Tuberculosis and the mystery of the missing genes
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In 2001, about a mile away from where I’m sitting right now in my office at the University of Leicester, there was a large outbreak of tuberculosis (TB) in a Leicester school. In August 2000 a student at the school was diagnosed with tuberculosis. He was thought to be non-infectious so only his close friends were screened for TB. This revealed one further case, which was also thought to be non-infectious. In February 2001 another student in the same year at the school was also found to have tuberculosis, and in March a teacher was found to be affected. Eventually, screening led to 67 of the 1208 students at the school being diagnosed with active tuberculosis and prescribed multi-drug therapy as is standard in tuberculosis cases. A further 246 children were been found to have strongly positive tuberculin (Heaf) test reactions and were offered the standard therapy. In addition, two staff members at the school and six family members of the students were diagnosed with active tuberculosis. Thankfully, there were no deaths associated with this outbreak. Large outbreaks of tuberculosis are uncommon in the UK, with one about every two years, normally involving 6 to 12 cases. It is very unusual for more than a dozen or so cases to be reported in such outbreaks.
Although tuberculosis is transmitted by airborne spread, it is not nearly so infectious as other diseases which spread in this way such as influenza or measles. Transmission usually takes place after prolonged close association such as within households. This is why large outbreaks are relatively unusual. The way tuberculosis affects children is different from adults. Children typically get a “primary” disease which is not usually infectious. Adults develop “post-primary” disease, which is infectious in about half of cases and sometimes very infectious.
Infections may also occur in the absence of any symptoms, and may be detected by a positive skin test or chest X-ray. Only one infected person in ten goes on to develop any disease but this ratio is altered in cases of immune suppression such as in AIDS. The time interval between infection and the development of disease (the incubation period) can be anywhere between six weeks and an entire life time. Once a patient has been on treatment for over two weeks they are generally regarded as non-infectious.
Work at the University of Leicester identified the type of Mycobacterium tuberculosis responsible for the outbreak as a strain which became known as CH. There are six major lineages of Mycobacterium tuberculosis which are preferentially transmitted amongst distinct ethnic groups. The CH strain is a variant of H37Rv, which is the most frequently found strain of TB in the East African-Indian ethnic group in the UK (Newton SM, et al. A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion. PNAS USA. 2006 103: 15594-8).
Work at Leicester and at other institutions has shown that the CH strain differs from its H37Rv parent in that it has a large deletion in its genome which allows persistence in humans. Although MTB strains often contain large sequence polymorphisms which may result in more than 5% of genes being present or absent in different clinical isolates, it may seem strange that losing a large chunk of its genome makes the bacterium more dangerous.
The effect of the deletion in the CH strain appears to be to induce less of the protective cytokine IL-12 and more of the anti-inflammatory cytokines IL-6 and IL-10 than the reference strain H37Rv. This altered pattern of cytokine secretion results in phagocyte deactivation and favours intracellular survival of the bacilli which would otherwise by killed by the immune system.
Professor Mike Barer from University of Leicester is continuing to study the function of the proteins affected by this deletion, and trying to determine whether the presence of this deletion in Mycobacterium tuberculosis strains other than CH has the same effect on pathogenesis.
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Is it worth mentioning the superiority of the gamma interferon assays in screening? NICE no longer recommend Heaf testing, and in fact the Quantiferon TB-Gold assay was designed as a screening tool.
AMH
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