Gaucher disease may protect Ashkenazi Jews against TB, say University of Cambridge scientists
The question of why Ashkenazi Jews are significantly more susceptible to a rare genetic disorder known as Gaucher disease appears to have been solved by Cambridge scientists – and the answer may have settled the debate about whether they are less susceptible to tuberculosis (TB).
Prof Lalita Ramakrishnan and colleagues from the University of Cambridge and the MRC Laboratory of Molecular Biology in Cambridge made the discovery while studying TB susceptibility in zebrafish, which have immune systems that share similarities to humans’.
They found genetic variants that increase the risk of Gaucher also help protect against TB, giving them a selective advantage, which means they are more likely to be passed down from one generation to the next.
They previously found zebrafish with mutations impairing the digestion of proteins by lysosomes became more susceptible to TB.
Lysosomes in our cells that break down unwanted materials, including proteins and fats, using enzymes. But if a mutation affects the production of these enzymes, toxic materials can build up.
This can affect macrophages, a type of immune cell that eats toxic material like bacteria and waste products.
In lysosomal disorders, macrophages become enlarged because of the accumulation of undigested material in their lysosomes.
Prof Ramakrishnan, who has just led a study showing over-the-counter drugs could shorten TB treatment, 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.”
When the researchers modelled a rare lysosomal storage disease known as Gaucher disease, they found TB resistance rather than susceptibility.
Gaucher affects about one in 40,000 to 60,000 births in the general population, but around one in 800 births among Ashkenazi Jews. It is relatively mild for most, with symptoms including an enlarged spleen and liver, and anaemia. About two thirds of people carrying two copies of the most common genetic variant are unaware they are carriers.
The researchers used genetically engineered zebrafish with genetic variants causing Gaucher disease common among Ashkenazi Jews. They found their macrophages were enlarged, as expected, and were unable to break down an unusual type of fat called sphingolipids, rather than protein. When the team exposed the fish to TB, they discovered that the fish were resistant to infection because of the fatty chemical that accumulates within the macrophages in Gaucher disease, called glucosylsphingosine.
Glucosylsphingosine acts as a detergent-like microbicide that kills TB mycobacteria within minutes by disrupting their cell walls.
Prof 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.”
Prof 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. Drugs that mimic the effects of Gaucher disease – specifically the build-up of glucosylsphingosine – might offer antimicrobial effects against TB.”
Several such drugs have been designed by co-author Professor Hans Aerts from Leiden. Since these drugs would only need to be administered for a relatively short amount of time, any side-effects should be limited and temporary.
The research was published in Proceedings of the National Academy of Sciences (PNAS) on Monday, and also involved researchers in the Netherlands, Spain, and Pennsylvania, USA.
