Malaria is a severe, multi-system disease that has affected humans since ancient times.
Transmitted by mosquitoes, today malaria remains very common in tropical and sub-tropical regions of the world where the mosquito vector is found, such as sub-Saharan Africa, Southeast Asia and central and South America.
Malaria is caused by Plasmodium parasites, with the most severe disease caused by Plasmodium falciparum. This parasite has the ability to evade the immune system, making it one of the leading causes of childhood mortality in endemic areas.
The life cycle of P. falciparum is complex, involving mosquito, liver and blood stages, but clinical illness occurs when it invades and replicates exponentially in red blood cells. Though anti-malaria agents exist, drug resistance is an ongoing issue and there is no effective vaccine.
Our work aims to understand the molecular details of how P. falciparum infects red blood cells.
We are particularly interested in uncovering the red blood cell factors that are used by this intracellular parasite to support its growth and development in these cells. By defining and characterizing host red blood cell determinants of malaria infection, we hope to lay the ground work for the future development of new therapeutics or vaccines for malaria.
In her postdoctoral research in Manoj Duraisingh’s laboratory, Dr. Elizabeth Egan developed the first forward genetic screen for host determinants of P. falciparum infection in red blood cells (Egan et al, 2015 Science 348: 711-14; see also “News and Views” in Nature, 2015 522: 158-159). Since red blood cells lack a nucleus and DNA, this required using a hematopoietic stem cell model in which progenitor cells could be genetically modified and then differentiated to mature red blood cells. This project identified two new candidate host factors for P. falciparum invasion, CD44 and CD55, as well as several other potential candidates.
Ongoing research areas
(1) What is the role of host CD55 and other candidate host factors in P. falciparum invasion of red blood cells?
(2) How does P. falciparum interact with the host red blood cell to ensure its successful development during the blood stage?
(3) How can CRISPR-Cas9 genome editing be used to understand host determinants of P. falciparum infection in red blood cells?
(4) Has there been natural selection for genetic variants in CD55 or other candidate host factors to protect humans against severe malaria?
(5) What is the relationship between innate malaria resistance and genetic blood disorders?
Screening for novel host factors using erythroid stem cell precursors
We use an in vitro stem cell model to investigate the role of red blood cell factors in parasite invasion and growth. Nucleated erythroid precursors (left) are gentically-engineered with CRISPR-Cas9 and differentiated into enucleated reticulocytes (right) that are susceptible to parasite infection.
Parasitology research at Stanford
We belong to a vibrant community of parasitology researchers at Stanford University. The Egan lab is a member of the Apicomplexan Supergroup (above) hosted by the Boothroyd Lab in the Dept of Microbiology and Immunology. We also run a monthly parsitology club where trainees and faculty share their research over dinner.