With the recent cold snaps, it is easy to feel under the weather.  In the lab where I study in at Simon Fraser University, almost half of the lab members are down with flu symptoms.  On top of that, being a daily commuter, I cannot help but wonder what kind of bugs are floating around in the sardine can that we call “bus”.  Incidentally the much deadlier disease pneumonia, fifth top cause of death in BC, Canada, can easily masquerade as the flu.  That is why a report on pneumonia research caught my attention*.  The report clarifies how pneumonia can occur when the bacteria Staph infects lungs, suggests new ways to save the lives of those infected with Staph, while also pointing to new treatment strategies against other antibiotic resistant bacterial infections.

Staphylococcus aureus, the bacteria commonly known as Staph, uses our skin as its natural habitat.  The beast attacks when our immune system is weak, causing an aggressive pneumonia which progress rapidly and causes extensive lung tissue damage.  Staph can also cause a plethora of other nasty conditions such as necrotic faciitis, better known as the disfiguring and deadly “flesh eating disease.”  Although antibiotics were once effective against Staph infections, new antibiotic resistant strains of Staph pose serious new threats.  In order to remedy this situation, scientists need to identify new points of intervention, and this will need to start with understanding how Staph invasion proceeds.

To put it simply, our body is like a building, with cellular “bricks” held together by a “cement” of various molecules, including one called E-cadherin.  At the surface where lung tissue meets our breath, the top cell layer forms a barrier which allows gas exchange with underlying blood vessels without the blood gushing out.  This barrier maintains tissue integrity and offers first line defense against microbes.

During infection, Staph damage cells by producing molecules called hemolysin, belonging to a group called pore forming cytotoxins (PFT).  As the name suggests, PFTs plug themselves into cells to cause cell contents to leak out, much like the old BC Place with punctured dome.  Hemolysin molecules in Staph function like barrel staves, with seven of these staves forming a whole barrel, and are critical for Staph to cause disease.

Although hemolysin damages cells, this process is slow and regional – the collective barrier remains largely intact. Scientists have suspected that another activity is responsible for the rapid and extensive tissue damage we see in Staph pneumonia and necotic faciitis.  A research group from the University of Chicago recently reported that for rapid, devastating disease progression Staph needs to hijack one of our own cell components – a molecule called ADAM10.  ADAM10 resides on the surface of our cells and releases molecules that serve as messages from one cell to another.  It is similar to tying messages on kites and releasing them by cutting the string, hoping the wind takes them to your target.  In this case, ADAM10 is the “scissors.”

The researchers discovered that PFT staves are attracted to ADAM10 as if ADAM10 is a piece of Velcro, allowing the staves to form barrels and insert into the barrier cells more efficiently, and thus faster leakage and ionic imbalance between the cell and outside environment.  The ionic imbalance pushes ADAM10 into overdrive and, in a cutting frenzy, it cuts molecules that it normally does not, one of which is the aforementioned E-cadherin “cement” that holds our cells together.  Loss of E-cadherin causes a breach of the protective barrier and body fluids then gushes out and interferes with air exchange.  This allows Staph to invade deeper into the body and blood stream, and so begins a deadly downward spiral.

Since the ADAM10 “scissors” seem to play such an important role, what would happen if the scissor function was blocked?  The team tested this by using the ADAM10 inhibitor, a drug that jams up the “scissors.”  The result was dramatic: blocking the scissors minimized barrier disruption and far fewer mice died from infection. Knocking down  ADAM10 effectively takes the punch away from Staph infections.  What is even more exciting is that since PFTs are not exclusive to Staph, infections by other pathogens that use PFT may also be treatable this way.

Unfortunately it will likely be quite some time before we see ADAM10 inhibitors available from our family doctors.  In these experiments scientists injected the inhibitor before Staph infection and we don’t know yet whether the approach will be effective post-infection treatment. This is especially important because early Staph pneumonia is frequently misdiagnosed as common flu.  Next steps will also include efficient drug delivery methods and assessment of side effects. This does not take away from the merit of the study, though.

These findings also have a broad significance beyond Staph infections. Many other pathogens hijack our own molecules in similar fashion, so knocking down host function instead of eliminating pathogen as we see here could prove useful against a range of antibiotic resistant infections.  This approach makes antibiotic resistance less relevant as we are raising the bridge and keeping the enemies at the moat.

* Inoshima et al. 2011. A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nature Medicine,  2011 Sep 18. V17, pp.1310-4.