Scientific American- March 26, 2007

Battling Bacteria with a Viral Protein

An enzyme used by viruses to break cell walls beats back bacteria that cause ear
infections, pneumonia

By Nikhil Swaminathan
After a bout of the flu, lingering germs can wreak havoc on the weakened immune system. These
pathogens are not influenza organisms but, rather, bacteria such as Streptococcus pneumoniae,
a microbe that normally lies dormant in the nose or throat of children but migrates on a path
cleared by the flu to the middle ear where it causes an infection called acute otitis. There are
more than 24 million cases of middle ear infections—which can cause pain, fever, vomiting and
appetite loss—diagnosed each year in the U.S.

"Secondary bacterial infections cause much of the sickness and about 25 percent of all deaths
during the flu season, and 50 to 95 percent of deaths during pandemics of influenza," says
Jonathan McCullers, an infectious disease specialist at St. Jude Children's Research Hospital
and co-author of a study that suggests a new way of treating such conditions. "Eliminating these
secondary infections could dramatically reduce the sickness and death rates among susceptible
populations such as infants and the elderly."

McCullers and Vincent Fischetti, co-heads of the Laboratory of Bacterial Pathogenesis and
Immunology at the Rockefeller University, provide evidence that the enzyme lysin can be tailored
to kill specific secondary pathogens before they pounce on compromised immune systems.
Fischetti notes that this technology could potentially be used to prevent pandemics during an
avian or other flu outbreak by destroying secondary germs that might attack when the immune
system is compromised. "If we can go in and, during a pandemic, treat individuals that are either
susceptible to flu—the elderly or young children—or basically everybody during that period of
time and decolonize them," he says, "we have a better chance of saving a lot of lives."

The researchers used lysin, a protein antibody typically produced by a virus after it has infected
and hijacked a host cell's machinery to replicate. Once several copies of the virus exist, it
manufactures lysin, which punches holes in the cell wall allowing it to escape. "You can't use
antibiotics to eliminate a carrier," or germs that lay dormant in the body, explains Fischetti,
"otherwise you run into a lot more serious resistance problems."

After injecting colonies of S. pneumoniae into the noses of mice, the scientists infected some of
them with an influenza virus and the others were given a harmless solution. Sixty-three percent of
the influenza-infected mice developed the flu and then also contracted middle ear infections.
Those mice that did not get infected with the flu also avoided the secondary bacterial illness,
despite carrying the bacteria. The researchers repeated the experiment, but this time they nasally
administered lysin to one of the groups after introducing the bacteria. The results, published in
PLoS Pathogens: after fighting off the flu, 80 percent of the mice that did not receive lysin
developed acute otitis. None of the mice given lysin were stricken with ear infections.

"In my mind, it's a no-brainer experiment," says Fischetti. "If the [S. pneumoniae] organisms are
there, they have the potential of causing disease; if they're not there, they can't cause disease.
Basically what we're doing is removing them very specifically, without disturbing the mucus
membrane organisms."

Fischetti notes that his research team has developed lysin complexes that target bacteria, which
cause illnesses such as strep throat, pneumonia and meningitis and are typically treated with
increasingly ineffective antibiotics. In addition, he says that one lysin in his arsenal targets the
bacterial agent anthrax, inhalation of which can lead to cold and flulike symptoms followed by
shortness of breath, muscle aches and, in some cases, death. "We've shown in animal models
that if you give an animal anthrax and then intravenous anthrax enzyme," Fischetti says, "you can
cure 90 percent of the animals."

He expects to begin human lysin trials within three years and says the drug could be available as
a nasal spray for public use in six or seven years.