The bone marrow as a major hub for P. vivax infection

The recently launched global effort to eradicate malaria has been stimulated by the dramatic decrease of the disease incidence in sub Saharan Africa. While Plasmodium falciparumis the deadliest of human malaria parasites, Plasmodium vivaxis a major cause of malaria morbidity within and outside of Africa. P. vivaxis now a major focus of the ongoing elimination agenda, with particular emphasis on development of in vitroculture systems and understanding of key biological featuressuch as latency and transmission.Though not well studied it is believed that both P. vivaxasexual and transmission stages(or gametocytes)of P. vivax are do not require tissue sequestrationfor development and therefore arepresent in circulation throughout their cycle. They appear in blood circulation 3-5 days after the first asexual parasites are detected microscopically, and therefore transmission can occur well before the patient is symptomatic. The goal of the present study was to revisitP. vivaxcirculation and sequestration patterns both in the non-human primate model and in human infections. Comparative transcriptional analysis of P. falciparumversus P. vivaxgametocytes demonstrated a conserved cascade of stage specific gene expression until maturity despite significantly different cyclelength. A subset of conserved gametocyte stage-specific markers was successfully validated by quantitative Real-Time PCR (qRT-PCR) and antibody assays in peripheral blood samples from infected Aotusmonkeys. To investigate possible tissue specific sequestration of P. vivax gametocytes during infection, we performed detailed histological analyses of asexual and gametocyte stagesacross organs. Analysis across 13 infected primates provided strong evidence for major accumulation of both asexual and gametocyte stages in the hematopoietic system of the bone marrow. Parallel transcriptional analysis of parasites in patient blood samples confirmed absence of these stages in circulation. These data confirm recent observationsof P. falciparum enrichmentin bone marrow and spleen and suggest that these organs play an essential role in proliferation and transmission of malaria parasites. These findings close a major knowledge gap in the P. vivax cycle, with critical implications for the ongoing malaria elimination agenda.