Nasal Spray Prevents Infections in Mouse Model

For parents, 8 million cases of acute middle ear infections every year add up to a lot of sleepless nights and trips to the pediatrician. But new research from a collaboration between RockefellerUniversity and St. Jude Children's ResearchHospital could change all that.

In the March 23 issue of PLoS Pathogens, Rockefeller's Vincent A. Fischetti and colleagues at St. Jude show that middle ear infections in mice can be prevented by giving the mice a nasal spray containing a lysin -- a protein derived from a virus that infects bacteria. The new technology may prevent children with the flu or upper respiratory viral infections from developing secondary ear infections and would be an attractive alternative to traditional antibiotics, to which bacteria are rapidly becoming resistant.

The bacteria that cause middle ear infections, Streptococcus pneumoniae, aren't transmitted at school. They already reside on the mucosal membranes in the nose, waiting for their chance to strike. When a child catches the flu, or another virus that causes an upper respiratory infection, the bacteria seize the opportunity and migrate to the middle ear, causing a secondary infection. The new treatment would kill the bacteria before it had a chance to move.

"These bacteria take advantage of a viral infection by striking when our resistance is lowered," says Fischetti, head of Rockefeller's Laboratory of Bacterial Pathogenesis and Immunology. "You should start taking an antibiotic the moment you come down with the viral infection to prevent the secondary infection, but physicians are reluctant to do this for fear of increasing resistance to antibiotics. So we're really in a catch-22 situation."

Fischetti's lab has done extensive research on lysins, which are proteins derived from viruses that normally infect bacteria. After a virus has infected the bacteria and replicated, it uses lysins to punch holes in the bacteria's cell wall, killing the bacteria, in order to escape. Fischetti's lab has studied many different lysins and found that they work even from outside the bacterial cell as well as from the inside. In addition, unlike antibiotics, which kill many of the body's beneficial bacteria along with the disease-causing ones they target, lysins are highly specific. Each lysin will only kill a specific type of bacteria, leaving the body's normal flora untouched.

"We knew from our previous experiments that if you treat an animal infected or colonized with pneumococci or streptococci with these lysins, you could cure or decolonize them," says Fischetti. "But I was looking for a way to see if lysins would work for secondary infections too, and John McCullers had a very nice model system."

The two researchers collaborated -- Fischetti sent McCullers, a physician at St. Jude Children's Hospital Department of Infectious Diseases, the lysin, and McCullers tested his mice. After colonizing the mice with S. pneumoniae, McCullers treated some of them with the lysin using an intranasal spray, then infected all of them with influenza virus. Eighty percent of the mice that did not receive the lysin came down with middle ear infections, but none of the mice given the lysin did. The treatment was 100 percent effective.

"It is really an obvious result," says Fischetti. "If the bacteria are not there, they cannot cause the secondary infection. A simple nasal spray may eventually be used weekly during flu season to keep kids free of the bacteria."

"Secondary bacterial infections cause much of the sickness and about 25 percent of all deaths during flu season," says McCullers. "Eliminating these secondary infections could dramatically reduce sickness and death rates."

Rockefeller University recently licensed the rights to the lysin technology to Enzybiotics, Inc., a start-up company that will develop the pneumococcal lysin for human use, as well as lysins directed to other disease bacteria. Fischetti serves as chairman of the company's scientific advisory board.

This research was supported in part by the National Institutes of Health.