"Strep throat" is a painful but transient inflammation of the pharynx - the site in the throat where gullet and windpipe join. Pharyngitis, as it's known to physicians, is caused by Streptococcus pyogenes, a busy-body bacterium that doesn't stop at the throat.
Its lengthy rap sheet of graver infectious diseases runs from impetigo, scarlet fever, erysipelas, rheumatic fever, glomerular nephritis, endocarditis and streptococcal toxic shock syndrome (STSS) to necrotizing fasciitis (NF) - the so-called "flesh-eating syndrome." Like the AIDS virus, S. pyogenes marshals potent outer-surface molecules to disarm vital parts of the human immune system. It hospitalizes 200,000 Americans annually and kills one in three of them.
Since the early 1980s, the re-emergence of streptococcal toxic shock and necrotizing fasciitis has been reported in several countries, including the U.S., Canada, Northern Europe, New Zealand and Australia. STSS and NF are rapidly progressive invasive infections with high mortality rates ranging from 30 percent to 80 percent despite prompt antibiotic therapy.
Why is it that the selfsame S. pyogenes can cause the mild illness of strep throat in one person, and life-threatening toxic shock syndrome in another? Immunologist Malak Kotb and members of her research lab at the University of Tennessee in Memphis tackled this long-standing puzzle - wrestled over by scientists and researchers for years - and came up with persuasive published answers.
Kotb, a tenured professor at the University of Tennessee, is one of two co-senior authors of a paper in Nature Medicine, released online Nov. 18, 2002. Its title: "An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections." Her co-senior author is an infectious disease physician and microbiologist Donald Low, at the University of Toronto.
The two teams analyzed the HLA-class II genes from 279 Canadian patients afflicted with severe invasive strep infections - toxic shock syndrome, necrotizing fasciitis or mild bacteremia - and compared them to the HLA-II genes of 256 healthy individuals. HLA, the human leukocyte antigen, is the major histocompatibility complex, which resides on the short arm of chromosome 6 and helps present chopped-up target antigens for removal.
"I think the overall finding of our paper," Kotb told BioWorld Today, "is that the host patient plays a very important role in deciding the outcome of an invasive streptococcal infection. He or she is not an innocent bystander, but actually interacts with the pathogen, and the host genetic factors, which can influence the course and climax of the disease. Our study," Kotb continued, "is the first to show an association between those genes and toxic shock. We revealed the underlying mechanism involved by showing that the variation in those molecules results in different levels of inflammatory cytokine response in the infected patient. The protective genes elicit a mild, attenuated response, while those who harbor the high-risk genes mount a very potent reaction that can go uncontrolled in the patient. And this is what causes the organ failure and toxic shock."
Enter Strep Superantigens - Grimly
"It opens a whole new area for novel therapeutics and vaccines," she observed. "Together with Don Low in Canada, we proposed a new therapeutic strategy for toxic shock. He gave their patients intravenous inoculations of immunoglobulin. It's possible to use our joint data for making decisions on therapies because - based on our previous findings - we reported that the bacteria produce superantigens, which are definitely major players in toxic shock and other strep infections. Now we're trying to interfere with the binding of those superantigens to the inherited genetic elements."
Superantigens are a unique group of substances that are among the most potent T-cell mitogens (cell division promoters) known. They are core elements in streptococcal offense mechanisms against human defense mechanisms. "The superantigens," Kotb pointed out, "are proven causes of strep and staph toxic shock.
"The variant response between patients," she noted, "is the essential functional data in our paper. Beyond a protective or high-risk genotype, we took a step further and explained the mechanism. The same superantigens are presented to the very same T-cells by the protective HLA class II type, which are receptors for the superantigens, presenting them to the T-cell receptors, but that peptide presentation is much less restrictive than normal antigens. Normal antigens stimulate one in 10,000 or one in 1 million T cells. The superantigens, because of their different presentation, can trigger a mere 20 percent to 30 percent of the resting T cells."
Loose-Cannon Cytokines Loose Toxic Shock
"It's our hypothesis that an elevated cytokine response causes toxic shock. So what we showed was that if the superantigen presentation was done by protective haplotypes - genes inherited together from maternal and paternal parents - the response is attenuated. It's lower in terms of the cytokines. But if the same superantigen is presented by the high-risk haplotype to the same T cell, the response is significantly higher. The class II HLA types are acting like thermostats: High risk dials you up; protective response dials you down. If responses and cytokines are high, the host becomes its own pathogen, causing multiple organ failure and toxic shock.
"When Toronto sent us the blood from their patient samples," Kotb recounted, "we isolated the DNA, and started genotyping those patients. We focused on chromosome 6 because its loci have a lot of genes involved in regulating the immune response. So we typed for variability in those genes. They are the HLA II genes that encode proteins on the surface of immune cells, and present the superantigens to the immune system. So if we all presented antigens the same way, the human species would be wiped out. There has to be variability in those antigens to ensure that some of us will respond and others may not. Our response to pathogens is different. And this study shows where it is different, and why.
"Our genetic data also showed," Kotb added, "what clinicians have suspected for years - that NF, the flesh-eating syndrome, is a different disease from toxic shock. A deeper understanding of these differences should lead to a better understanding of the disease mechanism," she concluded, "and may lead to more effective and specific therapeutic modalities."