Subversive Strep Bug Strategy Revealed

"The ability of this very common bug, which causes strep throat and other infections, to modulate the gene activity of an immune system cell is remarkable and has never before been seen on this scale," says Frank R. DeLeo, Ph.D., a researcher at NIAID's Rocky Mountain Laboratories (RML) in Hamilton, MT. The findings are scheduled to be published in Proceedings of the National Academy of Sciences, USA this week.

Insight into streptococcal infection is one product of a comprehensive picture of immune cell–bacteria interactions developed by the RML scientists. Using microarray technology, Dr. DeLeo and his colleagues created a "snapshot" of how all the genes in a type of white blood cell, called a neutrophil, react following exposure to a variety of bacteria.

"This is work of seminal importance," says NIAID Director Anthony S. Fauci, M.D. "By demonstrating that neutrophils respond with altered gene expression to bacterial invasion, the investigators have exposed dozens of possible targets for drug therapies. These findings are likely to be broadly applicable to many types of microorganisms that cause disease in humans, and could lead to new treatments that augment the immune response against multiple pathogens," he adds.

Neutrophils are the most abundant type of white blood cell and a central player in the body's innate immune system. Like a S.W.A.T. team, neutrophils swarm to the site of infection in the first few minutes after a bacterial attack. Quickly they engulf the invading organisms and destroy them.

Neutrophils are genetically programmed to shut themselves down after they engulf and kill microbes. Because of this controlled shutdown, cellular debris is cleared away from the site of the infection, and any inflammation subsides. Ordinarily, neutrophils are highly effective at their job. Indeed, notes Dr. DeLeo, the vast majority of infectious organisms never make it past this first line of defense.

The broad outlines of neutrophil action were known previously, Dr. DeLeo says, but details have been scarce because the cells are difficult to study. For example, scientists believed that the fate of a neutrophil was set during its maturation, well before any encounter with a disease organism.

The NIAID scientists examined the struggle between bug and blood cell as it played out at the gene level. First, they mixed neutrophils extracted from the blood of healthy volunteers with bacteria derived from clinical cases of such diverse conditions as pharyngitis, tick-borne relapsing fever, cellulitis, pneumonia and meningitis. Neutrophils engulfed most kinds of bacteria rapidly, between 10 and 60 minutes after encountering them. Three to six hours later, microarray analysis revealed that neutrophil genes involved in recruiting other immune system cells to the site of infection were active, as were genes required for controlled self-destruction. The degree of genetic activity by neutrophils surprised the researchers, Dr. DeLeo says. Far from being mere passive receptacles for microorganisms, neutrophils exhibit considerable genetic complexity and reactivity, the investigators discovered.

The greatest surprise in the study came when the researchers examined S. pyogenes. S. pyogenes stimulated almost 400 neutrophil genes that had not been activated by the other kinds of bacteria. Furthermore, activation occurred much sooner following engulfment. Most significantly, the bacterium caused neutrophils to self-destruct in an uncontrolled fashion. Essentially, explains Dr. DeLeo, S. pyogenes prevents the neutrophil from either recruiting help or completing an orderly shutdown sequence.

"Dr. DeLeo and his co-investigators have gained an important new insight into how S. pyogenes creates conditions favoring its survival," says Thomas Kindt, Ph.D., director of NIAID's Division of Intramural Research. "Knowing how this extremely common bug evades our immune defenses opens exciting new avenues for research into ways to hamper this evasive maneuver."

NIAID is a component of the National Institutes of Health (NIH), which is an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

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Reference: S D Kobayashi et al. Bacterial pathogens modulate an apoptosis differentiation program in human neutrophils. Proceedings of the National Academy of Sciences. DOI: 10.1073.pnas.1833375100.

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