Tag Archives: Cell biology

It’s just take take take with these GAS: Bacterial modulation of host cell metabolism

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.

Graphical representation of the described pathway Image credit: Cell
Graphical representation of the described pathway
Image credit: Cell

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.