Superbug attacks protective lung proteins during infection
University of Washington researchers have discovered how a bacteria that causes a difficult-to-treat and often deadly respiratory infection attaches to cells in the airways. The finding could lead to new ways to defeat this and other common respiratory infections.
The scientists used a new technique developed at the University of Washington called chemical crosslinking mass spectrometry. They wanted to see how proteins of the bacteria Acinetobacter baumanii interact during infections with the cells lining the lungs.
The study, "Host-Microbe Protein Interactions During Bacterial Infection," appears in the journal Chemistry & Biology. The lead author was Devin K. Schweppe, a senior fellow in the laboratory of James E. Bruce, UW professor of genome sciences, who led the project
“Acinetobacter baumanii has become a serious problem in U.S. hospitals,” said Bruce. “It’s hard to kill and can colonize equipment, including ventilators, and many strains can resist even the most powerful antibiotics. It’s critical that we learn new ways to fight this and other multidrug-resistant bacteria.”
Acinetobacter baumanii's genome was first described by UW researchers earlier this year. A key challenge has remained to work out the purpose of many of the bacterium’s genes whose function is unknown. Many of these genes, known as GUNKS , are thought to allow the bacteria to cause infections and resist antibiotics. If that is the case, these genes are ideal targets for new treatment strategies.
In their experiment, the UW researchers infected lung epithelial cells with the bacteria. They then treated the infected cells with a chemical that makes a chemical bond — or crosslink — between sections of proteins that are close together, an indication that the proteins are interacting.
Using this process, they identified 46 protein-protein interactions between the bacterial and human proteins. Of particular interest was the interaction of a bacterial protein, called outer membrane protein A, abbreviated OmpA, and several other of the bacterial GUNK proteins that they found crosslinked to human cellular structures called desmosomes. OmpA is a known “virulence factor,” meaning the bacteria needs it to cause disease. Desmosomes are structures on the surfaces of epithelial cells that allow them to stick together and form a continuous sheet of cells to keep out bacteria and toxins.
“This interaction suggests that, through evolution, the bacteria developed a strategy to target and overcome the barrier the desmosomes create. Because proteins similar to OmpA, homologs of OmpA, are present in other virulent bacteria, it is likely they, too, work by attacking desmosomes,” Bruce said.
In addition to revealing the structure OmpA is binding to, the cross-links also reveal which parts of OmpA interact with which parts of the desmosome proteins.
“We couldn’t see that before,” Bruce said, “now with this knowledge you might be able to prevent or treat A. baumannii and similar infections with antibodies that bind to and block either areas where OmpA interacts with the desmosomes or areas of the desmosomes that OmpA targets. If successful, either approach could keep the bacteria from attaching to and invading the cells.”
This work was supported by National Institutes of Health grants U19-AI107775-02, RO1-AI101307-03, RO1-GM086688-06 AND RO1-HL110879-04.