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X-ray crystallography has allowed US researchers to discover exactly how one type of New World haemorrhagic fever virus latches on to and infects human cells. The work offers a much-needed lead for new treatments. There are a whole range of viruses hosted by small rodents across South America. When these viruses infect people they can cause haemorrhagic fevers with symptoms similar to those of Ebola. Among their number is the Machupo virus, which attaches itself to cells through a binding mechanism to the butterfly-shaped transferrin receptor, a protein that regulates cellular iron uptake. Symptoms can be lethal, treatments expensive, and then only partially effective. "New World haemorrhagic fevers are nasty, serious, and often fatal diseases," explains Stephen Harrison of the Howard Hughes Medical Institute. He, and colleagues at the Harvard Medical School, Boston, Massachusetts, Jonathan Abraham, Kevin Corbett, Michael Farzan, and Hyeryun Choe, report details of a structural study of the transferrin receptor associated with viral infectivity in the 7th March issue of Nature Structural & Molecular Biology. Harrison adds that, "The need for new interventions is high." Machupo is an arenavirus, which generally cause severe inflammation and bleeding from the mouth, nose, eyes, and other orifices. Most outbreaks occur in rural regions of Bolivia, Venezuela, Argentina, and Brazil. "The outbreaks of New World haemorrhagic fever tend to be brief and brutal, with mortality rates of 20 to 30 percent," adds graduate student Abraham. "These viruses aren't a huge public health issue yet, but you could say the New World haemorrhagic fevers are an emerging disease threat." Arenaviruses have been known to medicine since the 1960s, but the molecular basis of their virulence and activity has not been tackled in detail until recently. In 2007, Abraham was working with Boston Children's Hospital virologist Choe. Together they identified transferrin receptor 1 as the human cell surface receptor on to which Machupo virus latches during infection. Almost every cell in our bodies has the transferrin receptor, which transports essential iron into the cells. In Choe's laboratory, Abraham had developed methods to produce the Machupo virus surface protein, which links to the human transferrin receptor. He then hooked up with his former mentor, Harrison, who had stocks of purified transferrin receptor to hand from earlier studies. The pair began to focus on making batches of Machupo surface protein bound to the transferrin receptor, which could then be analysed using x-ray crystallography. Work with a powerful X-ray beam at Argonne National Laboratory in Illinois, allowed Abraham and Harrison to produce a highly detailed atomic structure of the complex. The images show that the Machupo surface protein binds to the transferrin receptor in a surprising way: it uses an apical domain (shown in green in the diagram). The biological function of this loop in humans is unknown, Harrison explains. Other segments of the receptor bind iron-bearing transferrin, but the apical domain appears not to be involved in the process. "We don't know the normal function of the apical domain," he says, "Obviously it didn't evolve just to give Machupo virus a way to infect humans, but that's what the virus has evolved to latch onto." The apical domain represents an interesting target for drugs, especially as it may not have a critical cellular role. In theory, an antibody designed to attach to the apical domain would prevent the Machupo virus from attaching to cells, blocking infection, the researchers explain. A possible treatment strategy would be to infuse patients with this antibody early in their infection; this might then block viral replication enough to allow the patients to recover. Harrison says the finding might also help virologists predict which of the 22 known arenaviruses could be capable of crossing the species barrier to humans and emerging as new infective agents. At the moment, just five of these viruses can infect people; they all bind to the human transferrin receptor. The other 17 viruses produce surface proteins that presumably cannot use this infection route. For Abraham, the idea of finding a treatment for these New World haemorrhagic fevers is close to his heart. His family hails from Haiti, where there is a "huge burden of infectious diseases. I'd like to dedicate my career to studying pathogens in underserved parts of the world," he says.
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