MRC FAPESP: Defining the role of the hematopoietic parasite reservoir in Plasmodium vivax infection and pathology

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

Plasmodium vivax is the most widely distributed malaria parasite and a major public health burden. Recent studies suggest that the majority of parasites is present outside of circulation, making it difficult to track and target them. We have demonstrated that bone marrow in particular represents an under-appreciated reservoir which supports P. vivax growth and differentiation to transmission stages. Parallel studies have also reported major parasite accumulation in the spleen. Based on these findings we hypothesize that the haematopoietic niche of bone marrow and spleen represents the main parasite reservoir during infection and drives disease severity. In this ambitious research program, we will analyze infected bone marrow and spleen tissue from a series of cohorts of naturally exposed patients in endemic areas in Brazil. We will perform histological, molecular and phenotypic characterization of sequestered and circulating parasite and host cell populations to systematically investigate and quantify the role of bone marrow and spleen for parasite infection, transmission, diagnosis and pathology. This work will thus contribute much needed insights and critical tools for the ongoing global malaria elimination campaign.

Technical Summary

Plasmodium vivax (P. vivax) places a heavy disease burden across endemic regions worldwide and presents a major challenge for malaria eradication. Recent studies from our laboratories and others have demonstrated that the extravascular bone marrow niche and potentially the spleen represent a major tissue reservoir for parasite proliferation and transmission stage maturation across Plasmodium spp. lineages, with significant implications for malaria diagnosis and treatment success. P. vivax is restricted to invasion of the youngest red blood cells, known as immature reticulocytes, which originate in the bone marrow. This restriction results in a distinct and poorly understood biology that we believe has precluded previous efforts to establish in vitro parasite culture and systematic study of P. vivax. Importantly, P. vivax elicits a potent host response and causes severe and fatal manifestations at much lower parasitaemia than P. falciparum, suggesting that P. vivax restriction to host cells enriched in the hematopoietic niche of BM and spleen could induce alterations in host homeostasis such as anaemia, lymphopenia, thrombocytopenia and splenomegaly. This collaborative proposal will employ for the first time a systematic investigation of the biology of the P. vivax reservoir in BM and spleen and its role in disease pathogenesis, infection and transmission in a series of cohorts of patients in Brazil. We will characterize parasite and host biology in infected tissues and investigate their behaviour ex vivo using a series of cutting edge technologies and in collaboration with world leading experts. The proposed work will thus close a major knowledge gap in our understanding of P. vivax biology and pathogenesis and provide critical tools for the development of new P. vivax control measures to support the ongoing malaria elimination agenda.

Publications

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