Tbc-Raffle: Not every Ticket a Strike

2. November 2010

Tuberculosis is and remains a baffling disease. Why does it only break out in a minority of the infected people? The answer might be in the genes – and it could help to identify those really threatened by the mycobacterium.

Tuberculosis. What is that? A physician spending his entire professional life in a country like Germany might actually ask this question. Tuberculosis is not eradicated completely here in this country but in spite of all reports about an increasing risk, the number of tuberculosis cases remains descending for years. In 2009, the Robert Koch Institute reported just 4390 new cases – a historic low. The number of death cases caused by tuberculosis: 150.

There is need for research ‘in all four corners’ of tuberculosis

Despite those figures, priority of tuberculosis research increased significantly. Because a look at the total shows that Germany is a merry island of the blessed when it comes to tuberculosis. With nearly two million death cases per year, tuberculosis remains the most deathly infectious disease caused by bacteria also in the beginning of the 21st century. Professor Robert Loddenkemper of the Deutsches Zentralkomitee zur Bekämpfung der Tuberkulose (DZK, German central committee for fighting tuberculosis) says: “Currently the hot spots are the South of Africa, the former Soviet Republic, India, China and Southeast-Asia.” One example only: In South Africa tuberculosis appears 150 times more frequently per population unit than in Germany. And as if that is not enough, the fight against tuberculosis lacks pretty much everything you can think of: There are no fast and cost-effective tuberculosis tests available, especially in those regions where the tuberculin test does not get you anywhere. There is no satisfactory vaccination. And regarding therapy, multiresistant mycobacteria like MDR and XDR cause more and more worry, not to mention the extremely precarious tuberculosis-HIV co-infections…

The mother of all questions in infectiology: Why me, why not you?

In addition to those clinical-practical deficits, some essential questions about tuberculosis remain unsolved. In particular it’s the question why don’t many more people suffer from manifested tuberculosis, because the contagion is extremely high. About one third of the world’s population carries the pathogen as the WHO estimates. But why about 90 percent of the Tb infected people keep having a latent infection only – researchers just now start to get an answer to that.

Anne O’Garra and her team at the British National Institute of Medical Research and Matthew Barry at the Imperial College Healthcare NHS Trust have now discovered an important piece of the puzzle. The scientists reported in the professional magazine Nature. They were able to show a very specific pattern of gene activation in patients with active tuberculosis, a kind of genetic fingerprint of active tuberculosis. This “signature” consists of 393 genes, mainly those induced by different interferons. The interferons again are the reply of the organism to the mycobacterium infection, actually nothing new. But this observation starts getting interesting since the researchers analyzed genetic activity not only in patients suffering from active tuberculosis but also in those people with a latent Tb. And lo and behold: About every tenth in the latently infected group showed a similar genetic signature like the manifest infected patients; whereas 90 percent of the latently infected persons had inconspicuous blood samples in that regard.

Latently infected and already sick anyways?

The thesis now is that this difference reflects a differing genetic sensitivity to the mycobacterium tuberculosis. Candidates here would be genes having to do with type or degree of the interferon reply to the tuberculosis infection. “It is conceivable that our genetic signature at least allows prognoses who – at the end – will have to face the outbreak of tuberculosis”, explains O’Garra. “We might be able to treat these people preventively to inhibit distribution in the body.” For the time being though this is not more than a ray of hope though: “More work is necessary in order to validate whether signature really is predictive.”

By now it is beyond dispute that there are fundamental differences coming along with differing sensitivity to Tb. Shortly prior to the Nature publication of the British, other scientists at Oxford University and the German Bernard Nocht Institute for Tropical Medicine described in the Nature Genetics magazine a genetic variation coming along with an increased susceptibility to Tb in African people. We are talking about a region on chromosome 18 which might have a thing or two to say in genetic regulation. This genetic variation was identified in genome-wide association studies requiring 11000 blood samples – a novelty for the African population when it comes to tuberculosis. This discovery has no immediate therapeutic consequences though as well. But it is another step for a better understanding of a disease which by far is not a thing of the past yet.

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