects may involve mechanisms beyond canonical SGLT2 inhibition.

pathology↗