Plasmodium vivax in Hematopoietic Niches: Hidden and Dangerous

Silva‐Filho, João Luiz; Lacerda, Marcus; Recker, Mario; Wassmer, Samuel C.; Marti, Matthias; Costa, Fabio T. M.

doi:10.1016/j.pt.2020.05.006

Cited by 15 publications

(28 citation statements)

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“…In addition, by applying a supervised machine learning treestructured model, we were able to associate EC damage and thrombocytopenia with parasite biomass. In agreement with a previous study 8,39 our observations further suggest that total parasite biomass as measured by PvLDH is a better predictor of P. vivax host responses and pathogenesis than peripheral parasitaemia. Furthermore, these findings support the emerging paradigm of a major P. vivax parasite reservoir outside of circulation, in particular in the haematopoietic niche of bone marrow and spleen 39 .…”

Section: Discussionsupporting

confidence: 93%

“…Next, we ran K-means Clustering (k) followed by bootstrapping (Figure 2A, B; Figures S2, S3 Figure 3A). In agreement with previous findings 8,9,39 , z-score comparison further demonstrated that total parasite biomass was higher than and not correlated with peripheral parasitaemia levels or parasite load, in particular in patients of cluster 2 (Figure 3B, C). In addition, PvLDH was the input parasite variable with the highest loading score (correlation = 0.59) and lowest p-value (0.0000917) in the first PC dimension when compared with peripheral parasitaemia and parasite load ( Figure 2C, Table S2).…”

Section: Unsupervised Clustering Reveals Two P Vivax Patient Subgrousupporting

confidence: 92%

“…Total parasite biomass inducing EC activation might act synergistically with inflammatory changes potentially leading to splenic platelet pooling and platelet clumping in the vasculature without DIC20,47,51 . Likewise, increased activation-induced cell death (AICD) in T cells, splenic T-cell accumulation50 or decreased lymphopoiesis due to myeloid-biased HSC differentiation induced by inflammatory cytokines and EC activation in the BM36,37,39 might explain the severe lymphopenia and neutrophilia in vivax patients. Together such mechanisms could explain the link between parasite biomass and EC activation/damage with haematological changes observed in vivax patients that might contribute to pathogenesis and disease severity.…”

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Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations inPlasmodium vivaxpatients

Silva-Filho

Dos-Santos

Judice

et al. 2021

Preprint

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Plasmodium vivax is the major cause of human malaria in the Americas. How P. vivax infection can lead to poor clinical outcomes, despite low peripheral parasitaemia remains a matter of intense debate. Estimation of total P. vivax biomass based on circulating markers indicates existence of a predominant parasite population outside of circulation. In this study we investigate associations between both peripheral and total parasite biomass and host response in vivax malaria. We analysed parasite and host signatures in a cohort of uncomplicated vivax malaria patients from Manaus, Brazil, combining clinical and parasite parameters, multiplexed analysis of host responses and ex vivo assays. Patterns of clinical features, parasite burden and host signatures measured in plasma across the patient cohort were highly heterogenous. Further data deconvolution revealed two patient clusters, here termed Vivaxlow and Vivaxhigh. These patient subgroups were defined based on differences in total parasite biomass but not peripheral parasitaemia. Overall Vivaxlow patients clustered with healthy donors and Vivaxhigh patients showed more profound alterations in haematological parameters, endothelial cell (EC) activation and glycocalyx breakdown and levels of cytokines regulating different haematopoiesis pathways compared to Vivaxlow. Vivaxhigh patients presented more severe thrombocytopenia and lymphopenia, along with enrichment of neutrophils in the peripheral blood and increased neutrophil-to-lymphocyte ratio (NLCR). When patients’ signatures were combined, high association of total parasite biomass with a subset of markers of EC activation, thrombocytopenia and lymphopenia severity was observed. Finally, machine learning models defined a combination of host parameters measured in the circulation that could predict the extent of parasite infection outside of circulation. Altogether, our data show that total parasite biomass is a better predictor of perturbations in host homeostasis in P. vivax patients than peripheral parasitaemia. This supports the emerging paradigm of a P. vivax tissue reservoir, in particular in the hematopoietic niche of bone marrow and spleen.

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Section: Discussionsupporting

confidence: 93%

Section: Unsupervised Clustering Reveals Two P Vivax Patient Subgrousupporting

confidence: 92%

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confidence: 99%

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Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations inPlasmodium vivaxpatients

Silva-Filho

Dos-Santos

Judice

et al. 2021

Preprint

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“…Whilst there is strong evidence that hypnozoites cause relapses in P. vivax malaria, some recurrences of P. vivax malaria might have originated from non-hypnozoite cells, as in other human malarias [67][68][69]. Recently, it was reported that recurrence of parasitaemia had been recorded in some neurosyphilis patients who had received a P. vivax malaria patient's blood for malariotherapy [70][71][72]. Because P. vivax does not persist as sporozoites in human blood, no hypnozoite could have developed in the recipients.…”

Section: Recurrence Of Malaria and The Hypnozoitementioning

confidence: 99%

Plasmodium—a brief introduction to the parasites causing human malaria and their basic biology

Sato

2021

J Physiol Anthropol

187

117

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Malaria is one of the most devastating infectious diseases of humans. It is problematic clinically and economically as it prevails in poorer countries and regions, strongly hindering socioeconomic development. The causative agents of malaria are unicellular protozoan parasites belonging to the genus Plasmodium. These parasites infect not only humans but also other vertebrates, from reptiles and birds to mammals. To date, over 200 species of Plasmodium have been formally described, and each species infects a certain range of hosts. Plasmodium species that naturally infect humans and cause malaria in large areas of the world are limited to five—P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. The first four are specific for humans, while P. knowlesi is naturally maintained in macaque monkeys and causes zoonotic malaria widely in South East Asia. Transmission of Plasmodium species between vertebrate hosts depends on an insect vector, which is usually the mosquito. The vector is not just a carrier but the definitive host, where sexual reproduction of Plasmodium species occurs, and the parasite’s development in the insect is essential for transmission to the next vertebrate host. The range of insect species that can support the critical development of Plasmodium depends on the individual parasite species, but all five Plasmodium species causing malaria in humans are transmitted exclusively by anopheline mosquitoes. Plasmodium species have remarkable genetic flexibility which lets them adapt to alterations in the environment, giving them the potential to quickly develop resistance to therapeutics such as antimalarials and to change host specificity. In this article, selected topics involving the Plasmodium species that cause malaria in humans are reviewed.

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“…Recent data showed that late asexual blood stage Plasmodium vivax parasites are capable of cytoadhering due to endothelial host receptors [ 40 , 41 ]. In addition, data indicate that Plasmodium vivax parasites expand and replicate outside of the circulation in the hematopoietic niche of the bone marrow and possibly the spleen, affecting bone marrow function and host immunity [ 42 ]. However, this host-parasite interaction and its implication for diagnosis and treatment has to be further elucidated.…”

Section: Discussion Of Casementioning

confidence: 99%

Clinical-Pathological Conference Series from the Medical University of Graz

Bauer

Krippl

Fabian

et al. 2020

Wien Klin Wochenschr

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last menstruation was 4 months ago, now she is pregnant in the 15th week of gestation expecting twins. The patient's history is positive for one miscarriage; she and her husband are cousins, so they are blood related (consanguinity). Her travel history has been negative since she came to Austria. In the 13th week of gestation, a routine checkup in the obstetrics outpatient clinic of Graz University Medical Center revealed an unremarkable pregnancy with dichorionic diamniotic twins. In the 15th week of gestation, the patient again came to the outpatient clinic because of a cold, headache and cough. She was diagnosed with an upper respiratory tract infection and was given ambroxol, a saline nasal spray and paracetamol as needed. Laboratory data at that time showed: leukocytes 4.9 × 10 9 /L (normal: 4.4-11.3 × 10 9 /L), erythrocytes 3.37 × 10 12 /L (normal: 4.10-5.10 × 10 12 /L), hemoglobin 10.2 g/dL (normal: 12.0-15.3 g/dL), hematocrit 28.4% (normal: 35.0-45.0%), neutrophils 80% (normal: 50-75%), lymphocytes 13% (normal: 20-40%), platelets 196 × 10 9 /L (normal: 140-440 × 10 9 /L), C-reactive protein (CRP) 28.9 mg/L (normal: <5.0 mg/L) and fibrinogen 516 mg/dL (normal: 210-400 mg/dL). In case of persistent complaints the patient was advised to come to the emergency room (ER) of Graz University Medical Center. Two weeks later, the patient presented in the ER with a retrosternal pressure sensation radiating into the left arm and back, a 2-week history of headache, fever (39.9°C), and poor appetite for 2 days. The patient showed tachycardia with a heart rate of 129 bpm. Echocardiography and Duplex sonography of the leg veins were unremarkable. Laboratory data: leukocytes 3

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Plasmodium vivax in Hematopoietic Niches: Hidden and Dangerous

Cited by 15 publications

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Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations inPlasmodium vivaxpatients

Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations inPlasmodium vivaxpatients

Plasmodium—a brief introduction to the parasites causing human malaria and their basic biology

Clinical-Pathological Conference Series from the Medical University of Graz

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