Why do some people exposed to the bacteria that causes tuberculosis (TB) get sick, while others completely resist the disease? Research published this year in the journal Cell suggests that it all comes down to balance.
Scientists from the University of Washington used a combination of zebrafish experiments and human genetics to identify how a precisely tuned level of inflammation allows the body to fight off Mycobacterium tuberculosis, the causative agent of TB, but not go overboard. These findings not only help explain why some people are hypersensitive to TB, but may also have important implications for prevention and cure of this disease caused by a bacterium that can be found in one third of the world’s population.
The researchers began by creating random mutations in zebrafish and then exposing the animals to Mycobacterium marinum, a close genetic relative of the human TB bacterium and a natural pathogen for the fish. The reactions of these genetically altered fish varied from completely resistant to extremely susceptible. Further analysis showed that much of this variability was due to the LTA4H gene, which regulates the balance between pro- and anti-inflammatory factors.
Armed with findings from their zebrafish experiments, the researchers then turned to humans. They examined whether variations in the human version of LTA4H, known from previous research to affect inflammation, also affected susceptibility to TB. They analyzed DNA from 692 Vietnamese people with TB and 759 healthy controls. They found that heterozygosity – having one pro-inflammatory version of the LTA4H gene and one anti-inflammatory version – was the best position to be in. For example, having one copy of an A and one copy of a G at rs1978331 was associated with with about 30% lower odds of having TB compared to people with either two As or two Gs. The people with AG at this SNP who did develop TB were less likely to die if their disease reached a severe state.
Brinkmann/Schaible, MPI for Infection Biology
A study of a group of people in Nepal who had been exposed to leprosy, another disease caused by a mycobacterium, showed the same protective effect of having one copy of an A and one copy of a G at rs1978331. There was no effect on actually contracting leprosy, but people with AG at this SNP were less likely to develop a severe case.
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Having two different versions of certain LTA4H variations seems to keep pro- and anti-inflammatory response mechanisms balanced. The authors suggest that when inflammation is inadequate (as may be the case when a person has two Gs at rs1978331), the risk of infection with TB or leprosy is high, as are the chances of severe disease and possibly death. On the other hand, when inflammation is excessive (as might happen with two As at rs1978331), tissue damage can occur, which can also lead to severe disease and death. The sweet spot in the middle, when there is neither too little nor too much inflammation, allows the body to adequately control and eventually clear an infection, without destroying itself in the process.
If the researchers’ hypothesis is true, if a balanced immune response to TB is best, this could explain why people with TB often improve when given anti-inflammatory immunosuppressive drugs alongside the standard antibiotic treatments.
The identification of the LTA4H variants opens the possibility for the development of new treatments for TB. In a press release, the senior author of the paper notes that because the same variations they identified in LTA4H have also been associated with heart disease, it’s possible that drugs that target this pathway in heart disease might be useful for treating TB too. Many strains of Mycobacterium tuberculosis have become resistant to standard treatments, so finding new ways to fight the disease is a priority. The new genetic findings may help researchers develop treatments that focus on helping a person’s immune system fight the infection, instead of attacking the pathogen directly.
About TuberculosisTB is a highly contagious disease that is spread through airborne droplets containing the bacterium. While the highest incidence rates occur in South-East Asia and Sub-Saharan Africa, about one third of the world is thought to be infected with the bacterium that causes TB, with a new infection occurring every second. However, not all infected people have active TB, which is characterized by a chronic cough with blood-tinged sputum, a fever, night-sweats, and weight loss. People with latent TB do not experience any symptoms and are not contagious. They simply respond positively to a TB skin test and have a 5-10% chance of developing active TB. HIV infection is the strongest risk factor for the development of active TB because it compromises the immune system.
Current methods of prevention and treatment for TB are complicated, at best. A vaccine against TB does exist – the BCG vaccine – however efficacy varies based on age, geography, TB type, and duration. Treatment for TB depends on resistance. Directly observed therapy (DOT) entails taking a strict regimen of drugs for about six months under supervision. Multidrug resistant strains of TB (MDR-TB) have developed in response to mismanaged treatment and require a different drug regimen. Extensively drug resistant TB (XDR-TB) is virtually untreatable.
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