"Despite recent progress in controlling malaria worldwide, the disease continues to kill more than 700,000 people, primarily young children, every year," said NIAID Director Doctor Anthony S. Fauci, "Doctor Desai and his colleagues have discovered the genetic basis of a fundamental aspect of malaria parasite biology, and in doing so, they have opened up potential new approaches to developing antimalarial drugs."
Scientists have known for decades that malaria-infected red blood cells have greater nutrient uptake than non-infected cells, presumably to support parasite survival and growth, noted Desai. But, he added, "It was debated whether the parasite co-opts existing human channels or uses its own proteins to remodel the red blood cell membrane."
To answer this question, 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, Desai explained.
"We were surprised to discover a role for clag genes in PSAC activity," said Desai. This family of genes, which do not look like other ion channel genes, was previously thought to be involved in helping infected cells adhere to the inner lining of blood vessels. Clag genes are found in all species of malaria parasites, noted Desai, and this fact, along with the discovery that the parasites can choose between one of two channel genes to ensure nutrient uptake, strongly suggest that PSAC is required for parasite survival within red blood cells.
MEDICA.de; Source: NIH/National Institute of Allergy and Infectious Diseases