UC San Diego team unearths sequence of M protein

As of now, there is no current vaccine against the M protein, a surface protein of a bacteria cluster called Group A Streptococcus (group A strep). The M protein inhibits the body’s immunity toward this group of bacteria, enabling it to cause detrimental effects on humans. However, a group of researchers headed by Partho Ghosh, chair of University of California San Diego’s (UCSD) Department of Chemistry and Biochemistry, has recently been able to unearth unknown sequence patterns of the M protein.

In doing so, Ghosh’s team has the discovery of a vaccine against group A strep made possible. The most difficult part of countering the bacteria, according to Ghosh, was it’s overwhelming versatility.

Bacteria of group A strep arise in a vast number of strains, each of which holds claim to a different surface protein. Because of this variability, our immune system is not able to recognize each of these distinct proteins. It cannot launch the customary immune response of antibodies to the bacteria.

The issue with our body’s natural immune response to different strains of group A strep begins when our systems launch a response against a particular M protein on the surface of a particular strain. The response works against the specific strain infecting our body but leaves us helpless against other forms of bacteria from the group, which have unique M proteins of their own. The immune system’s response is specific to the surface M protein of the infecting bacteria and simply does not work against other strains.

The key, which the UCSD team was able to discover, was in recognizing that a previously discovered human protein, C4b-binding protein (C4BP), was being utilized by the group A strep bacteria. C4BP binds to approximately 90 percent of the M proteins on group A strep strains. The bacteria use the human protein to hinder our body’s immune attack.

This proved to be a two-part problem for Ghosh’s team. They needed to block the use of C4BP by the M proteins of the bacteria group, while still utilizing C4BP’s broad interaction with group A Strep. To do so, two graduate students at the university, Cosmo Buffalo and Rommie Amaro, collaborated to study the synergy between the M protein and C4BP.

The two graduate students, along with an undergraduate researcher, Adrian Bahn-Suh, and a professor at UCSD’s School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, Victor Nizet, were able to map four crystal structures of four unique strains of the M protein. Their combination of experimental and computational research proved profitable. They were able to locate the few and hidden common sequence patterns among the four different M proteins.

Cross-analysis of these four strains of M proteins from group A strep that enlist our own C4BP protein for their benefit shed light on which sequences allow for this detrimental effect. This is incredibly important in finding a vaccine for the group of infecting bacteria. The plan is to have antibodies operate the same way as C4BP.

If future research can enable the immune to target the common strains within the unique M protein types, the immune counterattack to the bacteria will not be limited to just one type of M protein. It will have the broad binding effect that C4BP exhibits and extend the defense to the majority of bacteria from group A strep.

The biochemists from UCSD and Nizet are currently in the process of developing the vaccine that uses the C4BP properties by applying them to our antibodies. In doing so, they hope create a vaccine that is effective against most, if not all, forms of the M protein in group A strep bacteria.