Researchers found the novel bacterium--which they named Granulobacter bethesdensis in recognition of Bethesda, Md., the location of NIH headquarters--in the inflamed lymph nodes of a patient with CGD. The bacterium is part of the Acetobacteraceae family that includes several types of bacteria prevalent in the environment and used industrially to produce vinegar. This is the first time, however, that any member of that bacterial family has been known to cause invasive human disease. Moreover, it represents yet another infection concern for people with CGD, and possibly other individuals as well.
"The discovery of new bacteria is not uncommon, but discovering an organism that causes human illness is certainly unique and warrants further research," says NIH Director Elias A. Zerhouni, M.D.
"This finding is an important discovery both in understanding new human pathogens and in revealing a new source of illness in a patient population particularly vulnerable to bacterial infections," notes NIAID Director Anthony S. Fauci, M.D.
CGD, which affects one in 250,000 people worldwide, is one of 80 inherited immune disorders known collectively as primary immune deficiencies. The disease is caused by a genetic defect in an enzyme called phagocyte NADPH oxidase. Certain white blood cells called neutrophils use this enzyme to generate hydrogen peroxide that the cells need to kill bacteria and fungi. Because people with CGD cannot effectively fight off bacterial and fungal invaders, these individuals are at greater risk of developing serious infections of the skin, lungs, lymph nodes and bones. People with CGD also are prone to developing obstructions in the digestive and urinary tracts caused by swollen areas of inflamed tissues known as granulomas.
In July 2003, a 39-year old man with CGD was referred to NIH after experiencing three months of unexplainable fever, chills, fatigue, night sweats and a 10-pound weight loss. Doctors first gave him two different antibiotics, which did not alleviate his symptoms. Two months later, he developed a painful swelling of the lymph nodes at the base of his neck. Because the infection did not respond to the antimicrobial medications and because there was no clear diagnosis for his symptoms, the doctors removed several lymph nodes for examination. The lymph nodes revealed extensive infection. Tests performed on three of the lymph nodes confirmed a bacterial presence.
Using genetic sequencing, the researchers eventually determined that the bacteria most closely resembled a member of the Acetobacteraceae family. Other tests revealed that the patient's immune system responded to the organism, indicating that it had been exposed to and hence recognized the bacterium, and confirmed that the newly discovered bacterium was indeed a pathogen.
To determine whether the bacterium specifically caused infection in connection with CGD, the researchers inoculated healthy mice and mice genetically altered to carry CGD with various amounts of the newly identified bacterium. Lymph nodes recovered from the CGD mice revealed a similar condition to those of the CGD patient. The lymph nodes of the disease-free mice appeared normal. Spleens recovered from both types of mice showed evidence of the new bacterium but in much greater amounts in the CGD mice. Genetic sequencing confirmed that the bacterium found in the mice was identical to the organism isolated from the patient. The bacterium was not fatal in the CGD patient nor the infected mice.
Since the initial acceptance of this study for publication, NIAID researchers have isolated Granulobacter bethesdensis bacteria from two additional patients with CGD who were experiencing clinical symptoms similar to those of the initial CGD patient.
"Until recently, about 50 percent of infections in people with CGD could not be diagnosed. Some of these patients were treated empirically with surgery and broad spectrum drugs. Other infections were never successfully treated," says Steven M. Holland, M.D., chief of NIAID's Laboratory of Clinical Infectious Diseases. "This newly identified organism could help us identify the source of those infections and allow for the development of targeted and curative therapies."
According to the study's lead author David E. Greenberg, M.D., a clinical fellow in NIAID's Laboratory of Clinical Infectious Diseases, further studies will be needed to
- Compare the immune response to the new bacterium in healthy people and in those with CGD
- Determine how the bacterium causes infection in people with CGD
- Explore the bacterium's importance, if any, for the population at large
"The fact that the CGD mice survived the infection raises the question, What is the critical component of the host's immune defense, and which patients other than those with CGD are most vulnerable to this newly discovered microbe?" Dr. Holland adds. "I suspect the bacterium has been around as long as we have and that we'll find it has been busier than we knew in terms of disease activity over the years."
Researchers from the NIH Clinical Center and the National Cancer Institute, additional components of NIH, also contributed to the research.
NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.
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.
Reference: DE Greenberg et al. A novel bacterium associated with lymphadenitis in a patient with chronic granulomatous disease. PLoS Pathogens DOI: 10.1371/journal.ppat.0020028 (2006).
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.