UH and UI Researchers Receive $2 Million Grant from the W.M. Keck Foundation

University of Hawaiʻi at Mānoa
Shawn Nakamoto, (808) 956-9095
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Posted: Feb 26, 2002

HONOLULU -- A luminous squid and a chronic lung infection in a person with cystic fibrosis (CF) may not seem to have much in common. However, both are examples of persistent infection of an animal host by a bacterium. Scientists at the University of Hawaiʻi and the University of Iowa plan to study the parallels between these two systems.

The investigation will be funded by a three-year, $2 million grant to the UI Foundation from the W.M. Keck Foundation and will draw on the unique expertise of researchers at the Kewalo Marine Laboratory, part of the Pacific Biomedical Research Center of the University of Hawaiʻi at Mānoa, and the UI College of Medicine.

Studying chronic infections in animals is difficult over the long term because the animals usually either beat the infections and recover, or succumb and die. However, UH Mānoa research on the lifelong infection of bobtail squid by a light-emitting bacterium (Vibrio fischeri) has resulted in an experimentally useful model of chronic infection. This model will be combined with the UI expertise in bacterial biofilms and the disease process of CF.

"There are many parallels between chronic infections in humans and the symbiotic relationship between the bobtail squid and this light-emitting bacterium," said E. Peter Greenberg, Ph.D., the Virgil L. and Evalyn Sheppard Professor of Molecular Pathogenesis and UI professor of microbiology. "The principles of engagement, as far as we can tell, seem to be the same. We just don't know what they all are."

Many persistent infections are caused by biofilms, organized groups of bacteria encased in a self-produced matrix. At the UI, Greenberg and his colleagues have shown that the bacterium Pseudomonas aeruginosa forms biofilms in the lungs of individuals with CF. These biofilms are highly resistant to antibiotics and cause an overactive inflammatory response by the CF patient's immune system.

The researchers hope that an improved understanding of persistent bacterial infection of animal hosts will lead to the development of drugs to treat chronic infection and inflammation in humans.

The W.M. Keck Foundation is one of the nation's leading philanthropic organizations. It funds pioneering research efforts designed to open up new fields of investigation and lead to breakthrough discoveries and the development of new technologies.

"The W.M. Keck Foundation grant allows us to put together a program that we couldn't otherwise do with the type of funding usually available even to well-funded senior faculty," Greenberg said. "It allows us to try all sorts of novel things."

UH President Evan S. Dobelle and UI President Mary Sue Coleman played key roles in developing this request to the W. M. Keck Foundation. President Coleman presented the proposal to the W. M. Keck Foundation.

According to Dobelle, "the grant will advance one of the most strategically important priorities of the University of Hawaiʻi — expanding research in the biomedical sciences."

"President Dobelle and I are excited about the interdisciplinary research and collaboration between our institutions made possible by this grant from the W. M. Keck Foundation," Coleman said.

A first step in the study will be to sequence the genome of the light-emitting Vibrio fischeri bacterium. This information will be used to construct a DNA microarray, or gene chip, containing DNA fragments representing the bacterium's genes. The researchers will collaborate with Integrated Genomics, a Chicago-based research firm, to build the microarray.

Greenberg and his colleagues have already used microarrays of Pseudomonas genes to investigate this bacterium as it exists as a biofilm. However, Greenberg explained that it can be difficult to obtain funding to make microarrays for bacteria like V. fischeri, which don't cause human diseases.

"This microarray is exactly the tool we need to draw these parallels between Pseudomonas and Vibrio fischeri," Greenberg said.

The team also plans to construct a microarray of genes from the squid. These various microarrays will be used to investigate the molecular and genetic interactions of the two host-bacteria pairings.

Greenberg's earlier work showed that chemical communication, or signaling, between individual bacterial cells is a critical step in biofilm development. The researchers believe that cell-to-cell signaling between a bacterium and its host also is important and complex.

"The host is detecting the bacteria and responding, and the bacteria are detecting each other and responding, and detecting the host cells and responding," Greenberg said. Fellow investigator Margaret McFall-Ngai, Ph.D., professor of biology at UH Mānoa, described it as a "whole dialogue going on."

"We want to understand the dialogue because every step is a possible point of intervention for treatment of chronic infections," Greenberg added.

A second project in the investigation also stems from an unusual combination of expertise between researchers at UH and the UI. Michael Apicella, M.D., UI professor and head of microbiology, is an expert on how particular bacterial cell-surface molecules trigger inflammation in humans. Together, researchers at UH and Apicella have discovered that the same surface molecules on the Vibrio bacteria also trigger a reaction in the squid, but in the symbiotic relationship, the reaction is not harmful.

"Somehow, the bacteria in the squid's light organ are limiting inflammation," Greenberg said. "That's a good trick because despite the chronic infection, the host cells are being told not to be alarmed."

Understanding how this trick works might lead to ways of limiting or preventing the harmful inflammation that often accompanies chronic infection in humans. Using the squid model, the team will study the interaction of the host cells with the bacteria cell surface signaling molecules.

Finally, Greenberg and his colleagues are interested in pursuing indications of other kinds of group behavior in bacteria. Potentially, these studies could uncover new types of cell-to-cell signaling between bacteria.

"The Keck grant gives us the opportunity to pursue these novel lines of investigation and we are the ideal group to do it because of our combined expertise," Greenberg said. "We plan to open up new areas of research."

The investigation's principal scientists at UH are Edward G. Ruby, Ph.D., professor of bacteriology, and Margaret McFall-Ngai, Ph.D., professor of biology. In addition to Greenberg and Apicella, the principal scientists at the UI include Michael J. Welsh, M.D., the Roy J. Carver Chair in Physiology and Biophysics, professor of internal medicine and physiology and biophysics, and a Howard Hughes Medical Institute Investigator; and Timothy L. Yahr, Ph.D., assistant professor of microbiology.

University of Iowa Contact:
Jennifer Brown, Health Science Relations, (319) 335-9917