New Scholar Award in Global Infectious Disease
Kirk W. Deitsch, Ph.D.
Weill Medical College of Cornell University

DNA Replication and var gene expression in Plasmodium falciparum

Malaria continues to be a disease of extreme importance in the developing world, infecting 300-500 million people yearly and resulting in 1-2 million deaths, primarily of young African children. The vast majority of malaria morbidity and mortality is caused by infection with the mosquito borne protozoan parasite Plasmodium falciparum. This parasite multiplies within the red blood cells of its host, causing disease through anemia resulting from red cell destruction and also through alterations made to the surface of infected red cells. These alterations make infected cells cytoadherent or “sticky”, allowing them to adhere to the walls of blood vessels, leading to obstruction of blood flow and such clinical manifestations as the often fatal syndrome of cerebral malaria. In addition, the parasites also continually change the identity of the proteins placed on the surface of infected cells, a process referred to as antigenic variation, thus avoiding the immune response mounted by the host. This process promotes a long term, persistent infection that is difficult for the infected individual to clear.

The proteins responsible for the cytoadherent properties of infected red cells are encoded by a mulitcopy gene family called var. While each parasite contains approximately 50 var genes within its genome, only a single copy is expressed at any given time. Over the course of an infection, expression switches to alternate copies within the family, resulting in antigenic variation and a persistent infection. The molecular mechanisms by which parasites manage to express only a single var gene at a time and how switches in expression are coordinated have remained a mystery since the discovery of the var gene family in 1995. Recent work has implicated changes in the structure of the chromatin that surrounds individual var genes as being important for controlling the _expression of this gene family. Work is now underway to investigate how DNA replication influences chromatin assembly and var gene expression patterns in hopes of shedding light on this important process and perhaps to identify potential targets for intervention.

Contact Dr. Deitsch.