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Host-parasite interactions in the bone marrow: a key role in Malaria pathogenesis

Grant number: 19/01578-2
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): May 30, 2019
Effective date (End): May 21, 2020
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Fabio Trindade Maranhão Costa
Grantee:João Luiz da Silva Filho
Supervisor: Matthias Marti
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: University of Glasgow, Scotland  
Associated to the scholarship:16/12855-9 - Mechanism of action of lipoxin in the protection against experimental cerebral malaria, BP.PD


Studies on Plasmodium vivax biology and immunopathogenesis have long been neglected due to the relatively reduced pathology compared to P. falciparum malaria. Detection of all parasite stages in blood circulation also suggested absence of significant levels of tissue sequestration in P. vivax, further supporting the lack of severe symptoms. However, several recent observations have challenged this paradigm. First, reports of severe clinical complications in vivax malaria have recently been published. Second, it has been shown that late asexual blood stage parasites are capable of cytoadhering to endothelial host receptors and that these stages are less abundant in blood circulation of P. vivax patients compared to earlier stage parasites. Third, estimation of parasite biomass based on circulating biomarkers indicates a hidden parasite reservoir outside of circulation, in particular in patients with complicated outcomes. In support of these observations it was demonstrated quantitative depletion of transcripts from late asexual and immature sexual (gametocyte) stages in the blood of P. vivax patients, and enrichment of these stages in bone marrow sinusoids and parenchyma of experimentally infected non-human primates. This finding has been confirmed in a P. vivax case study with matched bone marrow aspirates and blood sample. Moreover, it has been demonstrated a similar bone marrow phenotype in P. falciparum-infected malaria patients and experimentally infected mice. In these studies, hematologic disorders were also observed including severe anemia, dyserythropoiesis and vascular leakage. Meanwhile, initial mechanistic studies have suggested a crosstalk between infected red blood cells and resident bone marrow cells. Altogether, these findings define the bone marrow as a critical compartment for growth and transmission in malaria parasites - in particular for P. vivax with its preference for bone-marrow resident erythroid cells. However, the biological relevance of the host-parasite interactions established in the BM niches in terms of malaria pathogenesis remain far from clear and represents a key knowledge gap. In the BM parenchyma, specialized microenvironments, called niches (endosteal and vascular), regulate hematopoietic stem cell (HSC) maintenance and function through an active and complex set of cellular, chemical, structural, and physical cues. In addition, stromal cells and sinusoidal endothelial cells are important players in the bone marrow growth and maintenance. Thus, the active presence and development of Plasmodium sexual and asexual forms in the BM raises questions in regard the underlying molecular and physical cross talks between infected red blood cells and hematopoietic niche environments. In line with the major purpose of my post-doctoral project, we also measured in the plasma of healthy (endemic controls) and P. vivax patients the levels of molecules involved with the dynamics of thrombopoiesis and hematopoiesis. Our preliminary data demonstrate systemic changes upon P. vivax infection, which may also reflect alterations in BM function. Therefore, we hypothesize that the large parasite reservoir in the bone marrow contributes to both persistence and pathogenesis of vivax malaria. This will be able to contribute to a better understanding of P. vivax biology and pathogenesis, and hence to our efforts to reduce the burden of this important human disease. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SILVA-FILHO, JOAO LUIZ; LACERDA, MARCUS V. G.; RECKER, MARIO; WASSMER, SAMUEL C.; MARTI, MATTHIAS; COSTA, FABIO T. M.. Plasmodium vivax in Hematopoietic Niches: Hidden and Dangerous. Trends in Parasitology, v. 36, n. 5, p. 447-458, . (19/01578-2, 16/12855-9, 17/18611-7)
SILVA-FILHO, JOAO L.; DOS-SANTOS, JOAO C. K.; JUDICE, CARLA; BERALDI, DARIO; VENUGOPAL, KANNAN; LIMA, DIOGENES; NAKAYA, I, HELDER; DE PAULA, V, ERICH; LOPES, STEFANIE C. P.; LACERDA, MARCUS V. G.; et al. Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations in Plasmodium vivax patients. eLIFE, v. 10, . (16/12855-9, 19/01578-2, 17/18611-7)

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