Parents might one day give their children a weekly treatment with a nasal spray of virus enzymes to prevent them from getting a severe middle ear infection, based on results of a study done in mice by investigators from St. Jude Children's Research Hospital and The Rockefeller University in New York. Such a treatment would kill the disease-causing bacteria without the use of antibiotics, thereby avoiding the problem of antibiotic resistance. A report on this study appears in the March issue of the online journal "PLoS Pathogens."
Middle ear infection, also called acute otitis media, is an inflammation of the middle ear space that can cause pain, fever, irritability, lack of appetite and vomiting. The middle ear is the space just before the eardrum. About half of all children carry the bacteria that cause acute otitis media, which migrate from the nose and throat to the middle ear after an initial influenza virus infection paves the way.
The investigators based their treatment on the ability of viruses called phages to break out of bacteria they infect by using a special enzyme to destroy the cell walls. Phages infect bacteria in a way that is similar to how viruses infect animal cells. Once inside, the virus hijacks the cell's biochemical machinery and forces it to make many copies of the virus. After the new crop of viruses is made, a viral enzyme breaks apart the infected bacterial cell wall and allows the new viruses to escape and infect additional cells.
The success of the new treatment, which uses a phage enzyme to kill the bacteria that cause acute otitis media, suggests that the strategy could significantly reduce the incidence of the disease in the United States, where more than 24 million cases are diagnosed yearly. Even though the current pneumonia vaccine protects against Streptococcus pneumoniae--the bacteria that cause acute otitis media--this ear infection remains the leading cause of doctor visits and antibiotic prescriptions among preschool-aged children. In the current study, the researchers treated mice with the enzyme lysine, the same enzyme used by phages to break out of S. pneumoniae.
In addition to its promise for preventing acute otitis media, the virus enzyme treatment also appears to hold promise for preventing the secondary pneumonia caused when a person infected with S. pneumoniae is subsequently infected with the influenza virus.
"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," said Jonathan McCullers, M.D., associate member in the Infectious Diseases department at St. Jude. "Eliminating these secondary infections could dramatically reduce the sickness and death rates among susceptible populations such as infants and the elderly." This new approach might also offer some protection if the avian influenza virus, H5N1, sparks a pandemic among humans, he added. McCullers is first author of the "PLoS" paper.
The investigators demonstrated in mice infected with S. pneumoniae that lysin can eliminate these bacteria from the ear. The team conducted their study in mice developed at St. Jude that represented the first mouse model in which acute otitis media develops in a similar way that it develops the disease in children. The mice were treated by purified lysin that was prepared in the laboratory of Vincent A. Fischetti, Ph.D., a professor and co-head of the Laboratory of Bacterial Pathogenesis and Immunology at The Rockefeller University. He was assisted by Jutta M. Loeffler, postdoctoral associate. Fischetti is senior author of the "PLoS" paper.
The researchers developed a mouse model of acute otitis media by first establishing colonization of S. pneumoniae in the noses of mice. Scientists then infected some of the mice with influenza virus and mock-infected others with a virus-free solution. Although all the mice carried the bacteria in their noses, none of the mock-infected mice developed acute otitis media, while 63 percent of mice receiving influenza virus developed this middle ear infection.
In the second part of the study, the team treated bacteria-colonized mice twice, four hours apart, with either lysin or a mock treatment of fluid. The lysin treatment was 100 percent effective in preventing acute otitis media in the 10 treated mice while 80 percent of mice receiving the fake treatment developed the ear infection.
"The nasal spray may eventually be used weekly during the flu season to keep the person free of Streptococcus pneumoniae or after someone is infected with the flu virus, Fischetti said. "This might truly be a case in which an ounce of prevention would be worth a pound of cure."
Other authors of this paper include Åsa Karlström and Amy R. Iverson (St. Jude).
This work was supported in part by the United States Public Health Service and ALSAC.
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