TORRANCE (August 29, 2007) - With infections increasingly resistant to even the most modern antibiotics, researchers at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed) report in the September issue of Nature Reviews Microbiology on new clues they have uncovered in immune system molecules that defend against infection.
Drs. Michael R. Yeaman and Nannette Y. Yount present evidence that small proteins in the immune systems of humans and all kingdoms of life share fundamental structural and functional characteristics that enable these molecules to inhibit or kill microbial pathogens – even as these pathogens evolve to resist conventional antibiotics.
"These findings reveal that nature uses a recurring molecular strategy to defend against infection," said Dr. Yeaman. "A clearer understanding of this strategy provides new opportunities to develop innovative anti-infective therapies to better prevent or treat life-threatening infections that resist current antibiotics."
Most modern antibiotics work by targeting specific structures or functions in microbial pathogens. If the targets change due to mutation, pathogens can quickly become resistant to the antibiotics. In contrast, immune system molecules have retained the ability to fight infection – even as microbes evolve.
"While human ingenuity has thus far created antibiotics that pathogens seem to resist after just a few years, nature has created molecules in our immune systems that retain the ability to defend against infection even after millions of years of evolution," said Dr. Yeaman. "We have a lot to learn from nature."
The September article sheds new light on the molecular basis for the antimicrobial capabilities of these molecules. Drs. Yeaman and Yount report that a structure they discovered in these molecules in 2004 – known as the y core – allows for "hypermutability," or unusually high rates of mutation or modification at specific sites within these molecules.
To do so, the y core structure often contains a "b bulge" motif – a region that affords structural variations otherwise prohibited in protein biochemistry.
"The ability of host defense molecules to change so quickly and with such diversity may be nature’s way of keeping pace with rapidly evolving infectious microbes and other threats," said Dr. Yount.
These insights may drive new strategies for anti-infective discovery and development. Drs. Yeaman and Yount also said their discoveries significantly advance understanding of immune system evolution. Microbial pathogens are constantly moving targets; in turn – immune systems must adapt or lose effectiveness. Understanding how these molecules have continued to ward off infection could also accelerate development of immunotherapeutics to boost the body’s own defenses against infection or other diseases, and reduce the resistance issues that plague today’s antibiotics.
The article authored by Drs. Yeaman and Yount is entitled "Unifying themes in host defence effector polypeptides," and can be viewed at http://www.nature.com/nrmicro/journal/v5/n9/abs/nrmicro1744.html The authors are available for interviews.
Both researchers are LABioMed investigators who also have appointments within the Division of Infectious Diseases/Department of Medicine at Harbor-UCLA Medical Center. In addition, Dr. Yeaman is a Professor of Medicine at the David Geffen School of Medicine at UCLA.
About LA BioMed
LA BioMed is one of the largest independent, not-for-profit biomedical research institutes in the country. Founded more than 55 years ago, LA BioMed conducts biomedical research, trains young scientists and provides community services, including childhood immunization, nutrition assistance and anti-gang violence programs.
The institute has an annual budget of more than $75 million and employs 150 full-time and part-time researchers who conduct studies in such areas as cardio-vascular disease, emerging infections, cancer, diabetes, kidney disease, dermatology, reproductive health, vaccine development, respiratory disorders, inherited illnesses and neonatology.
LA BioMed researchers have invented the modern cholesterol test, the thyroid deficiency test and a test to determine the carriers of Tay-Sachs disease, an inherited fatal disorder.
One of the institute’s researchers also developed the paramedic model for emergency care, setting a precedent that transformed emergency medical services and became the basis for training paramedics across the country.
Among LA BioMed’s current research programs are a major effort to develop the next generation of antibiotics, new therapeutic and diagnostic approaches to lung disease, refining methods for earlier identification of Type II diabetes, studies in the relationship between cardiovascular and kidney diseases, development of enhanced breast cancer detection technology and a novel approach to treating several autoimmune diseases and certain solid tumors.
LA BioMed is an independent research institute that is academically affiliated with the David Geffen School of Medicine at the University of California, Los Angeles. The institute is located on the campus of Harbor-UCLA Medical Center near Torrance.
The institute has become an economic engine for the South Bay, pumping an additional $155 million into the local economy in 2005, according to a 2007 Los Angeles Economic Development Corporation report. With 1,460 employees working directly or indirectly for the institute, LA BioMed contributes to Los Angeles County’s economic viability while inventing the future of health care through its ground-breaking research, its training of the scientists of tomorrow and its service to the local community. Please visit our website at www.labiomed.org
Journal
Nature Reviews Microbiology