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MGH study identifies key immune system molecule
Cell receptor critical to defense against E.coli bacteria

BOSTON — March 24, 2002 — Researchers from MassGeneral Hospital for Children have identified a molecule that is key to how white blood cells called macrophages recognize the common bacteria E. coli. The study, which may lead to better ways of fighting infections, is being issued on March 24 as an advance online publication of the journal Nature. It will appear in a future print edition of the journal.

The body's immune response against baterial infection consists of the coordinated activities of a variety of white blood cells. Among these are cells known as macrophages, which ingest and destroy the invaders in a process called phagocytosis. In the current study, researchers from the Laboratory of Developmental Immunology at MassGeneral Hospital for Children, the pediatric service of Massachusetts General Hospital, studied macrophages from the fruitfly Drosophila.

"The basic templates of how organisms protect themselves against infection go back millions of years in evolution, so we can learn lessons from flies that apply to humans," says R. Alan Ezekowitz, MBChB, DPhil, chief of Pediatrics at MassGeneral Hospital for Children and head of the Laboratory of Developmental Immunology. "In this study we look at a very ancient but very important process: how bacteria are recognized and eaten by immune cells called phagocytes [a group that includes macrophages]." Ezekowitz is the study's senior author.

Using a new method of turning off specific genes, Ezekowitz's team - led primarily by postdoctoral fellow Mika Ramet, MD, PhD - identified 34 macrophage proteins that are essential to the process of phagocytosis. One of these proteins is a cell surface receptor - a molecule that sits on a cell's outer membrane and receives chemical signals - called PGRP-LC. The researchers found that inactivating PGRP-LC destroyed macrophages' ability to recognize and ingest E. coli bacteria but not another type of bacteria called S. aureus, suggesting that the protein is critical to the macrophage's specific response against what are called gram-negative bacteria. To confirm this association, postdoctoral fellow Pascal Mantruelli, PhD, created a group of Drosophila with a mutated version of PGRP-LC and found the flies were much more susceptible to E. coli infection than were normal fruitflies.

"PGRP-LC represents a new class of recognition molecules, and there are very similar genes in humans," Ezekowitz says. "The next question to ask is whether this protein plays a related role in humans. Understanding the role these proteins play could eventually lead to new ways of fighting infection and to helping us figure out why some people are more susceptible to specific infections."

Along with Ramet and Mantruelli, who share first authorship, additional study authors are Alan Pearson, PhD, of MassGeneral Hospital for Children, and Mernard Mathey-Prevot, PhD, of Dana-Farber Cancer Institute. The work was supported by grants from the National Institutes of Health, the Foundation for Pediatric Research, the Finnish Medical Foundation, the Maud Kristila Foundation and the American Cancer Society.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photomedicine.

In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.

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