Tag Archives: infection

MRSA superbug: a global concern

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.MRSA trend

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.

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. 

Bacteria in your intestine is linked to Type 1 diabetes

Type 1 diabetes is commonly found in young children and adults. It is an autoimmune disease, meaning that our immune system identifies and attacks our organ as a foreign infected unit. A model (shown on the left) of the disease development has been proposed. In the model, an unknown stimulant triggers the expansion of immune B-cells and T-cells which causes inflammation and destruction of cells within the pancreatic islet. The pancreatic islet contains hormone-producing endocrine cells, such as beta cells. The beta cells are responsible in producing insulin that distributes glucose from blood to tissues. As a result of the B- and T-cells expansion, destruction of beta cells disables the production of insulin. The reduction of insulin causes a high level of glucose remained in the bloodstream. This hyperglycemia state (high glucose in the bloodstream) is known as Type 1 diabetes.

Toll like receptor is a protein that sits on the surface of cell (in most cases) to detect foreign particles that come off from bacteria or viruses. When it is activated, the signal is relayed to MyD88 in the cytoplasm (shown on right), which then indirectly activates the production of inflammatory proteins. It is recently discovered that if you take out MyD88 gene from diabetic mice, mice no longer have symptoms of diabetes. This protection appears to involve in the change of bacterial composition inside the mice without MyD88 gene. Surprisingly, if you eliminate some bacteria from the intestines in the diabetic mice (without MyD88) by antibiotic treatment, 40% of the mice tested have symptoms of diabetes. And if you eliminate all bacteria from the intestines in the diabetic mice (without MyD88), about 85% of the diabetic mice have symptoms of diabetes in 30 days. So what if you expose this germ free mice (without MyD88) with bacteria? Exposing germ free mice with bacteria reduce inflammation in the pancreatic islet, indicating that intestinal commensal bacteria prevent diabetic mice from Type 1 diabetes.

Complexity of the immune system: changes soldiers to fight

So is it possible to transplant bacteria to Type 1 diabetes patients as a cure? Quite possibly. Fecal bacteriotherapy transplantation has already been used to treat c. difficile infection. This procedure transplants the bacteria in the fecal matter from a healthy individual into the sick individual. This is thought to restore the disrupted bacterial community in the sick individual. Restoring microbiota can be a cure for autoimmune diseases, but for now, this technique has yet fully incorporated into clinical practices.

Here is an idea, there is sperm bank and egg bank out there these days. Why don’t we have a bank that stores all the fecal bacteria when we are healthy? If we get sick, we can go to the bank and restore our normal bacteria.

References:

The “Perfect Storm” for Type 1 Diabetes. The Complex Interplay Between Intestinal Microbiota, Gut Permeability, and Mucosal Immunity. doi: 10.2337/db08-0331 Diabetes October 2008 vol. 57 no. 10 2555-2562

Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV.Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008 Oct 23;455(7216):1109-13. Epub 2008 Sep 21.