Viruses have a nasty habit of usurping the normal biological processes of their hosts. Take, for instance, adenovirus, which causes mild respiratory infections in humans. This virus takes advantage of a protein that is expressed naturally by the sheets of epithelial cells lining our lungs. It uses this protein, CAR, to latch onto the cells before entering them and multiplying.

Contrary to expectations, the CAR protein is found, not on the exposed surfaces of the cells, but rather on their sides, where one cell abuts on another. It seems that temporary breaks in the epithelium allow a few viruses to detect CAR and enter cells. But Michael J. Welsh and colleagues suspected that adenovirus's finely honed ability to bind this protein must also serve another purpose. As they describe in Cell (110, 789–799; 2002), they've now discovered what that purpose is.

Welsh and colleagues used a previously developed in vitro model of lung epithelial sheets that is similar to the human airway. They infected these sheets with adenovirus, and found that progeny viruses were released at the sides and base (the basolateral surface) of a cell, appearing only later on the exposed (apical) surface. The apical surface remained undamaged, suggesting that the viruses travelled up between the cells to escape. Supporting this idea, electron microscopy showed that there were unusual spaces between the cells.

The 'proper' function of the CAR protein is to allow epithelial cells to stick to one another and form a continuous sheet. It was known that the adenovirus fibre protein binds to CAR, allowing the virus to enter cells. Welsh and colleagues wondered whether this fibre protein could also cause the breaks in epithelial sheets that are seen after the production of progeny virus. When adenovirus multiplies in epithelial cells, it produces far more fibre protein than can be incorporated into new viral particles. The authors found that when they added fibre protein to the epithelial sheets, it disrupted cell-to-cell contacts, as seen in these before (top) and after (bottom) pictures.

So they propose the following sequence of events. Adenovirus enters cells through temporary natural breaks in the epithelial sheet, which allow it to use its fibre protein to bind to CAR. It multiplies in the cells, and progeny are released to the basolateral surface, along with surplus fibre protein. That protein again binds to CAR and prevents it from interacting with other cells in the sheet, thereby making large holes through which the virus can escape into the lungs. Neatly, then, the virus uses the same tools for both entry and exit.