Researchers at the Salk Institute for Biological Studies have discovered a powerful mechanism by which viruses such as influenza, West Nile and Dengue evade the body's immune response and infect humans with these potentially deadly diseases. The findings may provide scientists with an attractive target for novel antiviral therapies.
Published in the August issue of the journal Cell Host and Microbe, the findings describe a novel mechanism that this group of so-called "enveloped viruses" uses to disarm the host's innate immune response. The mechanism the scientists uncovered is based on these viruses activating a class of molecules, known as TAM receptors, which are located on the outside of certain immune cells.
In the immune system, TAM receptors are used by cells, such as macrophages and dendritic cells, to clean up dead cells, and they are also central inhibitors of the body's innate immune response to bacteria, viruses and other pathogens.
The Salk scientists found that a substance called phosphatidylserine (PtdSer), which is found on the surface of enveloped viruses (viruses with an outer wrapping of a lipid membrane), binds to extracellular proteins and activates TAM receptors on immune cells. In dendritic cells, a type of immune cell that interacts with T and B cells to initiate the adaptive immune response, TAM receptor activation turns off a set of genes called interferons that play a key role in antiviral defense.
"Our findings suggest a unique way in which TAM receptors contribute to the establishment of viral infection by disabling the interferon response," says co-lead study author John A.T. Young, a professor in Salk's Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis. "As a consequence, the interferon-stimulated defense genes are not turned on, rendering the target cell more permissive for virus infection."
This is a previously unknown mechanism for enveloped viruses, which are very common, to inhibit the body's normal antiviral response. Since PtdSer exposure seems to be a general feature of enveloped viruses, the researchers say many different viruses may use the mechanism to counteract the cellular antiviral response in cells with TAM receptors.
Understanding this mechanism allows researchers to work on developing broad-spectrum antiviral drugs that prevent viruses from shutting down the interferon response in cells by blocking TAM receptor activation. In their study, the Salk scientists tested a small-molecule drug called BMS-777607, initially developed for anti-cancer therapy, that does just that.
"With this small molecule, viruses can't activate TAM receptors, so they can't shut down the interferon response," says co-lead author Greg Lemke, a professor in Salk's Molecular Neurobiology Laboratory and the Françoise Gilot-Salk Chair, in whose laboratory TAM receptors were discovered.
With other scientists around the country, the Salk researchers are testing a variety of small molecule drugs in series of different viruses, including West Nile, Dengue, influenza, Ebola, Marburg, and hepatitis B. These drugs work, in large part, by blocking the virus' ability to activate TAM receptors, thereby leaving the interferon-mediated antiviral response intact.
"This is a completely novel approach," says Young, who holds the Nomis Foundation Chair at Salk. "It is a way of exploiting a normal piece of the cellular machinery in the immune system to block virus infections." And, if it works, it may prove to be an effective treatment to clear enveloped viruses during the acute phase of infection and perhaps also in chronic virus infections.
Other researchers on the study were co-first authors Suchita Bhattacharyya and Anna Zagόrska, as well as Erin D. Lew and John Naughton, from the Salk Institute; Bimmi Shrestha and Michael S. Diamond of Washington University; and Carla V. Rothlin of Yale University.
The study was supported by the National Institutes of Health, the Nomis and Auen Foundations, the James B. Pendleton Charitable Trust, a Salk Institute innovation grant, the Human Frontiers Science Program, and the Leukemia and Lymphoma Society.
About the Salk Institute for Biological Studies:
The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.
Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.
Kat Kearney | EurekAlert!
Mass spectrometry sheds new light on thallium poisoning cold case
14.12.2018 | University of Maryland
Protein involved in nematode stress response identified
14.12.2018 | University of Illinois College of Agricultural, Consumer and Environmental Sciences
The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.
Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...
What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...
A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.
The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...
A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.
Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...
Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...
12.12.2018 | Event News
10.12.2018 | Event News
06.12.2018 | Event News
14.12.2018 | Power and Electrical Engineering
14.12.2018 | Physics and Astronomy
14.12.2018 | Physics and Astronomy