By Eva Emerson
SAN DIEGO, Calif. – Chatter between bacterial cells may stall healing of skin wounds, and sabotaging that chitchat could offer another way to battle infection, new research suggests.
Making Pseudomonas aeruginosa deaf to the molecular signals that the bacteria use to talk to each other would offer a kind of antibiotic therapy that doesn’t kill bacterial cells but rather strikes at their ability to attack human cells en masse, Jasper Jacobsen of the Statens Serum Institute in Copenhagen said May 24 at a meeting of the American Society for Microbiology.
When P. aeruginosa infects human tissue, the bacteria coordinate their offensive using a language called quorum sensing. As the number of bacteria present grows, signaling molecules involved in quorum sensing build up, eventually binding with proteins encoded by two quorum sensing master genes: lasR and rhlR. This binding switches on hundreds of other virulence genes, producing a bevy of disease-causing proteins. The two genes are also involved in the creation of a biofilm – connected layers of bacterial growth that are harder for the immune system to combat than free-floating microbes.
Jacobsen and colleagues compared secretions released by a normal strain of P. aeruginosa with those from a strain in which the two quorum sensing genes had been turned off. “We wanted to see whether this ‘language’ could impair wound healing in cells,” he said.
The researchers arranged human skin cells in lab dishes with a gap in the middle to model a skin gash. Secretions from the normal bacteria reduced the ability of skin cells to move in and fill the gap, a key process in wound healing called migration, substantially more than secretions from the strain with disabled quorum sensing genes.
Most affected were cells called keratinocytes, which form the outermost layer of skin. In these, normal strain secretions led to substantially less cell migration – about 55 percent wound closure compared with 75 percent for the strain with impaired quorum sensing. The normal strain also decreased migration of fibroblast cells, which are abundant in the skin layer below, but to a lesser extent. Neither strain affected cell growth or the migration of endothelial cells, which are found in the deepest skin layer.
The signals used by the bacteria to talk to each other leads to the production of many virulence proteins, which are secreted into the environment around the cell, Jacobsen said, and “affect the closing of the gap in the wound.”
Pseudomonas aeruginosa is a leading cause of opportunistic infections in people, including in wounds healing after operations and in burns. Multidrug-resistant strains of the microbe are a problem in many hospitals. For the last decade researchers have discussed designing drugs that target the quorum sensing system as a way to battle the pathogen, said Pete Greenberg, a microbiologist at the University of Washington in Seattle.
In Pseudomonas, those two genes help regulate the production of a battery of compounds that promote infection, he said. A number of candidate drugs designed to target the proteins encoded by these genes are now under study.
Greenberg said the new study is the first he is aware of that looked specifically at wound healing and the quorum sensing system.
“They showed it blocks wound healing, at least in a petri dish,” he said. “Now they need to try to use some of the experimental inhibitors to see if that [would restore] healing.” If so, combining this approach with a more traditional antibiotic might help battle the worst infections.
Microbiologist Barbara Iglewski of the University of Rochester Medical Center in New York agrees that the study “is a nice starting place.” But, she says, to create a useful drug, researchers still need to pinpoint which of the many proteins in the mix exuded by the bacteria is actually inhibiting cell migration during healing.
