$24-Million Grant Funds Creation of Encyclopedia of the Innate Immune System

By Jason Socrates Bardi

The National Institute of Allergy and Infectious Diseases (NIAID) has awarded a multi-year, $24-million grant to a group of researchers at The Scripps Research Institute (TSRI), the Institute for Systems Biology (ISB) in Seattle, Washington, and The Rockefeller University in New York, New York.

The group's task is to create an "encyclopedia" of innate immunity—a comprehensive and detailed picture of this ancient, essential first line of defense against bacterial and fungal diseases that is mustered by humans, fruit flies, and all creatures in between.

"There are lots of questions we would like to ask about gene expression and protein expression in innate immunity," says TSRI Professor and Chair of Immunology Richard J. Ulevitch, the project's principal investigator. "But to accomplish this in the broadest terms we need to define gene and protein expression patterns when the innate immune system is triggered by invading microbes."

The funds will go towards discovering new ways to study the immune system in living tissue in real time and to provide materials and information to the scientific community at large. Knowledge generated could help scientists develop treatments for septic shock, certain autoimmune disorders, and diseases caused by potential agents of bioterrorism.

A Systems Approach to Innate Immunity

Innate immunity is essential for survival in a world filled with microbial pathogens. Cells of the innate immune system are the body's first responders, arriving soon after foreign elements are detected. Some innate cells find and engulf microorganisms, while others release chemicals that kill the organism directly. Still other cells begin recruiting other specialized immune components to the region.

Severe defects in the innate immune system make humans highly susceptible to normally benign infections, which can then become life threatening. For instance, babies born without functional neutrophils—one of the primary cell types of the innate immune system—do not live more than a few days due to the effects of infection.

While the adaptive immune system, which forms the other half of the human immune system, has been studied since the dawn of immunology, it is only in the last few years that researchers have begun to understand the innate immune system in detail, Ulevitch says. The innate immune system has turned out to be much more complex than anybody had imagined.

Ulevitch and his co-investigators face a daunting task—identifying the thousands of tiny molecular and biochemical changes that are triggered by encounters between innate immune system cells and infectious agents. Unlike the highly specific antibodies of the adaptive immune response, which are produced in almost infinite variety and which match a particular disease organism like a key in a lock, cells of the innate immune system react generically to a wide range of substances, including molecules found in the cell walls of many bacteria.

The grant investigators aim to identify and study the key players of innate immunity on both sides of the battle. Investigators are interested in the bacterial and fungal "ligands"—the molecules found in the cell walls of bacteria and other substances that are recognized by innate immune cells, as well as the "receptor" molecules on the immune cells that recognize the ligands. A multiplicity of different ligands are recognized by 10 or more different receptors in the innate immune system. The investigators are also interested in discovering the "signal transduction" pathways through which this immune recognition triggers the innate immune response.

The researchers will take a "systems biology" approach to identifying all these players. Dubbed "21st-century biology," the relatively new field of systems biology melds mathematics, computer modeling, and the new techniques of genomics and proteomics in an effort to gain a wide-angle view of biological systems.

In contrast to traditional hypothesis-driven research, in which a single gene or protein is selected for study based on its proposed function, the TSRI, ISB, and Rockefeller University approach will assemble information about multiple genes, proteins, and biochemical reactions without regard for function. The idea is that this data can then be integrated and examined from multiple perspectives to learn how the system as a whole behaves—information that will later form the basis for novel hypotheses.

A large portion of the funding will be dedicated to setting up certain shared core facilities at TSRI and ISB that will centralize and enhance some of the tasks common to the dozens of researchers with independently funded research projects at the institutions. The grant will help generate information and materials for the research community at large by funding a large database with free data access. Bi-monthly video conferences will bring participating scientists together on a regular basis.

"[We aim] to leverage the existing expertise in biology and high-throughput technology platforms at these institutions," says Ulevitch. "We appreciate the NIAID's vision in funding the huge project. Individual grants can only address individual questions—we are throwing out a huge net, and this would not be possible without the support of the NIAID."



TSRI Professor and Chair of Immunology Richard J. Ulevitch is the principal investigator of the new $24-million grant.