Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Hemorrhagic Fevers Can Be Caused by Body’s Antiviral Interferon Response

05.06.2014

Hemorrhagic fevers caused by Lassa, dengue and other viruses affect more than one million people annually and are often fatal, yet scientists have never understood why only some virus-infected people come down with the disease and others do not.

But now, virologists and immunologists at The Scripps Research Institute (TSRI) have found a major clue to the mystery of “hemorrhagic fever” syndromes. In findings reported this week in an Early Edition of the Proceedings of the National Academy of Sciences, the team showed that Interferon Type I (IFN-I) immune proteins are key drivers of a viral syndrome in mice that closely mimics these human hemorrhagic fevers.

“Blocking IFN-I signaling in certain genetic mouse strains completely prevented disease signs such as vascular leakage leading to death,” said TSRI Associate Professor of Immunology Roberto Baccala, who, with TSRI Professor Michael Oldstone, led this study.

While IFN-I proteins traditionally have been considered essential for an effective antiviral response and are still used to treat some chronic viral infections, the new study suggests that these proteins sometimes do much more harm than good—and that blocking them, or specific biological pathways they activate, might be a good therapeutic strategy against hemorrhagic fevers.

Striking Impact

The discovery arose from the team’s recent research with the New Zealand Black (NZB) mouse, an inbred laboratory strain whose overactive immune system leads, in midlife, to an autoimmune condition resembling lupus. Curious to see how a viral infection in early life would affect the mice, the team injected a group of the animals with a much-studied mouse virus called lymphocytic choriomeningitis virus (LCMV).

The parental LCMV Armstrong (Clone 53b) caused no symptoms and was quickly cleared by the NZB mice. But a variant (clone 13) that is efficient at infecting cells and causing a persistent infection—yet still causes only mild disease in most other mouse strains—had a strikingly different impact, showing serious signs of illness. Seven to eight days after infection, all the NZB mice that been injected with clone 13 had died.

Further examination revealed leaky blood vessels, fluid and immune virus-specific T cell infiltration into the lungs, decreased platelet counts and other pathological signs reminiscent of human hemorrhagic fevers.

As the scientists knew, LCMV is a member of the family of viruses that includes Lassa virus, which causes one of world’s most common hemorrhagic fevers—with a high fatality rate—in a subset of infected patients. “Lassa virus and LCMV infect the same cell type via the same cell-surface receptor,” Baccala said. Lassa virus infects hundreds of thousands of individuals annually, culminating in more than 20,000 deaths per year.

Most people infected with Lassa virus experience only mild illness, yet about 20 percent develop the hemorrhagic syndrome. Dengue virus manifests similarly, causing a hemorrhagic syndrome in only a subset of patients. The pathology seen in the LCMV clone 13-infected NZB mice suggested that they could serve as useful models of these human hemorrhagic syndromes, providing clues to how they develop and therapeutic stop-points for their treatment.

A New Target

Baccala and his colleagues soon found evidence that the hyperactivity of the NZB mouse antiviral CD8 cytotoxic T cell response is chiefly to blame for its fatal hemorrhagic disease. The researchers observed powerful CD8+ T cells in higher than normal numbers in affected NZB mouse tissues and a greater number of immune-stimulating molecules on the CD8+ cells’ surfaces. This CD8+ T cell overreaction damaged the endothelial cells that line pulmonary blood vessels, causing them to become leaky, which in turn led to the fatal buildup of fluid in the lungs.

IFN-I proteins historically have been known as the chief mobilizers of the protective antiviral response. When Baccala and his colleagues blocked IFN-I signaling, up to a day after infection, the CD8+ T cell response was virtually absent, and levels of clone 13 LCMV rose sharply in the NZB mice. Under these conditions, the mice showed no sign of disease and seemed able to tolerate the high viral load indefinitely—implying that the virus itself is virtually harmless when it doesn’t prompt an immune reaction.

“We are now working to determine whether we can target IFN-I itself to treat such conditions or whether we need to target the more specific signals, downstream of IFN-I, that cause pathology,” said Baccala.

In addition to Baccala and Oldstone, the co-authors of the study, “Type I interferon is a therapeutic target for virus-induced lethal vascular damage,” were Megan J. Welch, Rosana Gonzalez-Quintial, Kevin B. Walsh, John R. Teijaro, Anthony Nguyen, Cherie T. Ng, Brian Martin Sullivan, Alessandro Zarpellon, Zaverio M. Ruggeri, Juan Carlos de la Torre and Argyrios N. Theofilopoulos, all of TSRI. For more information on the paper, see http://www.pnas.org/content/early/2014/05/29/1408148111.abstract

The study was supported by the National Institutes of Health (grants AI099699, AI009484, CA127535, AR53228, AI077719 and HL42846).

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

For information:
Office of Communications
Tel: 858-784-2666
Fax: 858-784-8136
press@scripps.edu

Mika Ono | Eurek Alert!
Further information:
http://www.scripps.edu/news/press/2014/20140604baccala.html

Further reports about: CD8+ Interferon LCMV Scripps TSRI antiviral hemorrhagic immune lungs proteins vascular

More articles from Health and Medicine:

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

nachricht Flexible sensors can detect movement in GI tract
11.10.2017 | Massachusetts Institute of Technology

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

Ocean atmosphere rife with microbes

17.10.2017 | Life Sciences

Neutrons observe vitamin B6-dependent enzyme activity useful for drug development

17.10.2017 | Life Sciences

NASA finds newly formed tropical storm lan over open waters

17.10.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>