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Meningitis :: Scientists identify specific enzymes that make meningitis hard to fight

Two enzymes in meningitis bacteria which prevent the body from successfully fighting off the disease, and make the infection extremelyvirulent, have been identified in new research published today.

The study found that the two enzymes – which have distinct functions -work together to hamper the body’s efforts to fight off the disease.Together they repair damage done to the meningitis bacteria’s DNA by thebody’s white blood cells, which are sent to fight the infection.

Understanding the part these enzymes play in the process that enablesthe bacteria to elude the body’s natural defences could eventually helpscientists develop novel new treatments for meningitis and thesepticaemia it can cause. Both are extremely serious conditions with ahigh mortality rate, which take hold quickly and are difficult to treat- sometimes resulting in extreme measures such as limb amputation.

When the meningitis bacteria enter the bloodstream, the body’s naturaldefences send white blood cells to fight the infection. They ingest thebacteria and subject them to oxidative stress. Oxidative stress damagesthe base chemical compounds of the bacteria’s DNA. This should lead tocell death and the defeat of the bacteria. However, the virulentmeningitis bacteria are able to repair this harmful damage and aretherefore unaffected by the body’s defences.

The research team found that the two enzymes essential to the bacteria’srepair mechanism are AP endonuclease and 3′-phosphodiesterase. Contraryto the scientists’ expectations, these two enzymes carry out separatefunctions in the DNA repair process.

Professor Paul Freemont from Imperial’s Division of MolecularBiosciences explains: “Scientists have long understood that the secretof meningitis’ virulence lies in its ability to rearrange its DNA andthus change its external appearance to the body’s immune system.Significantly our research has now demonstrated that the ability ofmeningitis to repair its DNA is important for its ability to surviveattack from the body’s immune system. This work provides an insight intothe precise roles of two enzymes in mending DNA and gives us a greaterunderstanding than ever before into why these infections are so hard forthe body to fight.

“We have also discovered that this novel combination of enzymes ispresent in a wide variety of bacteria and that it has a direct impact onthe infectivity of human pathogens.”

Dr Geoff Baldwin from Imperial’s Division of Molecular Biosciencesadded: “The wide importance of DNA repair to the viability of allorganisms is well established. However, for the first time this researchshows an important role for DNA repair in meningitides fighting off theattack of the body’s immune system.

“We have examined two enzymes from a family that are known to cut theDNA during its repair. To our surprise we discovered that in themeningitis bacteria, one of the enzymes does not cut the DNA. Instead,it removes damaged DNA ends that prevent the DNA from being remadeduring the repair process. This has an important impact for ourunderstanding of the precise pathways of DNA repair and the significanceof the two separate functionalities that act in different DNA repairpathways within the pathogen.”

Professor Christoph Tang from Imperial’s Division of InvestigativeScience added: “After realising that the two enzymes had distinct rolesrepairing different types of DNA damage, were able show the pathogen can’fend off’ different types of DNA damage while in the bloodstream. Intheory, finding some way of disabling these enzymes would render thebacteria unable to repair itself, and therefore vulnerable to attack anddefeat by the body’s immune system.”

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