CAMBRIDGE, United Kingdom — Jewish people may hold the key to eradicating tuberculosis, one of the world’s biggest killers, a new study explains. Researchers say they are less susceptible to the deadly bacterial infection because of a rare genetic disorder. This could lead to better vaccines for a disease that led to the death of 1.6 million people in 2021.
“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,” says study co-author Professor Timothy Cox from the University of Cambridge in a media release.
The study notes that several of these drugs have been designed by Professor Hans Aerts at Leiden University in the Netherlands. Doctors would only need to administer the medication for a relatively short amount of time, so any side-effects should be temporary.
Scientists blocked TB infections in fish
Gaucher disease affects one in 40,000 to 60,000 births in the general population. However, cases rise to one in 800 among Ashkenazi Jews whose ancestors lived in France, Germany, Poland, and Russia. Common symptoms include an enlarged spleen and liver and anemia. Around two-thirds of people carrying two copies of the most common genetic variant are unaware they are carriers.
Experiments on zebrafish found the same biological mechanisms that underlie Gaucher disease are also effective at clearing TB infection. The tiny fish — a popular addition to household aquariums — is relatively easy to manipulate and has a similar immune system to humans. This makes it a popular species for scientific research.
When co-author Prof. Lalita Ramakrishnan and colleagues modelled Gaucher disease, zebrafish became resistant to TB. They genetically engineered them with mutations that cause the condition in Ashkenazi Jews. White blood cells called macrophages became enlarged and unable to break down toxic fats called sphingolipids. When the team exposed the fish to TB, however, they unexpectedly realized they did not contract TB.
The fatty chemical that accumulates within the macrophages, called glucosylsphingosine, acted as a detergent-like microbicide. It kills TB bacteria within minutes by disrupting their cell walls.
“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,” Professor Ramakrishnan adds.
TB affected over 10 million people in 2021
Throughout history, Ashkenazi Jews have experienced centuries of persecution. They were often forced to live in ghettos and migrate from country to country. Many would almost certainly have come into contact with TB, which spreads more widely among poorer living conditions and densely-populated urban areas.
The mutation making people more resistant to TB would likely have outweighed the potential fitness cost of Gaucher disease. This would have increased the likelihood of affected individuals passing on their genes to future generations, spreading the variant within the population.
A similar phenomenon is seen among some individuals who carry genetic variants that protect them from malaria but cause harmful anemia or even sickle cell disease when more than one copy is present. Only individuals who carry two copies of the Gaucher genetic variant — one from each parent — are likely to be protected against TB. One “healthy” gene generates enough of the enzyme to clear the macrophages of their accumulating material.
Worldwide, TB is the 13th leading cause of death and the second leading infectious killer after COVID-19, above HIV. In 2021, an estimated 10.6 million people fell ill, including 1.2 million children. TB is present in all countries and age groups.
The study is published in the Proceedings of the National Academy of Sciences.
South West News Service writer Mark Waghorn contributed to this report.
