Defining physiological correlates of the human malaria infectious reservoir

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 DESCRIPTION (provided by applicant): Malaria remains one of the leading causes of death worldwide and affects about half the global population, despite decades of public health efforts. The recent commitment to eliminate malaria by many endemic countries marks a shift in public health policy away from programs aimed at controlling disease burden towards one that emphasizes reducing transmission of the most virulent human malaria parasite, Plasmodium falciparum. Only a very small fraction of malaria parasites within human blood are able to infect mosquitoes, however, and these transmission stages have remained under-studied because they do not cause disease and are difficult to detect by conventional methods. Because malaria transmission stages are rarely detected, it has been assumed that only a small fraction of malaria-infected individuals are capable of infecting mosquitoes. Our recent preliminary data suggest that this dogma is wrong, however, and that people with low-density malaria infections can in fact transmit to mosquitoes very efficiently. In addition, we demonstrated that blood meals directly from the skin of an infected participant more commonly result in mosquito infection compared to blood meals from venous blood samples. This led to our hypothesis that transmissible malaria parasite stages cluster under the skin where mosquitoes can find them most effectively. If this hypothesis is correct, all previous analyses of infectiousness based on venous blood are not accurate. The clustering of transmission stages under the skin may contribute considerably to the phenomenally efficient spread of malaria parasites in populations. Here we aim to test this hypothesis directly using a unique set of autopsies from fatal malaria cases in Malawi and using mosquito-feeding experiments in Burkina Faso. We will analyze our human samples using both histology and a new Nanostring platform, a highly sensitive expression tailored for P. falciparum asexual and transmission stages. In parallel mosquito feeding outcome from the different human compartments sampled (skin and venous blood) will be determined. Together, this interdisciplinary study will test long-standing and powerful hypothesis using modern tools. As such it will lay the foundation for accurate predictions of malaria transmissibility at a population level that can inform public health interventions and timelines to achieve malaria elimination. If we indeed observe that gametocytes cluster under the skin, our study will form the starting point for systematic mechanistic studies and may lead to novel transmission- blocking interventions.