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News

UI study reveals how a virus escapes from host cells and returns to the environment

DOE/Brookhaven National Laboratory : 24 May, 2007  (Technical Article)
Your co-worker has a cold. You know it is only a matter of time before the virus spreads to you and other colleagues, causing a spate of missed workdays. The ability to spread from person to person makes viral infections, even those as benign as the common cold, a large public health problem.
Scientists have some understanding of how viruses enter cells and reproduce once inside. However, much less is known about how the newly generated viruses exit from the tissue and return to the outside world to infect new hosts. Now, University of Iowa researchers and colleagues have uncovered a strategy used by one particular virus to escape from its host's cells back into the environment.

Adenovirus, which causes colds and pneumonia, infects the airway epithelial cells that line the respiratory tract. The virus reproduces, and then escapes to find a new host. In general, epithelial cells line body surfaces and cavities. They form a physical barrier between the internal and external world.

A family of proteins called cell adhesion molecules hold the epithelial cells together, acting like a zipper. When the space between epithelial cells is 'zipped,' microorganisms cannot enter or exit from the host. One key component of this zipper, analogous to the teeth of a zipper, is the cell adhesion molecule CAR.

The UI study shows that infection of cells with adenovirus caused the epithelia to become leaky, or 'unzipped.' Closer inspection showed that viruses moved through gaps formed between cells to gain access to the environment. The investigators also described the specific molecular event that produces the gaps between the epithelial cells.

The newly made adenovirus contains a protein on its surface, called fiber. When fiber binds to CAR it disrupts cell adhesion by CAR. That is, it 'unzips' the epithelia.

'We found that fiber protein alone, even without the rest of the virus, caused a breakdown of cell-cell adhesion,' said Robert Walters, an M.D./ Ph.D. student in the UI Medical Scientist Training Program, and lead author of the study. 'Moreover, when we blocked fiber we prevented virus from escaping across airway epithelia.'

The virus also appears to stack the deck in favor of its escape. In addition to reproducing itself, the virus makes excess fiber protein and defective viral particles that are not infectious but that do possess fiber. Thus, when an infected cell dies and spills it contents, the CAR molecules in the vicinity are swamped by various forms of the viral protein and relinquish their hold on neighboring cells. Thus the 'zipper' falls apart, leaving a gap between the cells for the virus to use as an escape route.

Walters noted that it was particularly interesting that adenovirus also exploits the molecular interaction between fiber and CAR to gain entry into host cells.

'These results suggest that adenovirus evolved to use one tool for two quite different jobs,' Walters said.

Previous studies have revealed that several other viruses also commandeer cell adhesion molecules for entry into host cells, and the UI researchers speculate that the type of escape route used by adenovirus for exiting a host or crossing tissue barriers may be widely used by other viruses and also by bacteria.

'Our study tells us that CAR holds epithelial cells together and that the viral protein disrupts the interaction and allows the virus to get out,' Walters said. 'In most viral infections, people shed the virus before they are noticeably sick. So being able to understand how that shedding occurs might allow us to prevent spread of infection among people in close quarters, such as in schools or military barracks.'

In addition to Walters, the research team also included Paul Freimuth, Ph.D., professor of biology at Brookhaven National Laboratory, and UI researchers Thomas Moninger, research assistant in the Central Microscopy Research Facility; Ingrid Ganske, summer student in internal medicine; Joseph Zabner, M.D., associate professor of internal medicine; and Michael Welsh, M.D., the Roy J. Carver Chair in Internal Medicine and Physiology and Biophysics, and a Howard Hughes Medical Institute Investigator.
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