In order to spread disease inside the human body, the malaria parasite must evade the human immune system—which it does remarkably well. Now, researchers at Harvard School of Public Health (HSPH) have uncovered details about the mechanism by which the parasite, Plasmodium falciparum, avoids detection—it changes a critical protein on its surface that it uses as one of several molecular “keys” to enter into a new red blood cell. The gene that codes for this protein inside the parasite’s nucleus switches “on and off” at high frequency, which alters its presence on the surface of the parasite.
This process allows the parasite to travel undetected as it moves between red blood cells, which is when it is vulnerable to the immune system. The parasite becomes “itself” again once it is inside a new red blood cell, where it does its dirty work producing a new wave of daughter parasites.
This study, which appears in the December 13, 2012 issue of Cell Host & Microbe, is the first to describe the mechanism of the switching process that occurs in the malaria parasite in such detail, and is a key fundamental biological discovery that could help researchers find new ways of fighting malaria.
Malaria kills roughly 1.2 million people each year, mainly young children in sub-Saharan Africa. Transmitted through infected mosquitoes, the malaria parasite, once in the human bloodstream, multiplies inside red blood cells, which then burst after a few days, spreading more infection to other red blood cells and causing severe headache, nausea, vomiting, fever, coma, and other symptoms.
Manoj Duraisingh, senior author of the study and associate professor of immunology and infectious diseases at HSPH, and colleagues wanted to understand the molecular workings that allow the parasite to conceal itself so effectively.
“Even though the malaria parasite spends two days multiplying in a red blood cell, it has to get between cells, to propagate the infection, in a matter of minutes,” Duraisingh explained. “Even for that little period of time, it has to hide. So, as it’s jumping from one cell to the next it will vary its surface, otherwise it will get cleared away by the immune system.”
A gene that “packs,” “unpacks,” and travels
The researchers discovered a virulence gene located in the parasite’s nucleus called PfRh4. That gene encodes a protein on the surface of the parasite in order to enter red blood cells and can be switched on and off. To accomplish this, the gene in the nucleus is literally packed up into a tight ball to switch the gene off, and then is “unpacked” to switch the gene back on when either the immunity against PfRh4 has dwindled or the parasite is inside a new host. This process is known as epigenetic regulation.
“This ability of the parasite to vary its surface and persist in the bloodstream for a long time can contribute to the development of severe disease,” Duraisingh said.
A stealthy on-off mechanism
The team also found that the frequency with which the virulence gene in the parasite’s nucleus switches on and off—which allows the parasite to remain a step ahead of the human immune system—has to do with the location of the gene inside the nucleus. As the gene moves between special regions in the nucleus, the frequency of switching changes.
“These are important and fundamental biological findings,” said Duraisingh. “Because we now understand this mechanism, we can rationally go forward and identify the molecules that regulate these processes— the packaging and unpackaging of the gene and the movement of the gene around the nucleus—as targets for drug therapies.”
Other HSPH authors include lead authors Bradley Coleman, previously a PhD student who is now a curriculum fellow in Duraisingh’s lab and Ulf Ribacke, a research associate in the laboratory of co-author Dyann Wirth, Richard Pearson Strong Professor of Infectious Diseases and chair of the Department of Immunology and Infectious Diseases; and Amy Bei, research fellow in the Department of Immunology and Infectious Diseases.
— Karen Feldscher