A team of researchers led by Kasturi Haldar and Souvik Bhattacharjee of the University of Notre Dame’s Center for Rare and Neglected Diseases has made a fundamental discovery in understanding how malaria parasites cause deadly disease.
The researchers show how parasites target proteins to the surface of the red blood cell that enables sticking to and blocking blood vessels. Strategies that prevent this host-targeting process will block disease.
Malaria is a blood disease that kills nearly 1 million people each year. It is caused by a parasite that infects red cells in the blood. Once inside the cell, the parasite exports proteins beyond its own plasma membrane border into the blood cell. These proteins function as adhesins that help the infected red blood cells stick to the walls of blood vessels in the brain and cause cerebral malaria, a deadly form of the disease that kills over half a million children each year.
In all cells, proteins are made in the endoplasmic reticulum (ER) from where they are delivered to other parts of the cell. Haldar and Bhattacharjee and collaborators Robert Stahelin at the Indiana University School of Medicine-South Bend, and David and Kaye Speicher at the University of Pennsylvania’s Wistar Institute discovered that for host-targeted malaria proteins the very first step is binding to the lipid phosphatidylinositol 3-phosphate, PIP, in the ER.
This was surprising for two reasons. Previous studies suggested an enzyme called Plasmepsin V that released the proteins into the ER was also the export mechanism. However, Haldar, Bhattacharjee and colleagues discovered that binding to PIP lipid which occurs first is the gate keeper to control export and that export can occur without Plasmepsin V action. Further, in higher eukaryotic cells (such as in humans), the lipid PIP is not usually found within the ER membrane but rather is exposed to the cellular cytoplasm.
University of Notre Dame