TB's defence mechanism revealed

US scientists have discovered a chemical defence system used by tuberculosis bacteria to fend off human immune cells. The research could eventually lead to new drugs for TB, which remains one of the biggest killers among infectious diseases worldwide.

Biswarup Mukhopadhyay and Endang Purwantini at the Virginia Bioinformatics Institute revealed a previously unknown role for F₄₂₀H₂, the reduced form of a co-enzyme produced by Mycobacterium  species, including the TB bacterium. F₄₂₀H₂ helps the bacterium to survive bombardment with toxic nitrogen compounds when it is picked up by an immune cell called a macrophage.

’Mycobacterium tuberculosis is very adept in avoiding the anti-microbial activities of the macrophage and it can live dormant in the immune cell,’ explains Mukhopadhyay. ’Among other things, a macrophage tries to kill it by inundating it with nitrogen dioxide. This work shows one of the ways the cell can counter this attack.’

In aerobic conditions, F₄₂₀H₂ converts NO₂ into a less potent antimicrobial - nitric oxide (NO) - allowing the bacterium to lay low in the macrophage until it resurfaces as active TB. The team confirmed this by knocking out the genes responsible for F₄₂₀ and F₄₂₀H₂ production and found that the bacteria became hypersensitive to NO₂. Mukhopadhyay notes that their in vivo studies have so far been in the closely related species, M. smegmatis - although TB’s sensitivity to NO₂ is well established.

The researchers plan to carry out further studies in TB, as well as pinning down the exact chemical mechanism for the NO₂ to NO conversion. Mukhopadhyay also speculates that F₄₂₀H₂ may act like a sensor, keeping tabs on the activity of the macrophage via the levels of NO₂ it releases.

The co-enzyme is already attracting interest from various groups as a target for experimental TB drugs. Mukhopadhyay says his study is important because it validates their work. ’Our work gives a clear reason why blocking F₄₂₀ biosynthesis or the process of reducing F₄₂₀ may help to treat TB,’ he says.

Helena Boschoff, who studies TB at the National Institute of Allergy and Infectious Diseases in Maryland, says the study raises intriguing questions. ’It makes us question many ways in which we look at the mechanism of action of nitric oxide on not only TB but also other pathogens. NO₂ is often mentioned but not thought about as seriously as other reactive nitrogen intermediates.’

Mukhopadhyay agrees. ’The organism has a mechanism to handle NO₂, which tells you that it is really bad for the cell,’ he says. ’If we can find out why, that means we can come up with a new drug target.’

Hayley Birch