Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Discovery could lead to better control of hemorrhagic fever viruses

New World arenaviruses enter cells through a well-known iron-uptake receptor

Researchers report discovering the receptor through which a group of life-threatening hemorrhagic fever viruses enter and attack the body's cells, and show that infection can be inhibited by blocking this receptor. The findings, to be published online by the journal Nature on February 7, give a clue to the high lethality of New World arenaviruses, suggest a way of reducing the severity of infection, and point the way toward a sorely needed treatment strategy.

The four viruses, known as the Machupo, Guanarito, Junin and Sabia viruses, cause Bolivian, Venezuelan, Argentine and Brazilian hemorrhagic fever, respectively, with mortality rates of about 30 percent. No vaccine is available, though a weakened form of Junin virus has been given to Argentinean farmers with some success. In addition to causing occasional disease outbreaks, mostly in poor, rural areas of South America, the viruses are of U.S. government interest because of their potential as bioterrorism agents. All four are classified as NIAID Category A Priority Pathogens and must be handled in Biosafety Level 4 containment facilities.

The researchers, led by Hyeryun Choe, PhD, of Children's Hospital Boston's Pulmonary Division, and Michael Farzan, PhD, of Harvard Medical School (HMS), first investigated the Machupo virus. To identify its cellular receptor, they made copies of the "spike" protein, used by the virus to gain entry into cells, and added it to cells from African green monkeys, known to be highly susceptible to Machupo virus infection. Later, they broke the cells open and isolated the spike protein and the cellular protein to which it had attached itself. Then, using a technique called mass spectrometry, they analyzed this attached cellular protein to determine its identity.

The receptor, identified in Choe's lab by Jonathan Abraham, PhD, an MD-PhD student at HMS, turned out to be transferrin receptor 1 (TfR1), a well-known protein that is key in enabling cells to take 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. Knowledge of TfR1's structure will speed up the Choe lab's efforts to pinpoint the parts of the molecule that are exploited by New World hemorrhagic fever viruses, which is necessary for the development of targeted antiviral drugs that block those parts, but not the parts involved in iron uptake.

The findings of Choe and colleagues also suggest that iron supplements may reduce the severity of New World virus infections. Past studies have shown that when the iron level in the body is low, the number of transferrin receptors in tissues increases. Consistent with these findings, Choe's team found that New World arenaviruses infect cells more efficiently when iron levels are low, and that adding iron to cultured cells makes them less susceptible to infection. Choe notes that New World hemorrhagic fever outbreaks mostly occur in poor rural areas, where people are often deficient in micronutrients, including iron, possibly predisposing them to more severe infection when exposed to the rodents that carry the viruses.

Choe's lab is now trying to find the cellular receptor for other viruses that cause hemorrhagic fever in humans. In 2003, Choe's lab collaborated with Farzan's lab to identify angiotensin converting enzyme2 (ACE2) as the receptor for the SARS virus.

Rachel Pugh | EurekAlert!
Further information:

More articles from Health and Medicine:

nachricht Resolving the mystery of preeclampsia
21.10.2016 | Universitätsklinikum Magdeburg

nachricht New potential cancer treatment using microwaves to target deep tumors
12.10.2016 | University of Texas at Arlington

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>