The genes that help malarial parasites create feeding pores in human red blood cells have been identified in a new study led by an Indian-origin scientist.
Snug inside a human red blood cell, the malaria parasite hides from the immune system and fuels its growth by digesting hemoglobin, the cell's main protein.
AdvertisementThe parasite, however, must obtain additional nutrients from the bloodstream via tiny pores in the cell membrane.
Now, investigators from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, led by Sanjay A. Desai have found the genes that malaria parasites use to create these feeding pores.
For their study, the NIAID team screened nearly 50,000 chemicals for their ability to block nutrient uptake by cells infected with either of two genetically distinct lines of Plasmodium falciparum malaria parasites, HB3 and Dd2.
Most chemicals were equally active against the two lines, but one, ISPA-28, stood out because it was 800 times more active against the nutrient channels of Dd2-infected red blood cells than against those of HB3-infected cells.
If the PSAC protein is made by the parasite, the scientists reasoned, the strikingly different effects of ISPA-28 on the two lines may reflect genetic differences.
To explore this possibility, the investigators measured how well ISPA-28 inhibited PSAC activity in daughter parasites resulting from a genetic cross between the HB3 and Dd2 lines.
They found that most daughter parasites made channels that were identical to those of one or the other parent, indicating that parasite genes play an important role.
The inheritance pattern of ISPA-28 action on channels led the researchers to chromosome 3, where they found two parasite genes, clag3.1 and clag3.2, that appear to encode the PSAC protein.
This genetic evidence was bolstered when they showed that individual parasites express either the clag3.1 gene or the clag3.2 gene, but not both simultaneously.
They found that switching between the two genes produced changes in PSAC behavior that could be predicted.
Malaria parasites use gene switching as a way to protect essential proteins from attack by the immune system, said Desai.
The findings appeared online in Cell.