Daniel E. Goldberg, M.D., Ph.D.
Professor of Medicine and Molecular Microbiology
Co-Chair, Division of Infectious Diseases

Office: (314)  362-7180
FAX: (314)  367-3214
E-mail: goldberg@borcim.wustl.edu

Office/Lab: 561 McDonnell Sciences Building, Box 8230

Our laboratory is interested in the biochemistry of parasitic diseases. The organism we are studying is a protozoan parasite that causes malaria, Plasmodium falciparum.

Intraerythrocytic malaria parasites degrade vast quantities of hemoglobin to provide nutrients for their growth and maturation. This process occurs in the acidic digestive vacuole. Our laboratory is exploring various aspects of this catabolic process and its consequences. We are defining the proteolytic enzymes involved, their specificities and roles in hemoglobin breakdown, as well as their targeting to the digestive vacuole. We are investigating the action of inhibitors on each part of the pathway and are developing new inhibitors. Several aspartic proteases, a cysteine protease and a metalloprotease appear to participate in an ordered hemoglobin degradation pathway. One of the aspartic proteases has been crystallized and its structure reveals differences from mammalian homologs that can be exploited for drug development. The biosynthesis of the aspartic proteases is being studied; it appears to involve an unusual processing enzyme that we are characterizing.

Once intraerythrocytic malaria parasites mature and replicate, they must exit the host cell in order to infect new erythrocytes. We have found that this is a two-step process involving a specific proteolytic event. Further studies are focused on the identification and characterization of the implicated enzymes.

P. falciparum produces large quantities of a remarkable protein called histidine-rich protein II. HRPII is 75% His + Ala and has 50 dihistidine repeats. It is secreted by the parasite into the host erythrocyte. A portion is then ingested by the organism along with hemoglobin. Our studies have implicated HRPII in sequestration of the toxic heme release during hemoglobin degradation. A substantial amount of the HRPII is secreted by the parasite into the host bloodstream. Our data suggest that is is able to bind to the vascular endothelial glycosaminoglycans and may have an important role in falciparum malaria pathogenesis.

Our work involves a combination of biochemical, genetic, genomic and physiological approaches, to gain an understanding of the biology of this nefarious organism.