( up iron. Additional studies performed...)Discovery could lead to better control of hemorrhagic fever viruses

up iron. Additional studies, performed in Farzan's lab by HMS graduate student Sheli Radoshitzky, confirmed that TfR1 is also the receptor for the other three New World arenaviruses. (Abraham and Radoshitzky are both first authors on the study.) Expertise from Nancy Andrews, MD, PhD, an expert in iron metabolism at Children's, sped up the work.

Although not all hemorrhagic fever viruses use TfR1 to enter the body's cells, the discovery may help explain why these viruses wreak such havoc, damaging multiple organs and causing bleeding under the skin, in internal organs, and from orifices like the mouth, eyes or ears.

Because of TfR1's essential function in transporting iron into cells, it is found on the surface of virtually every cell of the body. It is abundant on endothelial cells, which line blood vessels, a fact that may help account for the bleeding and organ damage caused by the viruses. TfR1 is also especially abundant on activated immune cells ?the very cells that mobilize to fight the viruses ?making them especially vulnerable to infection.

"This may help explain why mortality is so high," says Choe, the study's senior author.

Choe now hopes to translate these findings into treatments to contain natural or intentional outbreaks of New World hemorrhagic fever. Serendipitously, several anti-TfR1 antibodies have already been developed as anticancer therapeutics (cancer cells are also high in TfR1), and some have already been through clinical trials. Choe's lab will test these antibodies, hoping to find one that inhibits virus entry without compromising TfR1's essential function in cellular iron uptake.

"If some of these antibodies work, they could be used clinically fairly soon," Choe says.

Coincidentally, Stephen Harrison, PhD, a structural biologist and Howard Hughes Medical Institute investigator at Children's, had crystallized TfR1 and determined its 3-dimensional structure in 1999. Knowled
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Source:Children's Hospital Boston

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