(Press-News.org) MADISON, Wis. - The influenza virus, like all viruses, is a hijacker. It quietly slips its way inside cells, steals the machinery inside to make more copies of itself, and then -- having multiplied -- bursts out of the cell to find others to infect.
Most drugs currently used to treat influenza are designed to attack the virus, to render it incapacitated. But influenza viruses are sneaky, capable of mutating to avoid destruction by the drug.
In a comprehensive new study published today in the journal Cell Host and Microbe, the University of Wisconsin-Madison's Yoshihiro Kawaoka and a team of researchers have set the stage for an entirely different approach. They have revealed methods for thwarting the hijackers by shutting down the cellular machinery they need, like cutting the fuel line on a bank robber's getaway car.
The findings will aid in the selection and development of new drugs that target the cellular machinery viruses rely on -- rather than attacking the virus itself -- lowering the chances it will mutate and become resistant to the drug.
"Whenever patients are treated with a drug, viruses are under selective pressure," says Kawaoka, a professor in the UW-Madison School of Veterinary Medicine. "In 2007, a (drug) resistant influenza virus emerged and within one-and-a-half years, it spread worldwide."
By combing through the cellular machinery, collaborating scientists at UW-Madison and several institutions in Japan identified 1,300 host cell proteins the virus may use to bind to and enter the cell, travel around inside the cell, replicate (make more of itself), or exit the cell.
While several other studies have performed human genome-wide screens to look for host cell proteins that interact with influenza virus, Kawaoka's study is the first to take it well beyond identification of potential targets.
One-by-one, the research team tested each protein to see whether eliminating it from human cells grown in the lab, using a technique called gene silencing, interfered with the infectivity of the virus. At the same time, the researchers assessed how harmful the approach was to the cells.
Negative, unwarranted side effects are one risk of targeting host proteins with drugs, so Kawaoka wanted to make sure the approach was not toxic.
The team identified 91 potential host cell targets, which they called their "top hits." These were proteins that could be reduced inside cells leading to lower concentrations of infecting virus but little to no cell death.
Using these candidates, the researchers then mapped each protein to its role in the viral infection cycle, providing a much greater understanding of how an influenza virus works inside cells and a platform for further exploration.
"The information described in this paper will be of great value to those who are interested in developing antiviral compounds that are targeted, but reduce virus titers," Kawaoka, also on the faculty at the University of Tokyo, says. "Also, these data are of considerable interest to basic researchers."
Going further, the team combed through drug databases to identify compounds that may suppress the cellular targets and shut down influenza virus infection. In doing so, they came up with several possible drugs -- and some surprises.
Two of the compounds inhibited host cell proteins the scientists would never have suspected as targets for antivirals, based on what is currently known about them. Several clinical drugs already exist for one of these targets and are already in advanced clinical testing for other conditions, demonstrating their therapeutic potential.
The research team continues to study their top hits, to assess their drug development potential. Kawaoka's overall goal is to identify strategies to either prevent or treat potentially lethal viral infections. The World Health Organization estimates there are 3-to-5-million cases of influenza worldwide each year, with as many as 500,000 deaths.
Kawaoka doesn't yet know how many host proteins may pose as good potential drug development targets.
"That is difficult to say," he says. "But, we are working on our top 20 for now."
INFORMATION:
The study -- whose co-first-authors are Tokiko Watanabe of UW-Madison, the University of Tokyo and the Japan Science and Technology Agency (JST); and Eiryo Kawakami of JST -- was supported by National Institute of Allergy and Infectious Disease Public Health Service grants, ERATO, and by the Strategic Basic Research Programs of JST.
Kelly April Tyrrell
ktyrrell2@wisc.edu
608-262-9772
EUGENE, Ore. -- Nov. 20, 2014 -- A potential path to identify imperfections and improve the quality of nanomaterials for use in next-generation solar cells has emerged from a collaboration of University of Oregon and industry researchers.
To increase light-harvesting efficiency of solar cells beyond silicon's limit of about 29 percent, manufacturers have used layers of chemically synthesized semiconductor nanocrystals. Properties of quantum dots that are produced are manipulated by controlling the synthetic process and surface chemical structure.
This process, however, ...
CHAMPAIGN, Ill. -- The majority of preschoolers may not be getting the amount of sleep they need each night, placing them at higher risk of being overweight or obese within a year, according to a new study.
Published online by the journal Sleep Medicine, the study investigated links between mothers' employment status and their children's weight over time, exploring the impact of potential mediators, such as children's sleep and dietary habits, the amount of time they spent watching TV and family mealtime routines.
"The only factor of the four that we investigated that ...
Washington, DC--Levels of testosterone and other naturally-occurring reproductive hormones play a limited role in driving menopausal women's interest in sex and sexual function, according to a new study published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism.
While testosterone is the main sex hormone in men, women also have small amounts of it. The ovaries naturally produce testosterone. Researchers set out to examine the role the hormone plays in sexual function as women go through menopause.
"While levels of testosterone and other reproductive ...
Washington, DC--As many as one in five people with Type 2 diabetes do not see any improvement in blood sugar management when they engage in a supervised exercise regimen, according to a new scientific review published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism.
People develop Type 2 diabetes when their bodies become resistant to the hormone insulin, which carries sugar from the blood to cells. This leads to excess sugar in the bloodstream. The U.S. Centers for Disease Control and Prevention projects about 40 percent of Americans will develop ...
Enzymes carry out fundamental biological processes such as photosynthesis, nitrogen fixation and respiration, with the help of clusters of metal atoms as "active" sites. But scientists lack basic information about their function because the states thought to be critical to their chemical abilities cannot be experimentally observed.
Now, researchers at Princeton University have reported the first direct observation of the electronic states of iron-sulfur clusters, common to many enzyme active sites. Published on August 31 in the journal Nature Chemistry, the states were ...
LIVERMORE, California -- Using ocean observations and a large suite of climate models, Lawrence Livermore National Laboratory scientists have found that long-term salinity changes have a stronger influence on regional sea level changes than previously thought.
"By using long-term observed estimates of ocean salinity and temperature changes across the globe, and contrasting these with model simulations, we have uncovered the unexpectedly large influence of salinity changes on ocean basin-scale sea level patterns," said LLNL oceanographer Paul Durack, lead author of a paper ...
BANGALORE, INDIA (November 20, 2014) - Participation of non-scientists as volunteers in conservation can play a significant role in saving wildlife, finds a new scientific research led by Duke University, USA, in collaboration with Wildlife Conservation Society and Centre for Wildlife Studies, Bengaluru.
The study has shown that citizen science projects greatly contribute to 'increased environmental awareness among the general public'. It also reported direct impacts on conservation including - shift in formal profession by volunteers to become conservationists, initiation ...
Moderate rainfall was occurring around the center of Tropical Storm Adjali before it dissipated, according to data from NASA and the Japan Aerospace Exploration Agency's Global Precipitation Measurement or GPM satellites.
Adjali became the first named storm of the Southwest Indian Ocean 2014/2015 cyclone season when it formed on November 16, 2014. Adjali became a strong tropical storm the next day and just two days later started to dissipate.
The GPM observatory captured data on Adjali's rainfall rates on Nov. 18. GPM's Microwave Imager (GMI) instrument is similar to ...
This new survey was released November 19 as a Web First by Health Affairs. The full text is available free until November 26.
International Survey Of Older Adults Finds Shortcomings In Access, Coordination, And Patient-Centered Care
By Robin Osborn, Donald Moulds, David Squires, Michelle M. Doty, and Chloe Anderson
All authors are affiliated with The Commonwealth Fund in New York.
This study was supported by The Commonwealth Fund and also will appear in the December issue of Health Affairs.
The study surveyed 15,617 adults ages sixty-five and older in Australia, ...
In many firms sales people spend as much time negotiating internally for lower prices as they do interacting with customers. A new study appearing in the November issue of Marketing Science, a publication of the Institute for Operations Research and the Management Sciences (INFORMS) finds that firms should allow their sales people to "waste" energy on internal negotiations. In fact, it says, firms should make the process wasteful on purpose.
The study, "Why do sales people spend so much time lobbying for low prices?" was conducted by Duncan Simester, the Nanyang Technological ...