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  Title: The Physiological Basis of Hypervirulence in Clostridium difficile: a Prerequisite for Effective Infection Control
Acronym: HYPERDIFF
Contract/Grant agreement number: 223585
EC contribution: 2992181 €
Duration: 36 months
Starting date: 01/11/08



Summary:

Clostridium diffficile is currently wreaking havoc within European health systems due to the emergence of hypervirulent strains (eg., ribotype 027), responsible for more severe disease, higher relapse rates, increased mortality and greater resistance to antibiotics. However, the physiological basis of hypervirulence is poorly understood due to an absence of mutational tools for functional genomic studies. The development of the revolutionary “ClosTron” technology by the University of Nottingham allows systematic inactivation of genes to assess the effects on virulence. Identification of the determinants that are required for infection and disease progression will permit the development of more rational countermeasures against C. difficile.



Problem:

Since the turn of the new millennium there has been a dramatic rise in the incidence of C. difficile. It is currently the most frequently occurring healthcare associated infection (HAI), killing over seven times as many people in the UK as MRSA in 2007. A number of reasons have been suggested for this increase, ranging from improvements in reporting procedures, the increasing age of the population and therefore the number at risk, lower standards of hygiene and overcrowding in hospitals. A further significant factor has been the emergence of so-called ‘hypervirulent’ strains, typified by ribotype 027.

Hypervirulent 027 strains are responsible for more severe disease, higher relapse rates, increased mortality and greater resistance to antibiotics. First reported in Canada in 2003, since its arrival Europe, it has rapidly across the community, and by June 2007 the presence of this strain has been reported in over 200 hospitals across 12 member states and Switzerland. These reports can be expected to rise as surveillance procedures are instigated in other member states in response to the increased incidence of CDAD.

The physiological factor(s) responsible for the spread of these strains are unknown. Indeed, aside from the toxins, the identity of C. difficile virulence factors is in general unknown. This has largely been a consequence of a lack of effective gene knock-out technologies for functional genomic studies. This problem has now been solved by the University of Nottingham with the development of ClosTron gene knock-out technology.



Aim:

The overall objective of this proposal is to determine the physiological factors that cause hypervirulence in C. difficile, to provide crucial information for both the development of more informed tests for diagnosis and epidemiological studies, and the formulation of more effective countermeasures for infection control and disease management. To establish the basis of hypervirulence, our basic strategy will be to systematically inactivate those 027-associated genes which encode products hypothesised to be involved in pathogenesis, and to assess the effects on virulence using infection models. Genes to be targeted will be guided by comparative genomic studies, in which hypervirulent strains are compared to ‘standard’ strains. To identify potential reservoirs of infection, the prevalence of the identified hyper virulence traits in the human and animal population will be determined by undertaking epidemiological studies. Special attention will be paid to the wider human population to gauge the prevalence of community acquired C. difficile.



Expected results:

To make progress, we need to identify the genes which are required for infection and disease progression. To prove that any gene product contributes to disease we need to inactivate the gene and compare the virulence of the mutant generated to the non-mutated organism. Using ClosTron technology, HYPERDIFF will lead to the identification of those physiological factors that cause hypervirulence, the underlying cause of their rapid spread within the community. Once identified and their role in disease established, rational countermeasures may be devised.

Whilst the focus to date has been on hospital-acquired disease and type 027 strains, there is mounting evidence that community acquired C. difficile is becoming an increasing problem, as is the incidence of the disease in animals. HYPERDIFF will establish the relationships between these strains and determine whether they act as a reservoir for hypervirulence traits. Moreover, HYPERDIFF will establish the relationships between healthcare associated, community and animal strains and to ascertain whether they share common hypervirulence traits.



Potential applications:


In the short term,
HYPERDIFF will lead to:-
  • the selection/ derivation of more meaningful diagnostic tests. Such tests would alert health authorities to the presence of hypervirulent strains and ensure implementation of appropriate infection control measures
  • the provision of urgently needed insight into the role of animals of as a reservoir of infection and a better appreciation of the importance of community acquired C. difficile disease

In the longer term:-

  • The identification of those factors most important in colonisation/adherence will allow the development of more effective protective vaccine(s)
  • The identification of the most important virulence factors should provide rational targets for the development of therapeutic drugs