To stick to cells in the respiratory tract and start an infection, the bacterium Haemophilus influenza has to secrete a glue-like protein. Researchers at Washington University School of Medicine in St. Louis report this week that a study of the valve that lets out the glue has produced some surprising information.
Scientists are studying the valve to better understand how bacteria interact with host cells. Insights into these interactions could lead to new targets for drugs to treat H. influenzae infection, which is a common cause of respiratory tract disease and in some parts of the world is responsible for most cases of childhood bacterial meningitis.
The study is available online in the Proceedings of the National Academy of Sciences and will appear October 5 in the print edition of the journal. The first author is Neil K. Surana, an M.D./Ph.D. student at Washington University.
Washington University researchers determined that the protein that makes up the valve, HMW1B, is structurally similar to other proteins found in a wide variety of life forms ranging from humans to plants to single-celled organisms and bacteria. Those proteins, which create openings that move substances from one side of a cell membrane to another, are collectively known as Omp85-like proteins.
In addition to the similarities, though, researchers also found that HMW1B has some unexpected quirks.
“Previous studies of Omp85-like proteins on other bacterial surfaces had suggested that they are monomers, proteins active when only a single copy of the protein is present,” says senior investigator Joseph W. St. Geme, M.D., a Washington University pediatrician at St. Louis Children’s Hospital and a professor of molecular microbiology and pediatrics. “But we found that four copies of HMW1B come together in a structure known as a tetramer to form an active pore.”
Discovery of the tetramer led researchers to expect that the four copies of HMW1B would form a ring-like structure with a single central opening. But based on data still under review, they now suspect that each copy of HMW1B may have an opening in its center that lets the glue-like proteins, called adhesins, cross the cell membrane.
“We were already curious about why the tetramer exists instead of a monomer,” says St. Geme. “Now we need to see if we can confirm whether each copy creates its own opening.”
St. Geme speculates that the tetramer may be more stably positioned in the bacteria’s outer membrane than a monomer. Alternatively, the tetramer may facilitate interaction among multiple copies of the glue, perhaps allowing the glue to become activated as it emerges onto the surface of the bacteria.
Scientists previously have found other proteins similar to HMW1B and the glues it secretes in infectious agents like Bordetella pertussis, the bacteria that causes whooping cough. According to St. Geme, it’s too early to tell if these similarities make this group of proteins good targets for drug development.
“The similarities to other Omp85-like proteins could make it difficult to develop drugs that block HMW1B without adversely affecting Omp85-like proteins normally active in humans,” he explains. “But another major part of this paper is the discovery that there are some unique aspects to the interaction between HMW1B and the adhesin it exports. We may be able to focus our efforts on this interaction. ”