Maria M. Mota and colleagues from the Howard Hughes Medical Institute have discovered that the same liver receptor that allows entry of cholesterol into hepatocytes is used by malaria parasite to sneak into the organ cells.
The SR-BI receptor is normally an entry point for HDL cholesterol and other lipids from the bloodstream into liver cells, which break them down. But new experiments show that the malaria parasite may also be using this doorway. When scientists disabled the SR-BI receptor, they saw a dramatic reduction in the number of infections from two species of malaria in mouse and human cells. The experiments are presented in the September 2008 issue of Cell Host & Microbe.
Previous research had linked the lipoprotein clearance rate by the liver to increased malaria infection, so Mota thought the parasite might enter liver cells by hijacking the liver’s own cellular machinery. The group focused its attention on the part of liver cells that filter fatty molecules like cholesterol and other lipids out of the bloodstream.
Mota’s team used RNA interference (RNAi) to examine the receptors that filter lipoproteins. The RNAi technique permitted the researchers to create cell lines with specific genes inactivated. They then tested each cell line to see how it responded to the malaria parasite. “We looked through 53 lipoprotein receptors and found one that really stood out from the rest,” Mota says. That receptor was SR-BI (class B, type I scavenger receptors). Removing SR-BI cut down infections in these cells more than any other receptor they tested.
To confirm their suspicions about SR-BI’s key role in malaria, the team conducted a series of experiments that examined mouse cells, human cells, and living mice. First, they induced mouse cells to produce much more of the protein than usual. When they exposed those cells to the parasite that causes malaria in mice, they found the cells were infected more readily than cells with a normal amount of the receptor. The team then tested the receptor’s role in a line of human cells with a human-specific malaria parasite, and got similar results.
Cells in living animals often respond differently than cultured cells, so Mota’s team explored SR-BI’s role in live mice. First they suppressed the gene for SR-BI in these mice, and later injected them with a malaria-causing parasite. Forty hours after exposure, the researchers examined whether the parasite infected the animals’ liver cells. They found that the mice with reduced SR-BI had liver infection levels 50-70 percent lower than the normal mice.
Press release: Cholesterol and Malaria May Use Same Doorway to Liver Cells