Turning MRSA’s Weapons On Itself

800px-cdc-10046-mrsaWhat infectious disease causes the most deaths in the United States? Most would probably guess HIV, or after last year’s H1N1 scare, influenza. But the deadliest infectious disease in our country is actually MRSA, the antibiotic-resistant form of Staphylococcus aureus sometimes referred to as a “Superbug.” Nearly one percent of the U.S. population is colonized with MRSA, and infection with the bacteria causes more than 100,000 hospitalizations and nearly 20,000 deaths each year.

What’s worse, MRSA is incredibly hard to treat, as its name suggests. For the last three decades, hospitals have seen more strains of S. aureus resistant to methicillin and similar antibiotics, and some strains have even shown resistance to vancomycin, the current last resort antibiotic. Even when a MRSA infection is successfully cleared, it has a high rate of relapse, as unlike other infections the body does not acquire immunity after the initial attack. A vaccine against the bacteria would thus be a valuable medical tool, a protection to prevent the infection from establishing a foothold.

Two recent papers from the laboratory of Olaf Schneewind, professor and chair of microbiology at the University of Chicago, offer promising strategies for how such a vaccine would work. We talked about Schneewind’s research back in April, when he presented the story of the MRSA vaccine search to the MacLean Center for Clinical Medical Ethics (video here). The new papers demonstrate the first signs of success for those strategies, with protection against the insidious bacteria seen in animal models.

One strategy, published today in the Journal of Experimental Medicine, turns one of MRSA’s most dangerous weapons against itself. Proteins on the cell surface of each MRSA bacterium help trick the cells of the body’s immune system into holding off their attack, and even helping to disperse the bacteria to other organs. Immune cells called B cells typically attach to surface proteins to generate specific antibodies that recruit “killer” T cells to attack the intruding infection. But when those B cells bind a MRSA surface protein called Protein A, a chain reaction leads to B cell death rather than antibody creation.

Schneewind and his colleagues decided to try to turn the tables once more against MRSA by using Protein A as the key component of a vaccine strategy. Critical genes for Protein A’s interaction with B cells were genetically scrambled, creating a non-toxic form of the protein that loses its deadly influence over the immune system. Instead, exposing animals to this neutered Protein A allows the immune system to generate protection against the normal Protein A, such that subsequent infection with MRSA is blunted. Mice injected with the modified Protein A and then later exposed to MRSA strains that cause infections in the US and Japan exhibited fewer bacterial abscesses and reduced mortality compared to control mice.

“I believe that Protein A may be the key to making a staphylococcal vaccine,” Schneewind said.

But the history of MRSA research has been riddled with promising vaccine strategies that have disappointed when tried out in humans. So Schneewind’s group explored a second strategy, published this month in PLoS Pathogens, which used another of MRSA’s weapons against itself. The abscesses that form in organs and tissues of the body during a MRSA infection rely upon proteins called coagulases that clot blood and create a protected sanctuary for the bacteria to reproduce. Blocking coagulase activity, either by deleting the genes or (more relevant clinically) generating antibodies to the proteins, protected mice against MRSA infection. Intriguingly, antibodies created from the coagulases of an entirely separate bacterial species, E. Coli, were also successful in reducing MRSA infection.

With a variety of strategies shown to work in animal models, the next step is testing out the vaccines in humans, either one by one or in combination. But the obstacles for development of a MRSA vaccine may be as much financial as they are scientific, as the clinical trials necessary for approval require the monetary support of pharmaceutical companies. Still, developing a full arsenal for the prevention of MRSA infection offers a glint of hope for a very scary disease that has so far evaded nearly all attempts to thwart it after the fact.

About Rob Mitchum (525 Articles)
Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.
%d bloggers like this: