Conflicting reports have indicated that the soluble factor IL-22 can have both IBD promoting and IBD controlling effects. But now, Atsushi Mizoguchi and colleagues at Massachusetts General Hospital, Boston, have established that IL-22 ameliorates disease in a mouse model of UC.
Expression of IL-22 is much higher in the intestines of individuals with CD than UC. To investigate the role of IL-22 in IBD, the authors used a new microinjection-based strategy to deliver the gene that makes IL-22 to the walls of the intestine of mice who suffer from an intestinal disease that models UC. Delivery of the Il-22 gene ameliorated local intestinal inflammation through enhanced mucus production. Consistent with this, when the same strategy was used to deliver a gene that makes a protein that neutralizes IL-22, IL-22 “binding protein, to the walls of the intestines of normal mice it enhanced chemical-induced intestinal inflammation. The authors therefore suggest that individuals with UC might benefit from local delivery of the IL-22 gene to their intestines.
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This FabM knockdown mutant is a living model that shows the exact impact of the enzyme in live bacteria. Without FabM, the mutant fills its outer membrane with other, smaller fatty acids that are much less acid resistant than those normally created via FabM, but that still provide some protection from acid. Thus, a goal is to design a treatment that would prevent S. mutans from forming both straight chain and smaller chain fatty acids.
As Quivey and others design next-generation antibacterial drugs, they are looking not just for a single way to stop the action of a single disease-causing enzyme, but how to shut down its three or four back-up systems. The process of cutting off genetic escape routes for bacteria applies to every trait central to the ability of the bacteria to survive and cause disease. Beyond acid durability, the team will also look at the genes and proteins that enable S. mutans to stick to teeth enamel like no other, which it does by producing a sugary polymer (plaque). Tooth decay is the result of plaque combined with acid.
Quivey's partners in the grant application were Elizabeth Grayhack, Ph.D., research associate professor of Biochemistry and Biophysics, Robert Marquis, Ph.D., professor of Microbiology and Immunology, and Eric Phizicky, Ph.D., professor of Biochemistry and Biophysics. The grant application succeeded with the NIH, Quivey said, because the team and proposal combined many years of experience in genomic projects (Grayhack and Phizicky) with extensive microbial experience (Marquis and Quivey).
As part of the grant, Grayhack and Phizicky will create a library of mutant strains for the 2,000 known S. mutans genes, with each strain having just one of the 2,000 genes shut off. They will then subject the library to acid, for example, and see which strains thrive. Knowing which gene is missing from each strain, researchers will then be able to draw conclusions about each single gene's contribution to not only to acid durability, but also to many aspects of the strep bacteria's ability to survive and cause disease.
Down the road, the finished library will enable researchers to determine every bacterial protein involved in oral disease, to learn their exact structure and to tailor drugs that interfere with them, said Marquis. Identifying and turning off say the top four ways in which bacteria might try to resist treatment is the team's strategy.
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