Group A Streptococcus (GAS) is not only responsible for millions of cases of “strep throat” and impetigo (skin infection), but also causes severe invasive diseases such as necrotizing fasciitis (“flesh-eating” disease) and the sudden onset of severe morbidity (illness) and mortality (death). Despite the fact that it remains sensitive to antibiotics, there is currently no vaccine for GAS and recurrent infections can lead to complications such as rheumatic heart disease.

In order to deal with infection, immune cells must both immediately kill the pathogen (innate immune response) and learn what the pathogen is to prevent future infections (adaptive immune response). Macrophages are a type of immune cell that bridge these processes. These cells phagocytose (eat) and digest bacteria to clear them from the body, then use the digested pieces to teach our adaptive immune system what the pathogen looks like (antigen presentation).

Because GAS is a human-specific pathogen, the bacteria has developed a number of mechanisms to help it defend against the human immune system. Our lab has shown that macrophages efficiently phagocytose GAS, but fail to digest them.

Once inside macrophages after phagocytosis, bacteria are in a compartment called the phagosome. Lysosomes (organelles with digestive enzymes) fuse with the lysosome to digest the contents (and the pathogen) within. However, data from our lab and others have shown that one of the pore-forming toxins of GAS called streptolysin O (SLO) can perforate the phagolysosome, allowing leakage of the digestive enzymes and bacterial survival.

Leakage of both lysosomal and bacterial proteins into the macrophage cytosol occurs. Our most recent work using proteomics reveals that we can detect leaked proteins and see overall changes in the cell activity in response. The most surprising finding was that histones, proteins that normally compact DNA and help control transcription, are released into the cytosol during infection.

Did you know that our immune cells make hydrogen peroxide (H2O2) and bleach to kill pathogens? These chemicals are known as reactive oxygen species (ROS). Some bacteria have enzymes that can convert hydrogen peroxide to water. GAS does not encode for such powerful antioxidant enzymes. Our lab has evidence that instead, GAS prevents the cell from producing these ROS by 1) depleting NADPH pools required to generate ROS and 2) preventing NOX2 complex formation, which is needed for ROS production.  A good defense is to not have to defend against anything!

If the macrophage doesn't digest the bacteria, what does it do with it? Plan B is usually to recapture the bacteria and try to digest it again (autophagy). However, there is evidence in the literature that GAS has tricks to avoid this recapture. There is also emerging evidence that if the cell can't digest the pathogen, it "spits" it out. This process is known as exocytosis. We have some preliminary data that GAS can be discharged from macrophages in extracellular vesicles (EVs). These EVs can protect bacteria from antibiotics. In addition, macrophages and other cells use smaller EVs to signal to other cells. We also have evidence that the histones released in response to GAS infection are expelled into the extracellular environment. Our newer lab projects focus on extracellular products after GAS infection.

Our lab currently receives funding from the National Institutes of Health (R15AI176429) to support our work. We have also received funding from the American Heart Association (17GRNT33410851). Funding from generous donors have also given our students opportunities to participate in research. Students have also received support through the Undergraduate Research Center, the Fletcher Jones Science Scholars Award and the COSMOS grant.