Pathogenic bacteria can be major causes of death or disability. Group B Streptococcus (GBS), for example, is the foremost cause of life-threatening bacterial infections in newborns. Most bacterial pathogens possess long filamentous structures known as pili that extend from their surface. These tendrils mediate the initial contact with cells and can quickly activate host signaling cascades as the cell attempts to subvert infection.
“The potential for signal transduction becomes quite interesting,” notes John L. Telford, Ph.D., project leader, Novartis (www.novartis.com) vaccine and diagnostics division. “We performed a genomic screening of GBS and looked at every single protein that could be a candidate for inclusion in a vaccine to prevent the disease. Interestingly, we found some of these proteins were components of the pili.”
Together with Guido Grandi, Ph.D., head of the biochemistry and molecular biology unit at Novartis Vaccines & Diagnostics, Dr. Telford then studied the interactions of these pilus adhesins in a model system of bacterial interaction with human cells. “Bacteria can interact with extracellular matrix proteins that form bridges with integrins on epithelial cells,” according to Dr. Telford. “This may initiate a signaling cascade similar to that which results in polarization of the cell.
“As we begin to determine which components of the pili initiate such reactions, we become better able to design vaccines and therapeutics,” Dr. Telford continues. “We can then, by immunization, induce antibodies against pili that promote opsonization and clearance, we can interfere with the initial adhesion, and we can thus create antigens that are protective. Our approach now is to develop recombinant versions of GBS pili components that could be used as vaccines.”
Small endogenous RNAs such as miRNAs play critical regulatory roles in animal development by modulating mRNA. Research is aimed at deciphering how they exert such complex control of biological pathways. Scientists are also mining them for their enormous therapeutic potential.
Vertebrates are not the only ones to possess such molecules, however. Regulatory RNAs have been discovered in all kingdoms of life, including bacteria. “We’ve known that there are small regulatory bacterial RNAs (sRNA) for several years, but the surprise was how many have now been identified that are crucial for regulation of bacteria,” says Susan Gottesman, Ph.D., chief, biochemical genetics section, laboratory of molecular biology, NCI.
Dr. Gottesman’s work focuses on the basic science of sRNAs in bacteria. “The precise role of most of the sRNAs is still unknown. Thus far two modes of action have been described as relates to E. coli sRNAs. Some can modify protein activity, for instance, by competing with the mRNA target site for proteins that act as translational regulators. A second mechanism is by direct base-pairing with the mRNA target.”
According to Dr. Gottesman, sRNAs impact signal transduction by regulating outer membrane proteins of bacteria as well as expression of transcriptional regulators. “Additionally, sRNAs target other pathways—iron binding proteins, sugar transporters, quorum sensing, etc. As more and more are discovered and characterized, we also can use this information to examine bacterial genetics, for example, to determine natural signals that affect the sRNAs, which in turn affect the network of responses to the signals.”
Although this work is in its infancy as it relates to therapeutics, Dr. Gottesman predicts that “numerous advantages will surface as we learn more about these multitalented molecules. The identification of functional homologs present in other bacteria will provide a more global knowledge of how bacteria regulate themselves and of their role in pathogenesis.”