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University of Iowa News Release

Oct. 23, 2003

Photo: William Nauseef, M.D., UI professor of internal medicine and microbiology

Multidisciplinary UI Team Awarded Grant To Study Innate Immune System

University of Iowa researchers have received a five-year, $6.3 million grant renewal from the National Institute of Allergy and Infectious Diseases (NIAID) to study innate immune system response to microbial infection.

The innate immune system is the body's first line of defense against microbes. Its job is to recognize and rapidly respond to microbial invaders, even ones that it has never seen.

"The innate immune system is hardwired to recognize patterns -- patterns that say 'I'm a microbe'," explained William Nauseef, M.D., UI professor of internal medicine and microbiology, and the principal investigator for the grant. "It uses pattern recognition receptors to recognize microbial non-self entities and then attacks them."

In particular, the innate immune system appears to be geared to recognize molecules known as endotoxins, which form part of the outer coat of certain types of bacteria. Nauseef and his colleagues will investigate the structural basis of interactions between endotoxins and components of the innate immune system to try to understand the recognition process and the resulting functional responses.

Understanding the innate immune system may suggest ways to amplify the innate response to infection. This information may decrease the reliance on antibiotics and other drugs for treating bacterial diseases.

The research also may provide useful insights for biodefense studies. Many potential bioterrorism agents are microbes that intervene at the level of the innate response by producing a marked early challenge to the host defense system.

The UI researchers and colleagues at the Veterans Affairs Medical Center (VAMC) in Iowa City will investigate the interaction of human innate immune system with two microbes that behave very differently but are each capable of producing life-threatening disease -- bacterial meningitis and tularemia. The endotoxins of these bacteria seem to play important roles in how the organisms cause disease.

Neisseria meningitidis causes the type of bacterial meningitis that can rapidly overwhelm and kill young healthy patients. Even with intensive medical intervention, patients can often lose digits (fingers and toes) or even die from meningococcal disease. Neisseria's endotoxin is different than endotoxins in similar bacteria. This difference may play a role in making this organism produce a disease that is so much worse than disease caused by similar organisms.

Francisella tularensis is the second organism under investigation by the UI team. This extremely potent and often deadly bacterium causes tularemia and could potentially be used as a bioterror agent. Interestingly, the endotoxin of tularensis appears to be silent and the innate immune system barely responds to it.

"This is a terrific way for the organism to bypass the innate immune system and get inside cells and then reproduce and produce disease," said Nauseef, who also is a staff physician and researcher with the VAMC. "It is a stealth organism and its endotoxin seems to be structurally different from other endotoxins. We are working to solve its structure and understand the basis for its modified potency."

Understanding the complex biology of the interactions between host and microbe is at the heart of the research funded under this grant.

"There is constant interplay between the host and its environment -- we are constantly changing and responding to organisms that in turn respond to us," Nauseef said. "Understanding the biology of this 'cross talk' is very important and that will be a focus of our studies."

Nauseef added that another type of "cross talk" -- between researchers from many different disciplines -- also will be a key to answering many of the questions and puzzles posed by these microbes.

"We have microbiologists, biochemists, cell biologists and protein chemists working together with infectious disease specialists and pediatric intensivists," Nauseef said. "The questions we can ask as a group are better than any of us could address alone."

In addition to Nauseef, UI researchers leading projects under the grant include Michael Apicella, M.D., professor and head of microbiology; Jerrold Weiss, Ph.D., professor of internal medicine and microbiology; Theresa Gioannini, Ph.D., research scientist in internal medicine; Lee-Ann Allen, Ph.D., associate professor of internal medicine; Jess Moreland, M.D., assistant professor of pediatrics; Dave Kusner, M.D., Ph.D., associate professor of internal medicine; and S. Ramaswamy, Ph.D., associate professor of biochemistry. Allen, Gioannini, Kusner and Nauseef also have VAMC appointments.

University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at www.uihealthcare.com.

STORY SOURCE: University of Iowa Health Science Relations, 5141 Westlawn, Iowa City, Iowa 52242-1178

CONTACT: Jennifer Brown, (319) 335-9917 jennifer-l-brown@uiowa.edu

PHOTOS/GRAPHICS: A photo of Nauseef is available from Jennifer Brown