Mechanisms of Cellular Remodeling during Plasmodium falciparum Sequestration and Transmission

Abstract

Despite significant progress in global malaria control, Plasmodium falciparum remains a major cause of morbidity and mortality world-wide. The need for new interventions demands better understanding of the underlying cellular mechanisms that mediate parasite survival and transmission. Asexual growth and the development of sexual stages, termed gametocytes, take place in human red blood cells, and sexual reproduction takes place in the mosquito vector. Blood stage parasites sequester in host tissues to survive, requiring extensive cellular remodeling. Sequestering asexual stage parasites export hundreds of proteins into the host cell to change its deformability and cytoadherence. Developing gametocytes also sequester in deep tissues before reentering circulation to mediate transmission, and they too are characterized by protein export, deformability changes, and likely cytoadherence. Although significant progress has been made in understanding remodeling changes that occur to mediate sequestration and transmission, many open questions remain. In this work, we identified and characterized proteins involved in cellular remodeling of asexual and sexual stage parasites. We first investigated red blood cell remodeling and sequestration during blood stage development, focusing specifically on the Plasmodium helical interspersed sub-telomeric c (PHISTc) protein family. Using a combination of biochemistry, biophysics, flow cytometry, and microscopy, we showed that PHISTc proteins are exported to the host cell of asexual and sexual stages and are required for the delivery of specific antigens to the surface of asexual stage infected red blood cells. Further, they play this specialized role in antigen delivery without drastically altering cellular architecture. Next, we investigated the mechanisms that drive the transition of stiff, sequestered gametocytes into deformable, circulating gametocytes. Using biophysical and transcriptional approaches, we identified genes that are enriched or depleted in deformable gametocytes. Some of these candidate genes likely remodel the host red blood cell while others may remodel the parasite itself, with some candidates required for the formation of deformable, infectious gametocytes. We anticipate that these genes either drive or delineate the deformability transition and could represent possible targets of therapeutics or diagnostics used to reduce malaria transmission. Together, these studies reveal both conserved and stage-specific mechanisms involved in the successful sequestration and transmission of Plasmodium falciparum.