UCSD team unmasks family of immune system invaders

Like a family of petty criminals gone wrong, researchers at the University of California, San Diego (UCSD) were surprised to find that bacterial pathogens found in a number of troublesome diseases are actually related. Not only that, their wrong-doing is carried out by disguising themselves, then hijacking their hosts.

Jack E. Dixon, Ph.D., Dean for Scientific Affairs and Professor of Pharmacology and Cellular and Molecular Medicine at the UCSD School of Medicine; Neal M. Alto, Ph.D., UCSD postdoctoral fellow and lead author, and their colleagues have identified a 24-member family of bacterial proteins. Called effector proteins, they are found in bacteria, including Salmonella, Shigella and pathogenic E. coli, that cause gastrointestinal diseases. The researchers' findings will be published in the January 13, 2006 edition of the journal Cell.

These proteins help bacteria do their job of infecting the host by warding off the body's immune system. The UCSD researchers discovered how the effector proteins are able to "hijack" the body's communication network, findings that could lead novel ways to fight bacterial disease.

"While discovery of this family of effector proteins was surprising, finding the mechanisms that these proteins use to attack human cells was even more exciting," said Alto.

When pathogenic bacteria are ingested into the body – as they generally are in diseases caused by E-coli or Salmonella commonly known as "food poisoning" – the bacteria use a syringe-like system to "inject" their mammalian host with bacterial proteins. Once inside the host, these protein hijackers re-direct the cells communication network. The protein hijackers allow the bacteria to persist and take up nutrients, and they also shut down the immune response.

"These proteins mimic known host proteins in the cell in a very interesting way," said Dixon. "They are functional mimics that work in the same way as proteins of the host cell, but they don't look anything like the host proteins. In a sense, they take over the host cell's identity like a bad actor."

When spoiled food is eaten, the pathogenic bacteria pass into the intestine and colon, where they meet up with a layer of cells lining these organs called the epithelial cells. The epithelial cells form a protective wall without any doors, a barrier that blocks bacterial entry from the intestine and colon into the rest of the body. However, bacterial pathogens can inject effector proteins into the intestinal epithelial cells, creating a door in the barrier.

"As a result, these bacteria proteins are the bad guys that make you sick," said Alto. "Instead of curing the illness by giving a patient antibiotics, it might be possible to target these effectors, turning their virulant actions into something benign."

The researchers used a molecular "fingerprinting" approach to identify the family of hijackers. Using this molecular fingerprint and computer-aided searches, they discovered a number of proteins having the same molecular pattern – all were proteins used by pathogenic microorganisms. UCSD researchers were able to determine that additional bacterial proteins used a common strategy to hijack the cells' communication network.

"The novel findings of this research are particularly gratifying since this work not only included scientists from our laboratory, but also other UCSD colleagues as well as investigators from the University of Toronto," said Dixon. "This illustrates how advances in a field like bacterial pathogenesis requires the talents and diverse expertise of many scientists."

Their insights into the mechanisms of bacterial pathogens could lead to novel treatments for diseases such as dysentery. These findings may prove to be especially helpful in fighting bacterial disease in Third-World countries, in children and those with suppressed immune systems, such as HIV/AIDS patients.

Contributors to the paper include Seema Mattoo, Feng Shao and Cheri S. Lazar, UCSD Departments of Pharmacology and Cellular and Molecular Medicine; Partho Ghosh and and Stephen A. McMahon,, UCSD Department of Chemistry and Biochemistry; and Renee L. Brost, Gordon Chua, Timothy R. Hughes and Charles Boone, Banting and Best Department of Medical Research and Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario.

Source : University of California - San Diego