Infectious agent thwarts typical defense mechanisms; Sheds light on immune system function

December 21, 2005

A new study found that an extremely infectious pneumonia-like disease in humans slips through the immune system's usual defense mechanisms.

The bacterium at fault, Francisella tularensis, causes the disease tularemia. Also known as rabbit fever, tularemia is fatal in less than 1 percent of treated cases and in about 5 percent of untreated cases. It is a rare disease with only about 300 cases per year occurring in the United States .

But the disease can make many people very ill very fast, said Mark Wewers, the study's lead author and an assistant director of the Davis Heart and Lung Research Institute at Ohio State University . He and his colleagues report their findings in this week's online edition of the Proceedings of the National Academy of Sciences.

In this study the researchers found that, unlike other kinds of bacteria, Francisella is fully detected by the immune system only after it gets inside a monocyte, an immune cell whose job is to detect pathogens when they enter the body. Most pathogens are detected by sensors on the surface of monocytes, and these cells immediately respond by launching an attack.

However, monocytes don't immediately recognize Francisella as a threat because the bacteria can bypass those sensors. They cause a reaction only once they are inside the monocyte.

The fact that Francisella can spread so readily makes it an excellent possible weapon for bioterrorism, according to some experts.

"We estimate that if a terrorist dropped Francisella on a city it could make tens of thousands of people seriously ill," said Wewers, who is also a professor of molecular virology, immunology and medical genetics. "A widespread infection would put a lot of people out of commission for a long time."

During the Cold War, both the United States and the former U.S.S.R. stockpiled highly infectious strains of Francisella, Wewers said.

In North America , tularemia most commonly affects hunters and other outdoor enthusiasts. The bacterium is usually transmitted by ticks or by contact with an infected animal. Symptoms of tularemia can include high fever, swollen glands, throat infection, diarrhea and vomiting and large, reddish ulcers on the skin.

Understanding how the human immune system reacts to F. tularensis may help scientists to better comprehend how the body reacts to other infectious diseases, such as tuberculosis and the plague. This ultimately could lead to better treatments.

In laboratory experiments, the researchers infected human blood cells called monocytes with live cultures of Francisella novicida, a less-infectious form of Francisella. Monocytes are the "soldiers" at the immune system's frontline - these cells are the first to react when a pathogen enters the body.

The surface of a monocyte is dotted with structures called Toll-like receptors. These receptors function like barcode readers in that they scan for and determine the type of pathogen that has entered the body. The feedback that these receptors give the monocyte tells the cell how to react to the intruder.

Also on the surface of every monocyte is a tiny opening for a "sack" called a phagosome. Resembling a garbage bag, in a healthy immune system, the phagosome consumes disease-causing pathogens, eliminating them.

This study found that for unknown reasons the Toll-like receptors can't completely read Francisella, so the monocyte doesn't immediately launch a full-blown attack against the pathogen. It's only when Francisella breaks through the phagosome's protective lining and enters the inside of the cell that the monocyte launches a complete attack.

It's only there, inside the monocyte, that the cell recognizes Francisella as an intruder and then launches a late assault.

"This study is one of the first to show that certain bacteria trigger an immune response only after the pathogens are inside the monocyte," Wewers said.

That response was characterized by an overwhelming increase of a chemical messenger called interleukin-1 beta (IL-1B). IL-1B tells the rest of the immune system and the body that an invader is present, and increased levels of IL-1B trigger a fever - one of the mechanisms the body uses to rid itself of some pathogens.

IL-1B levels typically increase as the immune system begins to fight an infection, but not to the degree that the researchers saw in this study.

"The response was greater here than with anything we'd ever seen with any other infection-causing stimulus," Wewers said.

Although they haven't yet studied the more pathogenic Francisella tularensis, the researchers suspect that this related bacterium also enters the monocyte by penetrating the lining of the phagosome.

"But tularensis may be able to sneak into the cell and not turn on the alarm that launches the IL-1B attack against the pathogen," Wewers said. "The next step is to find out if that is the case."

The researchers also plan to use Francisella as a tool to further understand how the immune system responds to different pathogens.

Wewers co-authored this study with Ohio State colleagues Mikhail Gavrilin, Imad Bouakl, Nina Knatz, Michelle Duncan, Mark Hall and John Gunn.
The work was supported by the National Institutes of Health's National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Disease.

Contact: Mark Wewers (614) 293-4925;

Written by Holly Wagner, (614) 292-8310;

Ohio State University

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