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 Correct connections are crucial
26.06.2017 | Charité - Universitätsmedizin Berlin

nachricht One gene closer to regenerative therapy for muscular disorders
01.06.2017 | Cincinnati Children's Hospital Medical Center

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: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Touch Displays WAY-AX and WAY-DX by WayCon

27.06.2017 | Power and Electrical Engineering

Drones that drive

27.06.2017 | Information Technology

Ultra-compact phase modulators based on graphene plasmons

27.06.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>