Bone Marrow Is a Major Parasite Reservoir in Plasmodium vivax Infection.

Nicanor Obaldia,Elamaran Meibalan,Martha A Clark,Curtis Huttenhower,William Otero,Manoj T Duraisingh,Juliana M Sa,Roberto R Moraes Barros,Siyuan Ma,Matthias Marti,Pedro Mejia,James R Mitchell,Danny A Milner,Thomas E Wellems,Dyann F Wirth,Marcelo U Ferreira,Jon P Boyle

doi:10.1128/mbio.00625-18

Abstract

ABSTRACTPlasmodium vivax causes heavy burdens of disease across malarious regions worldwide. Mature P. vivax asexual and transmissive gametocyte stages occur in the blood circulation, and it is often assumed that accumulation/sequestration in tissues is not an important phase in their development. Here, we present a systematic study of P. vivax stage distributions in infected tissues of nonhuman primate (NHP) malaria models as well as in blood from human infections. In a comparative analysis of the transcriptomes of P. vivax and Plasmodium falciparum blood-stage parasites, we found a conserved cascade of stage-specific gene expression despite the greatly different gametocyte maturity times of these two species. Using this knowledge, we validated a set of conserved asexual- and gametocyte-stage markers both by quantitative real-time PCR and by antibody assays of peripheral blood samples from infected patients and NHP (Aotus sp.). Histological analyses of P. vivax parasites in organs of 13 infected NHP (Aotus and Saimiri species) demonstrated a major fraction of immature gametocytes in the parenchyma of the bone marrow, while asexual schizont forms were enriched to a somewhat lesser extent in this region of the bone marrow as well as in sinusoids of the liver. These findings suggest that the bone marrow is an important reservoir for gametocyte development and proliferation of malaria parasites.

Highlights

Plasmodium vivax causes heavy burdens of disease across malarious regions worldwide
Research on P. vivax has generally lagged behind research on P. falciparum [3, 9, 10], while much of our knowledge of P. vivax biology has been founded on experimental infections of nonhuman primates (NHP) and mosquitoes [11]
Our previous work provided a comprehensive analysis of temporal relationships among P. falciparum gametocyte transcripts, including the transcripts of 591 genes that grouped into 29 clusters, from the onset of gametocytogenesis to final maturation [29]

Summary

Introduction

Plasmodium vivax causes heavy burdens of disease across malarious regions worldwide. Mature P. vivax asexual and transmissive gametocyte stages occur in the blood circulation, and it is often assumed that accumulation/sequestration in tissues is not an important phase in their development. Histological analyses of P. vivax parasites in organs of 13 infected NHP (Aotus and Saimiri species) demonstrated a major fraction of immature gametocytes in the parenchyma of the bone marrow, while asexual schizont forms were enriched to a somewhat lesser extent in this region of the bone marrow as well as in sinusoids of the liver. These findings suggest that the bone marrow is an important reservoir for gametocyte development and proliferation of malaria parasites. We present a systematic investigation of P. vivax tissue distributions and provide further evidence for enrichment of transmission and replicative stages in the bone marrow and liver, relative to peripheral blood

Methods

Results

Conclusion