January 2001

From Washington University School of Medicine

Scientists uncover break-and-entry strategy of disease-causing bacteria

St. Louis, Jan. 12, 2001 ó As bacteria become resistant to current antibiotics, scientists are searching for the root causes of infection in order to develop more effective treatments. Researchers at Washington University School of Medicine in St. Louis have come one step closer to understanding how bacteria such as Streptococcus and Staphylococcus operate: These pathogens introduce their toxins by punching holes in the host-cell membrane. The cover of the Jan. 12 issue of Cell features the research. Scientists have made great strides in understanding how Gram-negative bacteria, such as Salmonella and E. coli, infiltrate host cells and establish infection. However, a second class of bacteria called Gram-positive causes human diseases such as strep throat, necrotizing faciitis, toxic shock syndrome and rheumatic fever. "Gram-positive organisms are responsible for five of the top six bacterial infections that are now resistant to multiple antibiotics available today," says study leader Michael G. Caparon, Ph.D., associate professor of molecular microbiology.

The first authors of the study are M.D./Ph.D. student John C. Madden and Natividad Ruiz, Ph.D., now at Princeton University.

Gram-negative bacteria inject previously healthy cells with toxins that disrupt essential processes. Several laboratories have visualized needle-like projections from these bacteria into host cells. Presumably, the projections serve as syringes.

Caparon and colleagues discovered that Gram-positive bacteria use an equivalent technique. Most Gram-positive pathogens contain proteins called cholesterol-dependent cytolysins (CDC). Because these molecules have persisted throughout the evolution of this diverse group, they might play a critical role in infection, the researchers surmised.

Studying the molecular basis of infection has been difficult in the past. But thanks to improved techniques, Caparonís group was able to manipulate the bacteria genetically. The researchers made defined mutants of Streptococcus pyogenes, the Gram-positive, flesh-eating bacterium that also causes strep throat and impetigo. By studying the consequences of the genetic defects, they uncovered specific points in the infection pathway.

S. pyogenes contains a CDC called streptolysin O (SLO). The researchers found that this protein chips away at the outer membranes of targeted cells, creating large holes or pores. SLO does not enter cells, however. Instead, a protein called SPN (S. pyogenes NAD-glycohydrolase) gets into cells after SLO has done its work. "SLO appears to pave the way for the entry of SPN, which is useless outside cells," Caparon says. "Once inside, SPN manipulates certain cellular processes."

His group hopes to determine how SPN affects host cells. Once scientists learn exactly how Gram-positive bacteria cause disease, they can step back and see where they can intervene. "New classes of current antibiotics simply buy us a little time. We have to come up with new ways of thinking about the problem," Caparon says.

Madden JC, Ruiz N, Caparon M. Cytolysin-mediated translocation (CMT): A functional equivalent of Type III Secretion in Gram-positive bacteria. Cell, vol. 104 pp. 1-20, Jan. 12, 2001.

Funded by Public Health Service Grants from the National Institutes of Health.












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