European project to unravel C difficile genome

31 January 2009

Scientists in Germany, France, Italy, Slovenia and the UK have joined a project to unravel the genetic code of Clostridium difficile, a potentially lethal type of bacteria commonly acquired in hospitals. The HYPERDIFF project (full title: the physiological basis of hypervirulence in Clostridium difficile: a prerequisite for effective infection control) , which is part of an effort to control the spread of highly virulent, multi-drug-resistant bacteria, has been funded with approximately 3 million by the EU's Seventh Framework Programme (FP7).

Clostridium difficile (literally translated as 'difficult spindle') is anaerobic, spindle-shaped bacteria that live everywhere (especially in the soil) and grow very well in the human body. When stressed, C. difficile produces spores that tolerate extreme conditions, including very high heat and acid (they don't like bleach, though). They are perfectly at home on any hospital surface, and once ingested pass through the stomach to colonise the intestine. In small numbers, this does not normally lead to disease.

The bacteria, however, thrives in hospital and nursing home environments, where residents often go through antibiotic or chemotherapy treatments that drastically reduce their 'normal' intestinal flora. This leads to a rapid explosion in the C. difficile population, mutation and infection. Pseudomembranous colitis (PMC) in particular poses a risk to vulnerable patients, and pathogenic C. difficile is known to produce toxins (enterotoxin and cytotoxin) that cause severe diarrhoea and inflammation. Antibiotic treatment is problematic due to the bacteria's robustness and its increasing resistance to antibiotics.

Neither the exact behaviour of the bacteria nor the reasons why certain strains are more virulent than others are currently known. The HYPERDIFF team, led by Professor Nigel Minton of the University of Nottingham in the UK, is using gene knock-out technology to determine the role of specific genes in highly virulent strains of the bacteria. They hope to uncover clues to its pathology and resistance to antibiotics in order to learn how C. difficile infection might be eradicated. The project partners hope their findings will lead to better diagnosis, more effective treatments and possibly a vaccine.

"The idea behind the study is that we investigate the genomes of the hypervirulent strains and identify their differences to the so-called 'standard strains'," explained Professor Minton. "In this way, we should get a clearer picture of the whole range of factors involved in its spread and the way in which it causes disease."

The three-year study will centre on the application of ClosTron technology, a universal gene knock-out system for the genus Clostridium that was developed by researchers at the University of Nottingham in 2007. ClosTron will be used to produce mutant versions of the hypervirulent strains that are increasingly common in European hospital settings. The scientists will literally knock out the bacteria's genes one by one, and compare mutant versions to the standard organism in order to assess each gene's specific function.

Over the past few years, C. difficile has been the most frequently occurring healthcare-associated infection, and both incidence and mortality are on the rise. This may be due to improved reporting, poor hygiene standards (infection is often passed on by hand contact) or simply the fact that the population is ageing and becoming more vulnerable. However, the emergence of new, 'hypervirulent' strains in Europe, including ribotype 027, could be an important factor.

According to Professor Minton, "these hypervirulent organisms seem to be taking over as the dominant strain in outbreaks and, worryingly, there are only two antibiotics which are still effective against them. There is a very real danger that total resistance may arise, and if that happens then this will become an extremely serious problem."

It is hoped that the ClosTron studies will provide the knowledge needed to improve diagnostic testing and better inform infection control. Additionally, the HYPERDIFF researchers will look into whether pets and domesticated animals are carriers of the bacteria.'

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