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Biological Chemistry

Pathogens Turn Tables On Human Immune System

Microbiology: Some bacteria can convert to their benefit a chemical toxin that would otherwise wipe them out

by Sarah Everts
March 28, 2014 | A version of this story appeared in Volume 92, Issue 13

Many pathogens turn macrophage-produced itaconate into useful nutrients.
A reaction scheme depicting the conversion of itaconate into nutrient molecules.
Many pathogens turn macrophage-produced itaconate into useful nutrients.

When the human immune system fights off dangerous bacteria, one line of defense is the chemical weapon itaconate. Immune cells known as macrophages engulf invading pathogens, then produce itaconate, which interferes with bacterial metabolism. But many pathogens have evolved a strategy to sidestep this toxin, according to a new study (Nat. Chem. Biol. 2014, DOI: 10.1038/nchembio.1482).

A number of pathogens, including Yersinia pestis, which causes plague,and Pseudomonas aeruginosa, which can infect catheters placed in the body, degrade itaconate into useful building blocks that actually nourish the invading microorganisms, the researchers find. The enzymes involved in this process could be promising targets for new antimicrobial agents, says Ivan A. Berg, a microbiologist at Germany’s University of Freiburg who led the research.

The work also clarifies a conundrum of microbiology: how some pathogens survive the harsh conditions inside macrophages. The key was weaving together seemingly disconnected discoveries that traverse decades, comments Jay Hinton, a microbiologist at En­gland’s University of Liverpool. In the 1960s, researchers discovered that soil bacteria can break down itaconate into pyruvate and acetyl-CoA, two useful nutrients for the microbes. But the work didn’t seem to have much significance for human pathogenesis.

Then, about 10 years ago, researchers discovered that many pathogens must activate the expression of three genes to survive being engulfed by human macrophages. But nobody knew what these genes coded for, Hinton adds. Finally, in 2011, another group of researchers discovered that macrophages produce itaconate when the immune system is turned on. That’s when Berg guessed the itaconate was a poison intended for pathogens and that the three essential genes expressed by pathogens surviving in macrophages coded for itaconate metabolism. It was just a matter of proving the theory, he says.

This is not the first case of pathogens turning the tables on human immune defenses to survive. “It has become increasingly apparent that bacterial pathogens not only neutralize host defense mechanisms but even exploit some of them for nutrients,” comments Michael McClelland, a microbiologist at the University of California, Irvine. “A better understanding of itaconate metabolism in the macrophage might lead to ways to deny the bacterium a nutrient.”



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