Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists discover natural flu-fighting protein in human cells

21.12.2009
In findings that may lead to better ways to prevent and treat influenza and other viral infections, researchers report the discovery of a family of naturally occurring antiviral agents in human cells.

In experiments in human and mouse cells, the flu-fighting proteins prevented or slowed most virus particles from infecting cells at the earliest stage in the virus lifecycle. The anti-viral action happens sometime after the virus attaches itself to the cell and before it delivers its pathogenic cargo.

"We've uncovered the first-line defense in how our bodies fight the flu virus," said Stephen Elledge, the Gregor Mendel professor of genetics and of medicine at Harvard Medical School (HMS) and a senior geneticist at Brigham and Women's Hospital (BWH). "The protein is there to stop the flu. Every cell has a constitutive immune response that is ready for the virus. If we get rid of that, the virus has a heyday."

"When we knocked the proteins out, we had more virus infection," said geneticist Abraham Brass, an instructor in medicine at HMS and Massachusetts General Hospital (MGH), who led the study first as a postdoctoral fellow in the Elledge research group and then in his own lab at the Ragon Institute. "When we increased the proteins, we had more protection," Brass said.

The native antiviral defenders are also crucial after the cells are infected, Brass and his co-authors found. In the cells, the proteins accounted for more than half of the protective effect of the interferon immune response. Interferon orchestrates a large component of the infection-fighting machinery.

"Interferons gave the cells even more protection, but not if we took away the antiviral proteins," Brass said. The study is published online Dec. 17 in the journal Cell.

The potent interferon response is what makes people feel so sick when their bodies are fighting the flu or when receiving interferons as therapy. "If we can figure out ways to increase levels of this protein without interferon, we can potentially increase natural resistance to some viruses without all the side effects of the interferons," Elledge said.

In the study, the surprisingly versatile antiviral proteins protected cells against several devastating human viruses—not only the current influenza A strains including H1N1 and strains going back to the 1930s, but also West Nile virus and dengue virus. While IFITM did not protect against HIV or the hepatitis C virus, experiments suggested the protein may defend against others, including yellow fever virus.

The researchers do not know how the antiviral proteins deflect this variety of viruses, which use different mechanisms of entry into the cell. The protein family, called interferon-inducible transmembrane proteins (IFITM), was first discovered 25 years ago as products of one of the thousands of genes turned on by interferon. Since then, not much else has been discovered about the IFITM family. Versions of the IFITM genes are found in the genomes of many creatures, from fish to chickens to mice to people, suggesting the antiviral mechanism has been working successfully for millions of years in protecting organisms from viral infections.

In Elledge's lab, Brass began the study as a genetic screen to learn how the body blocks the flu. The researchers had previously run similar screens with hepatitis C virus and with HIV. In the screen, the researchers used small interfering RNA to systematically knock down one gene at a time by depleting the proteins the genes were trying to make. Then they examined what effect each blocked gene had on a cell's response to influenza A virus.

The screen revealed more than 120 genes with potential roles in different stages of infection. Four of those genes, when knocked down, allowed for a robust increase in the infection of cells by influenza A virus. Of these four candidate "restriction factors," the research team concentrated on the IFITM3 protein because of its known link to interferon and found two closely related proteins in the IFITM family with similar activity.

The most distinctive property of the first-line IFITM3 defense is its preventive action before the virus can fuse with the cell, said co-author and virologist Michael Farzan, associate professor of microbiology and molecular genetics at HMS and the New England Primate Research Center. "The virus is unable to make a protein in the cell to counteract the IFITM proteins, because the cell is already primed against the virus," Farzan said. "To find something that hits the flu and hits it so close to the entry stage of the viral life cycle is really interesting and unusual among viral restriction factors."

The researchers have more questions than answers about how the IFITM restriction factors actually work, but they are excited about the range of inquiry the discovery opens up. For example, variations in the protein from person to person may explain differences in people's susceptibility to flu and other viral infections, as well as its severity, the researchers speculate.

And if scientists can understand the mechanism of action, they may be able to design new therapies with even better antiviral actions. The proteins themselves may be useful for defending against infections in animals, like birds and pigs, which might prevent the emergence of new, potentially more dangerous influenza A strains.

In another potential application, if IFITM3 has a role in the chicken embryos or canine cells used to make flu vaccines, inhibiting the proteins may speed up vaccine production, which has been an issue this year with the manufacture of the H1N1 pandemic vaccine.

The research was funded by the Howard Hughes Medical Institute, the Phillip T. and Susan M. Ragon Foundation, the National Institutes of Health, New England Regional Center of Excellence for Biodefense, Cancer Research UK the Wellcome Trust, and the Kay Kendall Leukaemia Foundation. BWH and MGH have filed a U.S. patent application for this technology that relates to the identification and use of host factors to modulate viral replication/growth.

FULL CITATION

Cell, published online Dec. 17
"The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus"

Abraham L. Brass,1,2,4,9,* I-Chueh Huang,5,9 Yair Benita,3,10 Sinu P. John,1,10 Manoj N. Krishnan,6 Eric M. Feeley,1 Bethany J. Ryan,1 Jessica L. Weyer,5 Louise van der Weyden,8 Erol Fikrig,6,7 David J. Adams,8 Ramnik J. Xavier,2,3 Michael Farzan,5,* and Stephen J. Elledge4*

1-Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Charlestown, MA 02129, USA
2-Gastrointestinal Unit
3-Center for Computational and Integrative Biology Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
4-Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA
5-Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, Southborough, MA 01772, USA
6-Section of Infectious Diseases, Department of Internal Medicine
7-Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA
8-Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton Cambridge CB10 1SA, UK
9-These authors contributed equally to this work
10-These authors contributed equally to this work
*Corresponding authors
Harvard Medical School http://hms.harvard.edu has more than 7,500 full-time faculty working in 11 academic departments located at the School's Boston campus or in one of 47 hospital-based clinical departments at 18 Harvard-affiliated teaching hospitals and research institutes. Those affiliates include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Hebrew Senior Life, Joslin Diabetes Center, Judge Baker Children's Center, Immune Disease Institute, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.

Brigham and Women's Hospital (BWH) is a 777-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. In July of 2008, the hospital opened the Carl J. and Ruth Shapiro Cardiovascular Center, the most advanced center of its kind. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives and its dedication to educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 900 physician-investigators and renowned biomedical scientists and faculty supported by more than $485 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative.

Carol Cruzan Morton | EurekAlert!
Further information:
http://www.hms.harvard.edu
http://www.brighamandwomens.org

More articles from Life Sciences:

nachricht Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel

nachricht The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

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

14.10.2016 | Event News

 
Latest News

IHP presents the fastest silicon-based transistor in the world

05.12.2016 | Power and Electrical Engineering

InLight study: insights into chemical processes using light

05.12.2016 | Materials Sciences

High-precision magnetic field sensing

05.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>