A central pathogenic feature of P. falciparum infection is the sequestration of infected red blood cells to the endothelial lining of blood vessels. Sequestration allows parasites to avoid passage through the spleen where they would be eliminated, but it can act as a trigger for severe malaria when large numbers of infected red blood cells accumulate in specific vascular sites, such as the brain (cerebral malaria) and placenta (malaria during pregnancy). A major research interest for the Smith lab is to decipher how infected red blood cells attach to different microvascular beds and understanding vascular disease mechanisms caused by sequestered parasites.
Binding of infected red blood cells to blood vessels is mediated by a large and diverse family of parasite adhesion proteins, called PfEMP1. To avoid immune destruction, malaria parasites use a clever strategy called clonal antigenic variation to control PfEMP1 expression and specifically express only one PfEMP1 on the red blood cell membrane at a time. This immune evasion strategy enables parasites to gradually express different members of the PfEMP1 family and stay one step ahead of the host antibody response. As the parasite switches between different PfEMP1 proteins, this determines parasite-binding tropism for different blood vessels.
The Smith lab is interested in understanding the molecular mechanisms governing parasite-vessel wall interactions. We investigate the structure and function of PfEMP1 proteins and host receptor interactions associated with deadly malaria complications. We recently identified a distinct subset of PfEMP1 proteins that binds to brain endothelial cells using a host receptor called endothelial protein C receptor (EPCR). As EPCR plays a key role in regulating blood clotting and inflammation in blood vessels, our work suggests there are important linkages between IE cytoadhesion and vascular disease complications associated with severe malaria. We use a combination of laboratory and field based studies to better understand malaria disease pathogenesis and to design disease interventions.
Investigating the P. falciparum cytoadhesion virulence determinant
The goal of this project is to advance our understanding of malaria disease mechanisms and aid in the development of interventions to treat severe malaria. We are taking a multi-pronged approach that involves both laboratory and field based research studies. Our lab has pioneered novel approaches to broadly interrogate PfEMP1 function in a repertoire-wide manner. We are also working with collaborators at the University of Washington, Department of Bioengineering to develop better in vitro endothelial models to study parasite-host vessel wall interactions and characterize malaria vascular disease mechanisms. As part of our field-based research efforts, we belong to an International Centers of Excellence for Malaria Research (ICEMR) team based in India (PI, Pradip Rathod, University of Washington) where we are investigating the role of PfEMP1 proteins in severe malaria.
Malaria vaccine discovery
The goal of this research project is to aid in the design and development of malaria vaccine immunogens. One of the challenges for malaria vaccine development is the complex life-cycle and high polymorphism of P. falciparum parasite strains in the parasite population. The Smith Lab is interested in vaccine approaches to inhibit parasite invasion into host cells or prevent cytoadhesion of infected erythrocytes. We have worked on the preclinical development of vaccines to protect women from malaria during pregnancy and on the development and application of novel immunogen design strategies to focus antibody responses and improve vaccine efficacy.
Identification of deadly parasite binding variants:
In this study, we showed that a distinct subset of parasites is selected on human brain endothelial cells and characterized the parasite ligands mediating cerebral binding. This finding gives important clues into a deadly parasite binding phenotype and could help explain why some malaria infections result in more severe complications than others. It also suggests new targets for anti-disease interventions.