Tuberculosis (TB) is a common and often deadly disease caused by the infectious agent Mycobacterium tuberculosis (Mtb). The disease affects primarily the lungs (pulmonary TB) although the disease can also disseminate to other parts of the body such as the kidney and the brain.
Why is TB a problem?
TB is a major public health concern in many developing countries and a persistent threat in industrialized countries with almost 2 million TB-related deaths occurring each year. One third of the world’s population is estimated to be infected with Mtb and new infections occur every second.
How is TB contracted?
TB infection begins when airborn mycobacteria are inhaled via the lungs and reach the pulmonary alveoli where they are ingested by resident macrophages. Once inside the macrophage they are able to prevent the normal intra-cellular killing mechanisms and are able to replicate inside this protective niche. In healthy patients the immune system is able to wall off these infected cells in the lungs within a granuloma preventing the spread and growth of Mtb. Mtb can remain dormant within the granuloma for many years and these patients are classified as having latent TB as they display no clinical symptoms. Active disease can occur if the patient’s immune system is suppressed by HIV infection, cancer or corticosteroids etc. In this case the bacterium is able break out of the granuloma and the patient becomes highly contagious.
Why investigate host susceptibility to TB?
Approximately 90% of those infected with Mtb have asymptomatic, latent TB infection, with only a 10% lifetime chance of progression to clinically active TB. Host susceptibility is therefore considered to be an important risk factor for Mtb infection yet the factors, which control this, remain largely unknown. Improving our understanding of the genes involved in TB susceptibility provide the key for unlocking biological pathways, which will allow the development of novel therapeutics and improve disease diagnosis and prevention.
What evidence is there for a genetic contribution to TB susceptibility?
The involvement of host genetics in TB susceptibility has long been considered since early studies showed that the disease was more prevalent in families with a previous history of TB. Further support for this notion was provided by patients with a group of rare disorders called Mendelian Susceptibility to Mycobacterial Diseases (MSMD). These patients have rare genetic defects, which results in severe infections caused by non-pathogenic mycobacteria. Animal models have been extensively used to study Mtb infection and there are many reports that show mice lacking certain genes are much more likely to develop severe forms of the disease.
What has been done to investigate human genetic susceptibility to TB?
Much of the work in humans has focussed upon studying genes, which have been identified from animal models, however this approach has yielded little success. Recent advances in technology have now made it possible to study hundreds of thousands of polymorphic genetic variants throughout the genome of individuals with and without TB allowing scientists to identify small genetic regions, which may cause increased TB susceptibility or resistance. Studies involving thousands of subjects are required to discover multiple genes in the human genome that control susceptibility to TB.