Elizabeth Egan

Malaria is one of the leading causes of childhood morbidity and mortality in the world. The etiologic agent of severe malaria, Plasmodium falciparum, exclusively infects red blood cells during the blood stage of its life cycle, when all of the symptoms of malaria occur. P. falciparum is an obligate intracellular parasite, suggesting that it critically depends on host factors for its biology and pathogenesis. This concept is also supported by population genetic studies, which indicate that humans have evolved certain red cell traits, such as hemoglobinopathies, to protect against malaria. The importance of these host-pathogen interactions raises the possibility that critical red cell factors could serve as targets for new, host-directed therapeutics for malaria. However, our understanding of host determinants for malaria is limited because red cells are enucleated and lack DNA, hindering genetic manipulation. In the Egan laboratory we have surmounted this hurdle by adapting advances from stem cell biology to the study of malaria host factors. Specifically, we have developed approaches to differentiate primary human CD34+ hematopoietic stem/progenitor cells down the erythroid lineage to enucleated red blood cells that can be infected by P. falciparum. This thus gives us access to the nucleated progenitor cells for genetic modification using RNAi and CRISPR-Cas9 genome editing. We are using these methods to develop forward genetic screens to identify novel host factors for malaria, as well as to perform mechanistic studies to understand the specific functions of critical host factors during the developmental cycle of malaria parasites. In addition, the lab has projects focused on understanding human adaptation to malaria using clinical samples. Our long term goal is to explore the possibility of host-directed therapeutics for malaria.