Rare genetic disease may protect Ashkenazi Jews against tuberculosis
Research with zebrafish suggests Ashkenazi Jews at a greater risk of Gaucher disease, are less likely to get TB infection.
Scientific research suggests Ashkenazi Jews more susceptible to a rare genetic disorder may have greater immunity to tuberculosis (TB).
Gaucher disease affects around one in 800 births, with symptoms including enlarged spleen and liver, and anaemia. Two-thirds of people with the gene are unaware they are carriers.
Research published in Proceedings of the National Academy of Sciences (PNAS), Cambridge scientists – with colleagues in the Netherlands, Spain, and Pennsylvania, USA – show that the same biological mechanisms that underlie Gaucher disease are also effective at clearing TB infection.
The discovery – made while studying TB susceptibility in zebrafish – suggests that genetic variants that increase the risk of Gaucher also help protect against TB, giving them a selective advantage: making the genes more likely to be passed down from generation to generation.
Professor Lalita Ramakrishnan and colleagues from the University of Cambridge and the Medical research council laboratory of molecular biology, Cambridge, are interested in what makes some people susceptible to TB while others appear to be protected.
She uses zebrafish to model human disease, as it is relatively easy to manipulate zebrafish’s genetics, and their immune systems share many similarities with those of humans.
During their research, her team had previously found that zebrafish with mutations that impaired the digestion of proteins by lysosomes became more susceptible to TB. Lysosomes are components of our cells that break down unwanted materials, including proteins and fats, using enzymes. When a mutation affects the production of these enzymes, it can lead to a build-up of toxic materials.
One type of cell that is vulnerable to this build-up is the macrophage, a type of immune cell that ‘eats’ toxic material, including bacteria and waste products. In lysosomal disorders, the macrophages become enlarged because of accumulation of undigested material in their lysosomes and move slowly, hampering their ability to fight infection.
Professor Ramakrishnan said: “Macrophages need to move quickly to attack invading bacteria and viruses. Their name means ‘big eater’, and this is exactly what they do. But with lysosomal disorders, they’re unable to break down the food they eat, which makes them bloated and sluggish, unable to perform their duties.”
However, when Ramakrishnan and colleagues modelled a lysosomal storage disease known as Gaucher disease, they found something very unexpected: TB resistance rather than susceptibility.
When the researchers genetically engineered zebrafish with genetic variants causing Gaucher disease that are common among Ashkenazi Jews, as anticipated their macrophages became enlarged and unable to break down the toxic materials.
But when the team exposed the fish to TB, they discovered unexpectedly that the fish were resistant to infection, not susceptible.
The reason for this resistance to infection was because of the fatty chemical that accumulates within the macrophages in Gaucher disease, called glucosylsphingosine, found to act as a detergent that kills TB mycobacteria within minutes by disrupting their cell walls.
Professor Ramakrishnan said:: “We’d unknowingly landed in a debate that’s been going on in human genetics for decades: are Ashkenazi Jews – who we know are at a much greater risk of Gaucher disease – somehow less likely to get TB infection? The answer appears to be yes.”
The Ashkenazi Jewish diaspora, often forced to live in ghettos and migrate from country to country, would almost certainly have been exposed to TB, which spreads more widely among poorer living conditions and densely-populated urban areas.
Only individuals who carry two copies of the Gaucher genetic variant – one from each parent – are likely to be protected against TB.
Professor Timothy Cox from the University of Cambridge, a co-author on the paper, added: “Our discovery may provide clues to possible new treatments for TB.”
The research was funded by Wellcome, Gates Cambridge and the National Institute for health and care research Cambridge biomedical research centre.
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