Research Reveals How Strep Bacterium Evades Immune System

Like a well-trained soldier with honed survival skills, the common bacterium, Group A Streptococcus (GAS), sometimes can endure battle with our inborn (innate) immune system and cause widespread disease. By investigating the ability of combat-ready white blood cells (WBCs) to ingest and kill GAS, researchers have discovered new insights into how this disease-causing bacteria can evade destruction by the immune system. The research is being published in the online edition of the Proceedings of the National Academy of Sciences, USA at http://www.pnas.org/papbyrecent.shtml/.

Frank DeLeo, Ph.D., tenure-track investigator in the Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases (NIAID), Rocky Mountain Laboratories in Hamilton, Mont., directed the study.

"This is the first genome-scale look at GAS genes that are differentially expressed during interaction with the human innate immune system," he says. "We are excited about our findings and how they may lead to further investigation of therapeutics that can protect us from this major human pathogen." According to DeLeo, this type of study is

the next logical application of microbial genomics.

An estimated 15 million new cases of noninvasive GAS infections occur in the United States each year, with a direct healthcare cost of $2 billion. The noninvasive and milder types of infection, primarily strep throat and skin infections, occur mostly in children between the ages of 5 and 14 years old. Elementary school-aged children are at highest risk for noninvasive disease. In 2000, the reported incidence of the more serious invasive GAS disease, which includes streptococcal toxic shock syndrome (STSS),

cellulitis, pneumonia, bacteremia and necrotizing fasciitis (flesh-eating disease), was 8,800 cases and 1,000 deaths. The elderly, immunosuppressed, persons with chronic cardiac or respiratory disease or diabetes, African Americans, American Indians and persons with skin lesions (for example, children with chickenpox and intravenous drug users) have increased risk for GAS invasive disease.

Some GAS infections may be asymptomatic, and if untreated, can lead to life-threatening infections. With an early diagnosis, however, noninvasive GAS can be successfully

treated with antibiotics. On the other hand, it is much more difficult to treat invasive GAS disease, and these infections are associated with high morbidity and mortality.

By examining the interaction between disease-fighting human WBCs and a type of GAS that causes abundant disease in North America and Western Europe, the NIAID scientists have discovered how GAS elicits its own genome-wide protective response to evade destruction by the human immune system. The two opponents, WBCs and GAS, met face to face in experiments conducted by DeLeo, James Musser, MD, PhD, chief of the Laboratory of Human Bacterial Pathogenesis, and their colleagues.

For their study, the researchers used human WBCs called polymorphonuclear leukocytes (PMNs), an essential component of the immune system's defense against foreign invaders. These microbe-eating cells are in a class of cells termed phagocytes, which stand ready to seek and destroy foreign substances such as bacteria. During battle with most foreign microbes, PMNs successfully "eat" invading predators, a scientific process called phagocytosis. After microbes are engulfed, PMNs produce deadly oxygen radicals, such as hydrogen peroxide and hypoclorous acid (the active ingredient in household bleach), and release toxic granules to kill the enemy. Normally, this defense tactic can defeat most foreign invaders, but it is ineffective against highly evolved GAS bacterium.

The scientists examined how PMNs from healthy individuals ingest and kill GAS and tested their hypothesis that GAS revs up or slows down the production of specific factors to evade the innate immune system. The study indicates that GAS becomes more resilient to ingestion and killing by PMNs over time or it produces factors that alter normal PMN function. This resiliency is demonstrated by the increased expression of various GAS genes associated with the bacteria's virulence and cell wall repair as well as genes that encode proteins likely to promote immune evasion.

The study's lead author, Jovanka Voyich, PhD, states, "Our study identifies potential vaccine candidates and new targets for therapy interventions designed to control GAS infections."

The scientists hope that this new knowledge in combination with their earlier GAS research will lead to further investigation of how GAS evades destruction by our innate immune system and will inevitably spur the discovery of vaccine therapies and antibiotics that can prevent and treat invasive and noninvasive strains of this bacterium.

NIAID is a component of the National Institutes of Health (NIH), 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.