Biochemists have uncovered patterns in the outer protein coat of group A Streptococcus that could finally lead to a vaccine against diseases such as necrotizing fasciitis. [CDC]
Few things will conjure up innate fears more than tiny drug-resistant microorganisms steadily feasting on human tissue, with amputation often being the only recourse for survival. The bacteria that cause necrotizing fasciitis, or “flesh-eating disease”—group A Streptococcus (group A Strep)—is highly infectious and leads to more than 500,000 deaths per year.
Now, researchers at the University of California San Diego (UCSD) have uncovered patterns in the outer protein coat of the bacteria that could finally lead to a vaccine against the highly pathogenic strain. In their newly published findings, the researchers describe finding “hidden sequence patterns in the major surface protein and virulence factor” of group A Strep, called the M protein, which limits the body's immune response against these bacteria.
“At present, there is no vaccine against group A Strep, and our discovery of hidden sequence patterns has offered up a novel way to devise such a vaccine,” noted lead study investigator Partho Ghosh, Ph.D., professor, and chair of UC San Diego's Department of Chemistry and Biochemistry.
One of the major hurdles in developing a vaccine against these bacteria is the hypervariability of the M protein. Group A Streptococcus bacteria have a multitude of different strains, each of which displays a different protein on its surface. Because our immune systems must recognize these different proteins before launching an immune response with antibodies unique to the outer protein coat, the hypervariability of the M proteins makes it difficult for our immune systems to attach antibodies specific to each these proteins from different strains.
“When we become infected with a particular strain of group A Strep, we generally mount an immune response against the particular M protein displayed by that strain,” explained Dr. Ghosh. “But this immunity works only against the infecting strain. We remain vulnerable to infection by other group A Strep strains that display other types of M proteins on their surfaces. This is because the antibody response against the M protein is almost always specific to the sequence of that M protein, and M proteins of different types appear to be unrelated in sequence to one another.”
The UCSD team found that a previously identified human protein called C4BP was recruited to the surface of Group A Strep by many different protein types and was the key to resolving the hypervariability issue.
The findings from this study were published recently in Nature Microbiology in an article entitled “Conserved Patterns Hidden within Group A Streptococcus M Protein Hypervariability Recognize Human C4b-Binding Protein.”
“This was a puzzle, because the antibody response is specific and limited to a single M protein type, while C4BP binds a broad variety of M protein types, perhaps up to 90% of them,” Dr. Ghosh remarked. “Group A Strep brings C4BP to its surface to dampen the immune response. We wanted to combat this recruitment by blocking the interaction between M proteins and C4BP, but equally as important, we wanted to take advantage of the broad recruitment of C4BP by M proteins that would pave a path to the development of a vaccine.”
To confirm whether their approach was conceivable, Dr. Ghosh’s group collaborated with another laboratory that utilized computers to study protein structures—to initially look at the complex interactions between M protein and C4BP. “This allowed us to understand some detailed features of the interaction,” Dr. Ghosh stated.
In their experimental and computational study, the scientists meticulously detailed four crystal structures of four different M protein types, each bound to human C4BP.
“These structures revealed that even though the different M protein types appeared to be unrelated in sequence, there were common sequence patterns hidden within the differences that linked all these M proteins together,” said Dr. Ghosh. “These common patterns are what is used to recruit C4BP to the surface of group A Strep by the different M protein types.”
Dr. Gosh concluded by stating that “the idea now is to have antibodies do the same thing as C4BP—that is, recognize many different M protein types. That way, the antibody response will not be limited to one M protein type and one strain of group A Strep, but will extend to most, if not all, M protein types and most, if not all strains, of group A Strep.”
The research groups are currently working on developing a vaccine that, they hope, will be protective against most, if not all, strains of group A Strep.