The biologic mechanisms that mean Ashkenazi Jews are significantly more susceptible to a rare genetic disorder might also be the reason why they could be protected against tuberculosis (TB), according to new findings.
In a zebrafish study, researchers at Cambridge University, UK, found genetic variants that increase the risk of Gaucher disease also help protect against TB.
Professor Lalita Ramakrishnan and colleagues from the University of Cambridge and the Medical Research Council Laboratory of Molecular Biology, Cambridge, has previously found that zebrafish with mutations that impaired the digestion of proteins by lysosomes became more susceptible to TB.
When a mutation affects the production of these enzymes, it can lead to a build-up of toxic materials.
In this study, published in PNAS, she and colleagues in the Netherlands, Spain, and Pennsylvania, USA, modelled a lysosomal storage disease – Gaucher disease – and unexpectedly found TB resistance rather than susceptibility.
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.”
Gaucher disease affects about one in 40,000 to 60,000 births in the general population, but among Ashkenazi Jews it is about one in 800 births. In most cases, the disease can be mild and symptoms include enlarged spleen and liver and anaemia.
When the researchers genetically engineered zebrafish with genetic variants causing Gaucher disease that are common among Ashkenazi Jews, their macrophages became enlarged and were unable to break down the toxic materials.
But when the team exposed the fish to TB, they found the fish were resistant to infection. This was because glucosylsphingosine, the fatty chemical that accumulates within the macrophages in Gaucher disease, acted as a detergent-like microbicide that kills TB mycobacteria within minutes by disrupting their cell walls.
Prof Ramakrishnan added: “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.”
Although this genetic mutation is associated with Gaucher disease, the fact that it makes people more resistant to TB increased the likelihood of affected individuals passing on their genes to future generations and therefore spread the mutation within the population.
A similar phenomenon is seen among some individuals who carry genetic variants that protect them from malaria but, when more than one copy is present, cause harmful anaemia or even sickle cell disease.
The authors say unlike the example of sickle cell anaemia, only individuals who carry two copies of the Gaucher genetic variant are likely to be protected against TB because the one ‘healthy’ gene generates enough of the enzyme to clear the macrophages of their accumulating material.
Co-author Professor Timothy Cox from the University of Cambridge, said: “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.”
Fan, J et al. Gaucher Disease Protects Against Tuberculosis. PNAS 7 February 2023; doi: 10.1073/pnas.2217673120
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