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Scripps Research Scientists Find Pathogen Uses Unique Strategy to Inhibit Human Immune Response

Results Could Point to Potential Therapeutic Targets for Persistent Infection

LA JOLLA, CA, June 17, 2008—Scientists at The Scripps Research Institute have uncovered a unique strategy used by some common bacteria to disrupt the human immune system, maintaining persistent infections and ensuring the bacteria's survival. The findings shed new light on the complex relationship between pathogens and the immune system, and may one day lead to novel ways of fighting persistent infections.

The study was published on June 19, 2008, in Science Express, an advance, online edition of the journal Science.

The new study shows that an opportunistic bacteria called Pseudomonas aeruginosa secretes a small signaling molecule, N-(3-oxo-dodecanoyl) homoserine lactone (C12), which inhibits the expression of a number of key immune system regulators.

"Despite the activation of the innate immune system," said Richard Ulevitch, professor in the Scripps Research Department of Immunology who led the study, "opportunistic pathogens like Pseudomonas aeruginosa have evolved effective signaling mechanisms to establish and maintain persistent infections. Our study shows for the first time the biological mechanism they use to accomplish this in the mammalian host."

Pseudomonas aeruginosa, a Gram-negative bacteria, can cause respiratory, gastrointestinal, and urinary tract infections. It is the most common pathogen found in cystic fibrosis patients, and it is particularly harmful for immunosuppressed patients such as those with cancer or HIV/AIDS.

"We found that, in the case of Pseudomonas aeruginosa, at least, C12 disrupted NF-κB, a transcription factor that controls the expression of a number of critical genes, crippling the immune system and potentially opening up the host to the threat of persistent infection," Ulevitch said.

C12 is part of an array of molecules known as quorum sensing factors that can regulate gene expression based on bacterial density. Quorum sensing factors regulate a number of processes, including bacterial virulence and biofilm formation. Biofilms are encapsulated bacterial complexes that attach themselves to various surfaces.

The immune system is normally activated in response to invading pathogens through various receptor-dependent mechanisms. In mammals, the Toll-like receptor 4 recognizes lipopolysaccharide, a membrane component of Gram-negative bacteria. This leads to rapid activation of NF-κB and the expression of genes encoding proinflammatory cytokines, which help coordinate the immune response, and tumor necrosis factor α, which can initiate apoptosis or programmed cell death in the invading pathogens. Rapid inhibition of tumor necrosis factor expression would be highly beneficial for the survival of bacteria.

After showing that Pseudomonas aeruginosa produced C12 and affected levels of immune system molecules in samples, the scientists extended their studies by showing that C12 also significantly suppressed immune system responses in mice.

"In transgenic mouse models, we found that C12 significantly suppressed responses to lipopolysaccharide, which is a generic marker for a Gram-negative bacteria infection. C12 also impaired the ability of some specific immune response ligands to activate necessary gene expression."

In addition to Ulevitch, authors of the study, Modulation of Gene Expression Via Disruption Of NF-κb Signaling By A Bacterial Small Molecule, were Vladimir V. Kravchenko, John C. Mathison, David A. Scott, Alexander Z. Katz, David C. Grauer, and Mandy Lehmann of The Scripps Research Institute; Gunnar F. Kaufmann and Michael M. Meijler of The Scripps Research Institute and The Skaggs Institute for Chemical Biology; and Kim D. Janda of The Scripps Research Institute, The Skaggs Institute for Chemical Biology, and Worm Institute of Research and Medicine.

The study was supported by The Skaggs Institute of Chemical Biology.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus by 2009.


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