FOR IMMEDIATE RELEASE
Oct 7, 2010 #099
Contact: John Austin
UMKC researchers working to understand Staph infection
Recent findings published by the National Academy of SciencesThe reason that some Staphylococcal infections, such as MRSA, are so virulent lies in their ability to "evade" many of the human body's immune responses. Scientists at the University of Missouri-Kansas City (UMKC) School of Biological Sciences (SBS) are part of a research team working to understand the mechanisms that allow certain pathogens to evade immune system defenses, and they may have recently unlocked an important clue. The results of their most recent findings were published in the Proceedings of the National Academy of Sciences (PNAS).
"Staphylococcus aureus is a widespread and dangerous human pathogen that causes a variety of hospital and community acquired diseases, and it appears to be particularly adept and elaborate regarding its immune evasion mechanisms," said Brian V. Geisbrecht, associate professor of Cell Biology and Biophysics at SBS and co-author of the PNAS paper. â€œThe pillar of our body's innate immunity is the complement system, which triggers the activation of specific proteins to attack invading pathogens. The complement system not only marks invading organisms -- like fungi, bacteria, and viruses -- for elimination and destruction, but also serves a critical role in shaping the overall immune response of our bodies."
Geisbrecht said the most successful pathogens are ones that have evolved the ability to counteract or disrupt various defense mechanisms of the immune system. This general phenomenon, which is typically critical to a pathogen's virulence (its ability to cause an infection) is known as "immune evasion." Because the complement system is our first line of defense against invading organisms, it has been heavily targeted during the course of pathogen evolution as a particularly valuable point for deploying immune evasion strategies.
"The current PNAS paper represents an exciting extension of our previous work on the Staph immune evasion protein known as Efb (extracellular fibrinogen-binding protein)," Geisbrecht said. "In previous studies, we were able to show that Efb proteins from invading Staph bacteria are able to bind directly to, and thereby disable, the function of a central complement component known as C3."
C3 is found in large quantities in human blood/plasma, and is the central protein responsible for marking invading organisms for destruction by specific classes of white blood cells. Despite this previous work, the researchers weren't completely sure how the Staph Efb protein was able to disrupt C3 activation at the molecular level. In research reported in the PNAS paper, the investigators employed an integrated approach that relied on solution structural biology.
"Basically, we were able to understand how the Efb protein changes both the three-dimensional shape as well as the intramolecular motions of the much larger C3 molecule," Geisbrecht said. "Using this approach, we were able to identify Efb as the first-known allosteric inhibitor of the complement system."
Allostery is a common regulatory mechanism in biochemistry that is best described as controlling the function of molecules through "action at a distance" strategies, he explained. In the presence of specific biological stimuli, such as the introduction of Staph bacterial cells, a small fraction of the C3 protein becomes locally activated. This triggers the assembly of a multi-protein complex called the â€œC3 convertase,â€ which in turn activates much more C3 that ultimately becomes attached to any nearby invading bacterial cells.
Â "We were able to demonstrate that the Efb protein binds to the activated C3 molecules, yet affects the structure of critical functional areas that are far-distant -- at least in molecular terms -- from the Efb binding site," Geisbrecht said. "Most importantly, we found that Efb disrupts the formation of the C3 onvertase. By blocking formation of the convertase, less activated C3 molecules can be generated, and so less C3 binds to the surface of the Staph bacteria. Ultimately, this blocks bacterial uptake and destruction by white blood cells. In this way, this small bacterial protein can block the function of an essential human defense against bacterial infections."
While ongoing studies of Efb may yet hold important clues for the development of new anti-infective agents, Geisbrecht said they are perhaps more valuable in what they can tell the researchers about non-infectious human diseases. He noted that studies in recent years have demonstrated that disrupted or uncontrolled activation of the complement system is a contributing factor to a large number of human diseases, including autoimmune conditions such as rheumatoid arthritis, and ischemia/reperfusion injuries such as stroke and myocardial infarctions.
"By understanding the fundamental biology behind the various evasion mechanisms deployed by Staph bacteria, we may better understand how it interacts with and counteracts the defenses of an otherwise healthy human, and perhaps identify potential targets for new drugs to treat or prevent Staph infections," Geisbrecht said. "It is also entirely possible that more complete understanding of the structure, function, and mechanisms of Staphylococcal immune evasion proteins might lead to the identification of new therapeutic strategies against diseases where complement-mediated inflammation is an underlying cause."
This research is funded by grants from the National Institutes of Health (NIH). Geisbrecht's co-investigators in this study include Brandon L. Garcia and William J. McWhorter, from UMKC; Hui Chen, Daniel Ricklin, Georgia Sfyroera, You-Qiang Wu, Apostolia Tzekou, and John D. Lambris, from the University of Pennsylvania; Michal Hammel from the Lawrence Berkley National Laboratory; and Sheng Li and Virgil L. Woods, Jr. from the University of California, San Diego. Click here for the abstract and link to full text on the PNAS Web site.
About the UMKC School of Biological Sciences
The mission of the School of Biological Sciences is to provide outstanding undergraduate and graduate education in modern biology and to advance our understanding of molecular biology through basic research. The school comprises two academic Divisions â€” Cell Biology & Biophysics and Molecular Biology & Biochemistry. The Schoolâ€™s pioneering programs in molecular genetics, structural biology and proteomics nurture the intellectual capital necessary to fuel the economic development of biotechnology in Kansas City. Learn more about the School at www.sbs.umkc.edu or find us on Facebook.
About the University of Missouri-Kansas City
The University of Missouri-Kansas City (UMKC), one of four University of Missouri campuses, is a public university serving more than 15,000 undergraduate, graduate and professional students. UMKC engages with the community and economy based on a four-part mission: life and health sciences; visual and performing arts; urban issues and education; and a vibrant learning and campus life experience. For more information about UMKC, visit www.umkc.edu. You can also find us on Facebook, follow us on Twitter and watch us on YouTube.
This information is available to people with speech or hearing impairments by calling Relay Missouri at (800) 735-2966 (TT) or (800) 735-2466 (voice).