There is an increasing amount of news coverage on the superbug, which is also known as the methicillin-resistant Staphylococcus aureus (MRSA). But how much do you really know? Here, I will talk about the reason why we should be concerned about the spread.
The history of this bacteria, Staph. aureus, can be traced back to the Egyptian mummies, which historians had recovered pathological changes that are consistent with staphalococcal osteomyelitis. Staph. aureus can be found in 20% to 45% of normal healthy adults. In the hospital-associated cases, serious infection is often caused by the bleach of protection. For example, the skin barrier protection is disrupted after going through an invasive surgery, which allows the colonization of Staph. aureus in tissues.
The concern of MRSA grows as the healthcare community now faces with strains of Staph. aureus that are equipped with methicillin and vancomycin resistance genes.
If you look at the timeline (from Nature Magazine), shortly after the introduction of penicillin in the 1940s, some strains of Staph. aureus were already found to have penicillinase/resistance to penicillin. And if you look at when methicillin is introduced to treat Staph. aureus infection, you can see that methicillin resistant strains can be found shortly after the introduction. Typically, vancomycin is used as a last resort due to its toxicity. But the resistance of vancomycin is also emerging.
Are we running out of options to treat Staph. aureus infection? Not now. But if we don’t take action soon to accelerate the antibiotics discovery, we will run out of options when vancomycin resistant strains dominate.
Infections generally follow a similar path with some consistent steps. The microbe gains entry to the host, replicates in the host and is shed, in order to spread to a new host. Commonly this has the unfortunate side effect of making the host a bit ill.
For bacteria, replication within a host relies upon, among other things (such as avoiding the murderous cells of the host immune system), the ability of the microbe to obtain essential nutrients from the environment it finds itself in. A study published in Cell now shows that the pathogenic bacterium, group A Streptococcus (GAS), uses a mechanism that directly modulates the metabolism of the host cells in order to stimulate its own replication and proliferation.
GAS causes a variety of human infections and in fact only infects humans. Causing the well-known “strep throat” the majority of illnesses involving this bacterium are relatively mild. This is because the bacterium is commonly only found on the skin or in the throat. If this changes and the bacterium finds its way into more internal tissues, the blood or lungs for example, severe disease such as necrotising fasciitis and streptococcal toxic shock syndrome can result. Worldwide there are 700 million cases of mild GAS infection with about 650,000 cases becoming severe invasive infections. These 650,000 cases are associated with a mortality rate of around 25%.
Upon entering the host it is important for the bacteria to quickly gather nutrients in order to proliferate and truly establish itself at the site of infection. GAS attaches to host cells and releases the toxins streptolysin O (SLO) and streptolysin S (SLS) into the host cell. These toxins stimulate endoplasmic reticulum (ER) stress within the host cell. ER stress causes an increased unfolded protein response, ER-associated protein degradation (ERAD) and eventually cell death through a variety of pathways. It is associated with a medley of diseases such as diabetes and Alzheimer’s disease. In this case the change we are interested in is the increase in production of the enzyme asparagine synthetase that catalyses the production of asparagine (ASN). The researchers found that the host cell secretes increased levels of ASN which are detected by the bacterium, causing a sweeping change in gene expression that affects nearly 17% of the bacterium’s genes. These changes in gene expression include the up-regulation of genes involved in proliferation. In the absence of ASN these genes were down-regulated and the production of SLS/SLO was increased.
This mechanism was only active locally and temporarily upon initial attachment, implying that this is a mechanism used by GAS to establish infection early on. Interestingly the detection of the increased ASN uses the two component system TrxSR, which is heavily involved in regulation of the bacterium’s virulence and metabolic genes. The researchers claim that this demonstrates that this pathway is an “important attribute to GAS pathogenesis” and helps the bacterium to cause severe disease. Other bacterial pathogens have been reported to benefit from host cell metabolism modulation, such as Agrobacterium tumefaciens, which makes plant cells produce opines required by the bacterium. The scientists point out that there are other pathogenic bacteria that use SLS/SLO-like toxins such as S.aureus and L.monocytogenes (both known for their ability to ruin a good takeaway or cream cake) and that it would be interesting to see if they use similar pathways.
Influenza virus places a large burden on our society. It is estimated that the costs of everything related to influenza virus infection comes to about $87.1 billion US dollars in the United States. With the existing vaccination program against influenza virus, you may ask why there isn’t a “one size fits all” that can make us completely immune from influenza virus infection with a single vaccine. My parents have asked me that question a few weeks ago. The way how I explain it is through the use of umbrellas. Let’s say the virus carries a bright red umbrella. The immune system recognizes the red cloth on the umbrella and then mount an immune response against the red cloth. But next year, the virus mutates due to selective pressure. The virus now carries a blue umbrella. The immune system now has to go through all the processes from sensing the infection to getting rid of the infection, instead of recognizing the virus at the beginning of the infection. The current strategy that the scientists are trying to develop is the use of broadly neutralizing antibody. The broadly neutralizing antibody recognizes not the cloth of the umbrella, but the stalk of the umbrella which is common among all subtypes of influenza.
A recent review article by Dr. Krammer and Dr. Palese from Mount Sinai has covered the challenge of this antibody in an elegant way. The real challenge behind the application of a broadly neutralizing antibody against influenza virus is that different age groups tend to have totally different exposure history to the subtypes of influenza virus. Children tend to be naive for influenza virus infection when adult are exposed to it multiple times. Furthermore, the elderly appears to mount a less effective response after a flu shot. Thus, the application of the broadly neutralizing antibody needs to be tested extensively in different age groups before rolling out.
“The initial cost of conducting these trials might seem high, but investment in universal influenza virus vaccine approaches might make it possible to overcome the threat of seasonal and pandemic influenza.”