A research team from University of California, San Diego has demonstrated feasibility of using stabilized version of a streptococcal M surface protein for immunizations against Strep infections:
In the March 7 issue of the journal Science, the researchers describe, for the first time, the detailed structure of the streptococcal M protein, which is critical to the virulence of Group A Streptococcus (GAS). GAS causes a wide variety of human diseases including strep throat, rheumatic fever, and the life-threatening “flesh-eating” syndrome called necrotizing fasciitis. Studies were performed using M1 protein, which represents the version of M protein present on the most common disease-associated GAS strains.
The team also produced a variant of M1 protein that stimulates the immune system in mice, without the serious side effects caused by natural M1 protein. They say that their results should help scientists develop M1 protein-based vaccines against GAS.
“Using X-ray crystallography, we determined that M1 protein has an irregular, unstable structure,” explained Partho Ghosh, a professor of chemistry and biochemistry in UCSD’s Division of Physical Sciences. “We created a modified version of M1 with a more stable structure, and found that it is just as effective at eliciting an immune reaction, but safer than the original version of M1, which has serious drawbacks to its use in a vaccine.”
…“This is a crude analogy, but if you imagine that M1 protein is a zipper, then the front half of the molecule is zipped up,” said McNamara, who is currently a postdoctoral fellow at the Genomics Institute of the Novartis Research Foundation. “However, unfavorable amino acids prevent the molecule from zipping up all the way. It was clear from the literature that mutations of these unfavorable amino acids to favorable amino acids would allow the molecule to continue to zip up.”
Unstable coils provide a protein with the flexibility to perform different functions, according to Ghosh. Proteins with structures similar to the original version of M1 are found in the human body, including in heart muscle. The researchers hoped that modifying the structure of M1 would make it less likely that an M1 vaccine would trigger an autoimmune response against heart muscle.
This indeed turned out to be the case. In tests with antibodies against heart muscle, Madeleine Cunningham, a professor of microbiology and immunology at the University of Oklahoma Health Sciences Center, determined that engineered M1 was much less reactive than natural M1. In addition, Annelies Zinkernagel, a postgraduate researcher in Victor Nizet’s laboratory, discovered that unlike mice injected with natural M1, mice injected with stabilized M1 did not develop lung injuries.
Therefore, the instabilities in M1 are responsible for its toxic properties and tendency to trigger autoimmune reactions.
Press release: Engineered Protein Shows Potential as a Strep Vaccine…
