Bacterial superbugs such as methicillin-resistant Staphylococcus aureus (MRSA) are now endemic in many U.S. hospitals, posing a serious public health threat and a global priority for disease control.
Scientists at the Johns Hopkins University School of Medicine have accidentally discovered that blanket inhibition of all caspases is a promising immunotherapy that targets the host’s immune system against MRSA and other bacterial skin infections. Caspases are a class of enzymes that mediate programmed cell death that removes worn-out and damaged cells in the body.
The study published in the Science Translational Medicine article, “Pan-caspase inhibition as a potential host-directed immunotherapy against MRSA and other bacterial skin infections” is funded by the National Institutes of Health (NIH) and is the basis of a patent application.
“It was an accidental finding by Alexander Fleming that led to the golden age of antibiotics, but now that’s nearing the end because of antibiotic-resistant bacteria,” says Lloyd Miller, MD, PhD, former professor of dermatology, infectious diseases and orthopedic surgery at the Johns Hopkins University School of Medicine, and now with Janssen Research and Development, and senior author on the study. “It seems fitting that another surprise in the lab could be the start of a second golden age, the use of host-directed immunotherapy.”
The original focus of the research team was to study the mechanisms behind MRSA skin infections in mouse models incapable of synthesizing interleukin-1 beta (IL-1β), says Miller. IL-1β enhances immunity by helping immune cells such as neutrophils, monocytes and macrophages fight bacterial infections. Inactive IL-1β is activated by caspases.
“We gave the mice a blocker of all caspases [pancaspase inhibitor], a compound known as Q-VD-OPH, thinking it would leave both sets of mice [with and without IL-1β] more vulnerable to MRSA infection,” Miller says. “To our surprise, blocking caspases had the opposite effect, resulting in a rapid and remarkable clearing of the MRSA bacteria by keeping the immune cells alive and boosting their protective function.”
To confirm that this fortuitous finding was not a fluke but a viable means to suppress fatal MRSA infections, Miller and his colleagues performed other experiments with encouraging results.
“A single oral dose of Q-VD-OPH decreased the size of MRSA skin lesions and rapidly cleared the bacteria compared with vehicle-treated [given the carrier solution without Q-VD-OPH] and untreated mice,” says Martin Alphonse, PhD, dermatology postdoctoral fellow at the Johns Hopkins University School of Medicine and first author on the paper. “And surprisingly, the treatment worked whether IL-1β was present or not—and without administering any antibiotics.”
Alphonse says, Q-VD-OPH reduces apoptosis of neutrophils and monocytes, leaving them in plentiful numbers and better able to clear MRSA bacteria. Apoptosis is a form of regulated, non-inflammatory cell death mediated by caspases 3 and 7.
“It’s like a fire department where older firetrucks are kept operating to help put out blazes, when otherwise, they would have been taken out of service,” says Miller.
The study shows, in addition to increasing apoptosis, the pancaspase inhibitor also increases necroptosis of mature monocytes also called macrophages. Necroptosis is another form of regulated inflammatory cell death mediated by binding of the tumor necrosis factor (TNF).
“The destruction of macrophages by necroptosis releases large amount of TNF, a protein that triggers bacteria-fighting immune cells to swarm into an infected area of skin,” says Alphonse.
The researchers tested whether Q-VD-OPH in mice could have broader activity against two other dangerous skin bacteria, Streptococcus pyogenes and Pseudomonas aeruginosa. S. pyogenes causes multiple diseases including scarlet fever, necrotizing fasciitis and toxic shock syndrome and P. aeruginosa is a threat to hospitalized patients on ventilators, with catheters or recuperating from wounds after surgery or burns.
Targeting of the body’s immune system against bacteria via the pancaspase inhibitor proved just as successful in clearing these two bacterial strains as it had been for MRSA.
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