Like a faithful, well-trained dog, there’s a breed of bacterium, observed microbiologist James Musser, “that is solely a human pathogen. It’s uniquely adapted to the human species, and has no animal or environmental reservoir. Its name is Streptococcus pyogenes.”
But unlike your classic loyal canine, S. pyogenes is more of a pit bull attack dog. Musser continued: “It causes things like pharyngitis strep throat which everyone has had many times during their life. The pathogen can also inflict a more severe, though rarer, infection called necrotizing fasciitis the so-called flesh-eating syndrome. It also brings on a post-throat condition called rheumatic fever [RF], which often goes on to strike children and young adults with heart disease.
“In 1999,” Musser noted, “rheumatic fever and the heart damage that can follow were responsible for 3,600 deaths in the U.S., which has a high standard of health care and therapy.” But in India, for example, where medical service has lagged behind urbanization and industrialization, 250,000 new cases of RF are diagnosed in school children each year.
“Rheumatic fever in the U.S. has decreased dramatically over the last 40 years,” Musser pointed out. “In fact, at one point RF was generally viewed as essentially eradicated in this country. However,” he recounted, “In the mid-1980s in Salt Lake City for reasons that remain largely unknown there was a dramatic outbreak in rheumatic fever cases largely among children or very young adults. They had well over 100 patients in a one-and-a-half-year period.
“Then in the late 1990s 97, 98 and ’99 Salt Lake City had a second epidemic that affected another 100 people,” Musser continued. “Over the last 15 years, that Utah city has had more than 500 people largely children infected by this strep microorganism carrying rheumatic-fever disease.”
Musser is chief of the Laboratory of Human Bacterial Pathogenesis at the Rocky Mountain Laboratories in Hamilton, Montana. It is a branch of NIAID the National Institute of Allergy and Infectious Diseases. He is senior author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated April 2, 2002. Musser’s article is titled: “Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks.”
“One of our critical findings,” Musser told BioWorld Today, “is that we have now solved the complete genome sequence of Streptococcus pyogenes, a microoorganism that is the commonest cause of preventable pediatric heart disease globally. We’ve shown through this analysis that the pathogen contains a variety of novel toxins, and that epidemics caused by this streptococcal organism represent recycling of the same M18 strain, rather than reintroduction of new strains.”
Finally, Prospect For A Vaccine
“We’ve shown as well,” Musser continued, “that the major mediator for strain-to-strain variation in this pathogen are phage or bacterial virus-related genes. No vaccine is available against group A strep, especially its S. pyogenes strains that cause rheumatic fever. These findings will permit us to move forward rapidly with vaccine-related research.”
He continued: “S. pyogenes attacks human targets largely through a combination of proteins that it expresses on the outer surface of the microbial cell. There are roughly 100 of these actively secreted proteins that form the armamentarium of the group A Streptococcus. They include potent exotoxins molecules that can inactivate components of the host human immune system. Their multiprong strategy revolves around this ability to express many extracellular proteins. The bacterium,” he noted, “is transmitted from person to person, usually by aerosol droplets, or touching contagious materials.
“Phages turn out to be quite an interesting story,” Musser allowed. “In the strain that we sequenced there are five different of these bacterial parasite viruses. Each of these contains potent toxins. Those phages are responsible for getting new toxin genes into new strains of group A strep, and moving those genes around in natural carrier populations. The phages insert their genes into the bacterial chromosome, and therefore, whenever the bacterium is transmitted from person to person, phage genes, which include toxin genes, are transmitted, too.”
S. pyogenes tracks a linear trajectory from transient strep throat pharyngitis to rheumatic fever to often pediatric rheumatic heart disease. In this cardiac condition, the heart valves are damaged by not-so-innocuous RF, following that initial pharyngitis. A damaged valve doesn’t fully open or fully close. This may eventuate in congestive heart failure, in which the organ enlarges, and can’t pump out all its blood. Its usual onset occurs in children between 4 or 5 years old and the mid-teens. Their resulting heart disease can last for life.
Not Just Cardiology; Neurology Too
“Treating strep throat with penicillin, rather than ignoring it, is considered the best way to prevent those later cardiac complications,” Musser observed. “But S. pyogenes does not spare the nervous system. Primary symptoms of RF largely involve heart problems, but there can also be unusual choreaform movements, the molecular basis of which are unknown. These neurological contortions are thought due to human antibodies that cross-react with brain tissue.” This Sydenham chorea syndrome, as it’s called, may appear several months after a bout of RF. It features rapid, purposeless, nonrepetitive, involuntary bodily movements, facial grimaces and flailing limbs. These may last for months before gradually petering out.
“Everything that we do in my lab,” Musser pointed out, “has a high-throughput capability much like what most people find in biotech for sequencing, for proteomics, for liquid-handling robots. In many regards we make a small pharma situation here.
“One of the strategies against S. pyogenes that we’re pursuing in our laboratory,” Musser said, “is vaccine-related research. The group A strep makes its living,” he explained, “by expressing its extracellular proteins. We’re focusing on high-throughput characterization cloning, over-expression and purification of these potentially immunogenic proteins in mice and nonhuman macaque monkeys. We’re moving along quite rapidly, but vaccine-related research is a very slow process. It will be many years,” Musser concluded, “until any of the candidate vaccines that we’re interested in get into humans.”