Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Discovery could lead to better control of hemorrhagic fever viruses

09.02.2007
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:
http://www.harvard.edu

More articles from Health and Medicine:

nachricht Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine

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: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

NRL clarifies valley polarization for electronic and optoelectronic technologies

20.10.2017 | Interdisciplinary Research

Metallic nanoparticles will help to determine the percentage of volatile compounds

20.10.2017 | Materials Sciences

Shallow soils promote savannas in South America

20.10.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>