Ebola May Enter Cell via Folate Gate.

Every virus thrives by invading cells, replicating within them, and then spreading to other cells. Unlike a burglar who crudely breaks into a residence, however, a virus uses its own proteins as molecular keys to unlock cells.

Deadly Ebola virus and its cousin Marburg virus are among the most efficient intruders known. Yet scientists haven't discovered their means of cell entry. New findings in the July 13 CELL point to a possible lock for the viruses' key: a cell-surface molecule that normally binds to a member of the vitamin B family.

This vitamin, called folate, is fundamental to growth and development. Many cells in the body, though not all, display folate receptors to capture the vitamin.

The new experiments show that a glycoprotein on the outside of both Ebola and Marburg viruses can latch on to one type of folate receptor, enabling the viruses to sneak into the underlying cell, says study coauthor Mark A. Goldsmith, a virologist and immunologist at the University of California, San Francisco School of Medicine.

Goldsmith and his colleagues experimented with lymphocytes, a type of white blood cell that the viruses don't typically attack. After genetically altering the lymphocytes to make them produce various receptor proteins, the researchers found that the viruses infected cells displaying the folate receptor.

The study is "clearly incriminating the folate receptor as being involved in cell entry of Marburg and Ebola virus types," says Asok C. Antony, a hematologist and oncologist at the Indiana University School of Medicine in Indianapolis.

The folate receptor "could be the right molecule" permitting some Ebola and Marburg infections, but probably not all, says Paul Bates, a virologist at the University of Pennsylvania in Philadelphia. Earlier research hinted that another cell-surface molecule, the asialoglycoprotein receptor, is an entry point for Marburg virus.

Ebola, in fact, appears to invade some cells that don't have folate receptors, Bates says. "There have to be other keys out there unlocking the doors to these cells," he says.

Ebola virus was first described in Zaire, now the Democratic Republic of Congo, in 1976. Recognition of Marburg virus dates from a 1967 outbreak in Marburg, Germany, that apparently spread to people from monkeys imported from Uganda. Both viruses can cause hemorrhage, fever, organ failure, and death.

Scientists haven't yet determined all the cells that the viruses attack. Candidates include liver cells and cells lining blood vessels and the respiratory system.

There is some evidence that airborne droplets may spread Ebola virus, Antony says. Perhaps it's not a coincidence, he says, that respiratory-system cells are among those displaying folate receptors.

Antony hypothesizes that if folate receptors are truly the viruses' dominant cell-entry points, then being folate deficient--as many people in developing countries are--could leave a person susceptible to infection. Such an individual would have many unoccupied folate receptors and so, plenty of places for viruses to attack.

However, Goldsmith doubts that simply giving virus-exposed people heavy doses of folate would help them avoid the disease. He finds more promising some test-tube experiments in the new study showing that an antibody designed to occupy the folate receptor can block cell entry by the viruses.

A third treatment option suggested by the new results would introduce a free-floating decoy receptor to which a virus could bind. That might keep it from infecting cells, Goldsmith says.

Decoys sopping up the virus might work, says Antony, but scientists would be left with the problem of how to remove accumulated viruses from the blood.

Before any of these therapies can be pursued, says Goldsmith, "it's more important to discover what other [vulnerable] receptors might be out there."