May 6, 2005 New research on a bacterium that can survive encounters with specific immune system cells has strengthened scientists' belief that these plentiful white blood cells, known as neutrophils, dictate whether our immune system will permit or prevent bacterial infections. A paper describing the research was released today online in The Journal of Immunology. Frank R. DeLeo, Ph.D., of Rocky Mountain Laboratories (RML), part of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, directed the work at RML, in Hamilton, MT, in collaboration with lead author Dori L. Borjesson, D.V.M., Ph.D., of the University of Minnesota in St. Paul.
Scientists analyzed how neutrophils from healthy blood donors respond to Anaplasma phagocytophilum, a tick-borne bacterium that causes granulocytic anaplasmosis in people, dogs, horses and cows. A. phagocytophilum is carried by the same tick that transmits Lyme disease and was first identified in humans in 1996. Human granulocytic anaplasmosis (HGA) -- formerly called human granulocytic ehrlichiosis -- is prevalent in Minnesota and along the East Coast. HGA typically causes mild symptoms that include fever, muscle aches and nausea. Some 362 U.S. cases were reported to the Centers for Disease Control and Prevention in 2003.
HGA is considered an emerging infectious disease, and Dr. Borjesson is working to understand how it affects blood cells -- and neutrophils in particular. "Few people know about this pathogen, but it is important because it is transmitted by ticks and causes disease in both animals and humans," Dr. Borjesson says.
Neutrophils, which make up about 60 percent of all white blood cells, are the largest cellular component of the human immune system -- billions exist inside each human. Typically, neutrophils ingest and then kill harmful bacteria by producing molecules that are toxic to cells, including a bleach-like substance called hypochlorous acid. Once the bacteria are killed, the involved neutrophils self-destruct in a process known as apoptosis. Recent evidence suggests that this process is vital to resolving human infections.
A. phagocytophilum is unusual in that it can delay apoptosis in human neutrophils, which presumably allows some of the bacteria to replicate and cause infection.
"This particular bacterium specifically seeks out neutrophils -- possibly the most lethal of all host defense cells -- and remarkably, can alter their function, multiply within them and thereby cause infection," says NIAID Director Anthony S. Fauci, M.D.
Dr. DeLeo says the findings contrast with what is known about other bacterial pathogens, most notably Staphylococcus aureus, which is of great interest because of its increasing resistance to antibiotic treatment. S. aureus, often simply referred to as "staph," are bacteria commonly found on the skin and in the noses of healthy people. Occasionally, staph can cause infection; most are minor, such as pimples, boils and other skin conditions. However, staph bacteria can also cause serious and sometimes fatal infections, such as bloodstream infections, surgical wound infections and pneumonia.
In their experiments, the research team compared the neutrophil response to A. phagocytophilum with that of a weak strain of S. aureus. Using microarray technology that allowed them to compare about 14,000 different human genes, the researchers discovered how the response to A. phagocytophilum deviates from that of S. aureus, and thus permits the HGA agent to survive.
"This study has given us a global model of how bacteria can inhibit neutrophil apoptosis," says Dr. DeLeo. "Our next step is to look at specific human genes or gene pathways within this model and try to determine which of these molecules help prolong cell life following infection." Information gathered from these and similar studies, he adds, could help researchers develop therapeutics to treat or prevent bacterial infections.
Other RML collaborators included Jovanka Voyich, Ph.D., and Scott Kobayashi, Ph.D., now an assistant professor at the University of Idaho.
RML is part of the National Institutes of Health (NIH). NIH is an agency of the U.S. Department of Health and Human Services. 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 transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
Reference: D Borjesson et al. Insights into pathogen immune evasion mechanisms: Anaplasma phagocytophilum fails to induce an apoptosis differentiation program in human neutrophils. The Journal of Immunology 174(10):6364-72 (2005).
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