Key to Protection Against Deadly Bacteria Discovered by Jefferson Scientists
The Achilles’ heel of deadly bacteria classified as a biological weapons agent, which causes Tularemia (also known as rabbit fever) has been discovered by researchers in the Department of Biochemistry and Molecular Biology at
Thomas Jefferson University and the
Kimmel Cancer Center at Jefferson.
In their study, reported in the March 28 online edition of Nature Immunology, the scientists say they pinpointed a single molecule named AIM2 that can sense the bacteria and mount an effective immune response that alerts the body to the presence of these bacteria. AIM2, which is found within specialized immune cells called macrophages in humans and mice, also kills the infected macrophages to limit the spread of infection to other tissues of the body.
The findings may provide insight into how to develop a clinical strategy to protect humans against the bacteria, known as Francisella tularensis.
“By now knowing that AIM2 can sense the bacteria and ratchet up an immune response, we can think about ways to activate that key receptor in humans,” says the study’s lead investigator, Emad Alnemri, PhD, a Thomas Eakins endowed professor in the Department of Biochemistry and Molecular Biology at Jefferson Medical College of Thomas Jefferson University.
Francisella tularensis infects small mammals as well as humans that come in contact with the infected animals. Because of its extreme virulence, low infectious dose, ease of aerosol dissemination, and capacity to cause severe illness and death, the U.S. has declared the bacteria as a class A bioweapon. The World Health Organization (WHO) has estimated that 50 kilograms of the bacteria sprayed in aerosol form over a city of 5 million inhabitants would result in 250,000 incapacitating casualties and 19,000 fatalities.
In early 2009, the same Jefferson researchers reported in Nature that they had discovered that AIM2 (absent in melanoma 2) is involved in detection and reaction to cytosolic DNA produced by viral or bacterial infection. AIM2 is a specialized receptor that floats freely inside macrophages, the white blood cells that gobble up viruses, bacteria, and other “foreign” bodies it encounters in the blood stream or sites of infection, and then displays bits of them to other immune cells. They are part of the innate immune system – the body’s first response to such invaders. Dozens of molecular sensors, each reacting to a different trigger, are found within macrophages.
At the time, Dr. Alnemri and his team showed that once AIM2 sensed foreign DNA inside the macrophages, it formed a complex known as an inflammasome that induced a large-scale immune response. But they didn’t know what, specifically, AIM2 was reacting to – whether it was bacteria and viral DNA in general, or a specific strain of pathogen.
This study provides an answer. The researchers generated mice that are missing AIM2 and found that the mice could no longer mount an immune response to some selected pathogens. Among them was a modified version of rabbit fever bacteria designed for laboratory use. Mice missing AIM2 that were infected with the bacteria all died within 72 hours, but 60 percent of control normal mice survived the infection.
“Somehow, Francisella tularensis does not activate any other inflammasome except AIM2, and when activated, it provides protection against a systemic infection with this bacteria,” Dr. Alnemri says.
The researchers further found that priming macrophages of control mice with interferon enhanced and accelerated their response against Francisella tularensis. Interferon helps immune cells communicate with each other and mount a strong pro-inflammatory response.
Dr. Alnemri suggests that humans are more susceptible to rabbit fever infection because the bacterial strain that infects humans developed a way to avoid or delay detection by AIM2. “Given that, there may be a number of ways to outsmart the bacteria,” he says. “We can try to see if interferon helps, or it might be possible to develop a vaccine that can deliver antigens that allow early detection of the bacteria.”
The researchers are continuing their work to see what other pathogens AIM2 is capable of sensing, and whether it is also involved in non-infectious nucleic-acid dependent autoimmune diseases such as lupus erythematosus.
The study was funded by grants from the National Institutes of Health. The authors declare no competing financial interests.
Media Only Contact:
Jackie Kozloski
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 3/28/2010