TB withstands immune attack by chemical conversions
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.’
E E Purwantini and B Mukhopadhyay, PNAS, 2009. DOI: 10.1073_pnas.0812883106