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Persistent bacterial infection exploits killing machinery of immune cells
November 03, 2008A new study reveals an important and newly discovered pathway used by disease-causing bacteria to evade the host immune system and survive and grow within the very cells meant to destroy them. This discovery may lead to new treatments and vaccines for tuberculosis (TB) and certain other chronic bacterial and parasitic infections.
The research, supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is the work of the laboratories headed by Peter Murray, Ph.D., at St. Jude Children's Research Hospital in Memphis, Tenn., and Thomas Wynn, Ph.D., of the Laboratory of Parasitic Diseases at NIAID. Their findings appear in the November issue of Nature Immunology.
Clearing the body of disease-causing bacteria is the job of specialized white blood cells called macrophages. The word "macrophage" means "big eater" in Latin and that is just what these cells are--they gobble up cell debris, infected cells and disease-causing bacteria found in the body. To help them digest and destroy what they eat, macrophages make compounds that in most cases kill pathogens. One of these chemicals is the free radical nitric oxide (NO).
However, some harmful bacteria, known as intracellular pathogens, live inside cells and can even survive and replicate within macrophages, somehow inhibiting or escaping killing by NO. One natural NO inhibitor made by macrophages is the enzyme arginase. Arginase steals and degrades the material required to make NO, therefore limiting how much NO is made.
"The bacteria designed to live inside the cell are highly adapted to their environment," says Dr. Murray. "We wanted to determine just how intracellular bacteria were turning on the genes that make arginase, thereby controlling the expression of NO and escaping killing by macrophages."
The research team discovered that intracellular pathogens increase levels of arginase, thereby reducing the amount of NO the macrophages produce, enabling intracellular pathogens to survive. The presence of persistent intracellular bacteria is particularly harmful to people with compromised immune systems, such as people with HIV or cancer, who often contract chronic bacterial and parasitic infections.
To test the significance of arginase production induced by the intracellular bacterium that causes TB, Mycobacterium tuberculosis, the researchers generated mice lacking the arginase gene in their macrophages (arginase knockout mice). After infecting the arginase knockout mice with the TB bacteria, they observed that the mice had fewer bacteria and higher levels of NO in their lungs.
The researchers then infected arginase knockout mice with an intracellular parasite that causes toxoplasmosis, a disease that also is controlled by NO. They observed that mice lacking arginase had higher survival rates than mice that produced arginase.
However, when knockout mice were infected with bacteria that are not killed by NO, the lack of arginase did not affect the macrophages' ability to clear the infection.
"Although NO was named 'molecule of the year' in 1992 by Science Magazine and studied as an important part of the immune response to bacterial infections, arginase, its counterbalance, was widely ignored by the immunology community," comments Dr. Wynn. "This work suggests that targeting arginase may be helpful in treating chronic, intracellular bacterial and parasitic infections."
Drs. Murray and Wynn hope to next determine what other parts of the immune system are affected when arginase is blocked.
NIH/National Institute of Allergy and Infectious Diseases
However, some harmful bacteria, known as intracellular pathogens, live inside cells and can even survive and replicate within macrophages, somehow inhibiting or escaping killing by NO. One natural NO inhibitor made by macrophages is the enzyme arginase. Arginase steals and degrades the material required to make NO, therefore limiting how much NO is made.
"The bacteria designed to live inside the cell are highly adapted to their environment," says Dr. Murray. "We wanted to determine just how intracellular bacteria were turning on the genes that make arginase, thereby controlling the expression of NO and escaping killing by macrophages."
The research team discovered that intracellular pathogens increase levels of arginase, thereby reducing the amount of NO the macrophages produce, enabling intracellular pathogens to survive. The presence of persistent intracellular bacteria is particularly harmful to people with compromised immune systems, such as people with HIV or cancer, who often contract chronic bacterial and parasitic infections.
To test the significance of arginase production induced by the intracellular bacterium that causes TB, Mycobacterium tuberculosis, the researchers generated mice lacking the arginase gene in their macrophages (arginase knockout mice). After infecting the arginase knockout mice with the TB bacteria, they observed that the mice had fewer bacteria and higher levels of NO in their lungs.
The researchers then infected arginase knockout mice with an intracellular parasite that causes toxoplasmosis, a disease that also is controlled by NO. They observed that mice lacking arginase had higher survival rates than mice that produced arginase.
However, when knockout mice were infected with bacteria that are not killed by NO, the lack of arginase did not affect the macrophages' ability to clear the infection.
"Although NO was named 'molecule of the year' in 1992 by Science Magazine and studied as an important part of the immune response to bacterial infections, arginase, its counterbalance, was widely ignored by the immunology community," comments Dr. Wynn. "This work suggests that targeting arginase may be helpful in treating chronic, intracellular bacterial and parasitic infections."
Drs. Murray and Wynn hope to next determine what other parts of the immune system are affected when arginase is blocked.
NIH/National Institute of Allergy and Infectious Diseases
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Sperm may play leading role in spreading HIV
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Reactive oxygen in fruit flies acts as a cell signalling mechanism for immune response
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To regenerate muscle, cellular garbage men must become builders
For scientists at the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, what seemed like a disappointing result turned out to be an important discovery.
Pitt study finds molecular link between insulin resistance and inflammation
An exploration of the molecular links between insulin resistance and inflammation may have revealed a novel target for diabetes treatment, say scientists at the John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh of UPMC.
Einstein researchers identify potential target for metastatic cancer
The deadliest part of the cancer process, metastasis, appears to rely on help from macrophages, potent immune system cells that usually defend vigorously against disease, researchers at Albert Einstein College of Medicine of Yeshiva University report.
Scientists open doors to diagnosis of emphysema
Chronic inflammatory lung diseases like chronic bronchitis and emphysema are a major global health problem, and the fourth leading cause of death and disability in developed countries, with smoking accounting for 90% of the risk for developing them.
Researchers capture bacterial infection on film
Whilst most studies of bacterial infection are done after the death of the infected organism, this system developed by scientists at the University of Bath and University of Exeter is the first to follow the progress of infection in real-time with living organisms.
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