A team of MedImmune scientists was published on February 27 in Cell Reports for new findings in the fight against Staphylococcus aureus (S. aureus) superbug.
S. aureus is a type of bacteria that about one third of the population carry in their noses without experiencing harm. However, sometimes S. aureus causes infections that can be life threatening and even fatal. S. aureus has earned “Superbug” status for its resistance to many commonly used antibiotics and its ability to cause a wide variety of diseases from skin infections to pneumonia. In 2016, MedImmune scientists were published in Science Translational Medicine for uncovering that S. aureus alpha toxin prevents destruction of the bacteria within macrophages, the white blood cells that are supposed to clean up foreign invaders on behalf of the immune system.
The presence of alpha toxin in respiratory infections is associated with increased disease severity and worse clinical outcomes. In fact, about 99 percent of S. aureus isolates contain the alpha toxin gene, making it a target for researchers who are seeking new treatments for S. aureus pneumonia.
MedImmune experts wanted to better understand how the S. aureus alpha toxin is hampering the macrophages from doing their job. They studied the complex process that S. aureus alpha toxin sets off inside host cells and uncovered that the toxin prevents mitochondria from co-locating with bacteria within the macrophage, therefore disabling the macrophage’s killing function.
Through a series of experiments leveraging robust imaging and modeling capabilities, the MedImmune team found that re-engaging mitochondria in the macrophage’s process of killing S. aureus bacteria was more effective at protecting against pneumonia than stopping the production of cytokines – another approach that the rest of the scientific community had been focused on with limited success.
As the scientists wrote in Cell Reports
We conclude that AT [alpha toxin] protects S. aureus from macrophage killing by spatially disengaging mitochondria from internalized bacteria, and neutralization of this toxin protects against respiratory infection not by limiting cytokine production but rather by enabling mitochondrial and bacterial co-localization within the cell.
The MedImmune team was able to uncover and publish detail about how the mitochondria help cells fight back against intruders like S. aureus. With the application of suvratoxumab, formerly known as MEDI4893, an investigational monoclonal antibody in Phase 2 development, MedImmune scientists were able to neutralize S. aureus alpha toxin and therefore activation of the NLRP3 inflammasome, allowing mitochondria to work and providing protection to the host cells.
As they wrote in Cell Reports,
Our data suggest a more global role for mitochondria in the innate immune response than just macrophage phagocytic killing.
If your biology is a little rusty, here is a helpful analogy:
Say you wanted to eliminate dirt (S. aureus) from your carpet (lungs) with a robotic vacuum (macrophage) that not only removes dirt from the carpet, but also disposes of it for good using an internal incinerator (mitochondria). One way the dirt (S. aureus) could save itself is by disabling the incinerator (mitochondria) within the vacuum, allowing the dirt to be taken in but otherwise undeterred from potentially damaging your carpet again.
Taylor Cohen is a scientist who joined MedImmune’s Infectious Disease team four years ago and is the lead author on both the Science Translational Medicine and Cell Reports papers. He conducts research in Microbiology, Immunology and Cell Biology and describes his team as follows:
We are an exciting multi-disciplinary research group that has the freedom to dig deeper. We are not just focused on target and the outcome but on understanding how our targets influence the bigger picture.
Read more about the work of Cohen and team here.