Persistent bacterial infection exploits killing machinery of immune cells

November 02, 2008

A 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.
-end-
Reference: KC El Kasmi et al. Toll like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nature Immunology. DOI: 10.1038/ni.1671.

NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH)--The Nation's Medical Research Agency--includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

NIH/National Institute of Allergy and Infectious Diseases

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.