Staphylococcus aureus, or “Staph” as I’m going to call it, is a spherical bacterium that grows in grape-like bunches. It is mainly found in the nose and skin of humans and for most of the time is completely harmless there. Staph can cause many infections if it gains access to areas of the body that it’s not normally in, like a cut in the skin. From abscesses to boils and full on systemic infections (that’s infecting all of the major organs and blood), it’s a tricky customer. It also doesn’t help that this pathogen has gathered a number of antibiotic resistances, and many strains have evolved into Methicillin Resistant Staphylococcus aureus (MRSA) that you have probably heard of in the news and whatnot. Staph can do all of this because it encodes in its’ genome a huge array of different proteins, enzymes, polysaccharides as well as other nasty weapons that allow it to cling onto and damage the host’s tissues. These are collectively called ‘virulence factors’ which are defined as being any molecule or system that aids a pathogen in causing disease to a host. Staph has enzymes that target immune cells, killing them before they can take a swipe at the invading bacteria. Additional enzymes can burst red blood cells to get at the delicious iron ions found in haemoglobin or destroy the host’s extracellular matrix; a protein complex that act as a scaffold for keeping our cells and tissues together. As if this wasn’t enough, scientists have just discovered two new enzymes secreted by Staph that help the pathogen to dodge the host’s immune system1. These are;
- Staphylococcal nuclease (Nuc)
- Adenosine synthase A (AdsA)
But first of all, we’re going to need a little understanding of the human immune system to know how these two enzymes aid in the Staph disease process.
Neutrophils are large cells of the immune system filled with granules (bags) of degrading and deadly enzymes that kill invading pathogens. They are attracted to sites of infection and can spew their contents over the invading pathogen or devour them in a process called phagocytosis. Interestingly it is the neutrophils which are the main phagocytes of the immune system, contrary to the popular belief that this title falls to macrophages. But if the neutrophils’ phagocytosis or granules fail to clear an infection then these brave, clever cells can sacrifice themselves in one last desperate bid to stop the pathogen in its’ tracks. A neutrophil can undergo the unique ‘NETosis’ pathway of cell death in which the neutrophils’ DNA, granular enzymes and other cytoplasmic proteins are released in a sticky net that entraps pathogens and stops them from spreading. This mesh of DNA and protein is known as a NET; a Neutrophil Extracellular Trap2. In most situations this NET is enough to isolate an infection long enough for the body’s immune system to resolve the issue; macrophages can then infiltrate the inflamed, infected tissue to help in the clear up of cellular debris and dead cells for example.
However, the immune system didn’t take Staph into account. This is where the newly discovered Nuc and AdsA come into play. Nuc is an enzyme that degrades DNA, essentially dissolving the ‘strings’ of the NET into its’ base nucleotides1. The AdsA then takes over, and converts the ‘A’ base of DNA, the adenosine, into deoxyadenosine2. This is depicted in Fig.1 below. Deoxyadenosine is lethal to macrophages as it triggers the cell death pathway, mediated by the caspase-3 enzyme, so that any recruited immune cells are killed and can’t help in clearing the infection. As a result more neutrophils join the fray, produce a NET, and the cycle continues whilst the Staph infection lingers to fester happily inside the host.
What’s really fascinating about this is the way in which Staph takes an effective mechanism to combat itself and turns our own defences against us. One could almost imagine the glee it takes in subverting our own wrath upon us.
I think it’s beautiful and ironic, all at the same time.
1) Thammavongsa V, Missiakas DM, & Schneewind O (2013). Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death. Science (New York, N.Y.), 342 (6160), 863-6 PMID: 24233725
2) Brinkmann V, & Zychlinsky A (2012). Neutrophil extracellular traps: is immunity the second function of chromatin? The Journal of cell biology, 198 (5), 773-83 PMID: 22945932
Image taken from Wikipedia article “Staphylococcus.” On 28/11/13 at 9.40pm. http://en.wikipedia.org/wiki/Staphylococcus