Malaria is one of the deadliest infectious diseases and kills an estimated 2 million persons every year. Even though a considerable body of knowledge exists on the parasite cycle, our understanding of how the parasite infects its vertebrate host is incomplete. Infection is initiated when an infected mosquito delivers sporozoites at the time of blood feeding. The sporozoites find their way to the circulation and of all organs through which they transit, they specifically target and infect the liver. Previous work has established that sporozoites attach to highly sulfated, liver-specific glycosaminoglycans (GAGs) that protrude the fenestrated walls of the liver blood vessels, called sinusoids. Two cell types line the sinusoids: endothelial cells and specialized macrophages, termed Kupffer cells. It is known that to reach the hepatocytes, sporozoites invade Kupffer cells, not endothelial cells, indicating that sporozoite-Kupffer recognition takes place. Despite its importance for the outcome of infection, the molecular basis for this recognition step remains largely unknown. In preliminary work we have identified three peptides from a phage display library that bind specifically to Kupffer cells causing an inhibition of sporozoite invasion. By crosslinking the peptides to their target protein on the Kupffer cells, we will identify and characterize candidate Kupffer cell receptors for sporozoite invasion. We hypothesize that the peptides mimic the conformation of sporozoite proteins that interact with the Kupffer cells. We will produce antibodies against each of the peptides and use these antibodies to identify and characterize the sporozoite proteins that presumably interact with the Kupffer cells during invasion. Such proteins have the potential of becoming candidates for development of a malaria vaccine that prevents liver infection.

Public Health Relevance

Malaria is one of the deadliest infectious diseases and kills an estimated 2 million persons every year. After an infected mosquito delivers Plasmodium sporozoites to its host it enters the circulation and specifically recognize and invade liver macrophages (Kupffer cells). This project is to identify and characterize the proteins (Kupffer receptors and sporozoite ligands) involved in sporozoite invasion of liver Kupffer cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080668-04
Application #
8279442
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
2009-06-05
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$361,658
Indirect Cost
$141,135
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218