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Gaucher Disease Might Protect Ashkenazi Jews Against TB

A diagnostic test request form that reads "Gaucher Disease"
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While studying tuberculosis (TB) susceptibility in zebrafish, scientists believe they have solved the query as to why Ashkenazi Jews are significantly more susceptible to a rare genetic disorder, and less susceptible to TB. The research is published in Proceedings of the National Academy of Sciences (PNAS).

The burden of TB

TB is the 13th leading cause of death worldwide, killing an estimated 1.6 million people in 2021. The TB bacteria is spread from one person to another through the air. Some individuals that are infected clear the bacteria and do not become ill, while others develop TB disease.

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Professor Lalita Ramakrishnan’s work at the University of Cambridge aims to understand the different susceptibilities to TB. In her laboratory, zebrafish are used as disease models due to the similarity of their immune system compared to humans. Previously, Ramakrishnan’s team identified that zebrafish carrying mutations that affect how lysosomes break down proteins showed increased susceptibility to TB.

What are lysosomes?

Lysosomes are membrane-bound cell organelles that are responsible for breaking down toxic materials in the body, including fats and proteins. Mutations affecting lysosome production can therefore lead to an accumulation of such materials. Macrophages, a type of immune cell, are particularly impacted by this accumulation. In patients diagnosed with lysosomal disorders, macrophages become enlarged and less mobile, adversely impacting their ability to function as part of the immune defence system.

Gaucher disease model shows resistance to TB

Several lysosomal diseases exist, including Fabry, Pompe and Gaucher disease. Gaucher disease affects 40,000–60,000 births in the general population. The prevalence of the conditions is greater among Ashkenazi Jews however, where it affects approximately 1 in 850 births.

In a new study, Ramakrishnan and team genetically engineered zebrafish to express gene variants known to cause Gaucher disease that are common in Ashkenazi Jews. The fish’s macrophages increased in size and were unable to break down molecules, including a type of fat – sphingolipids. Unexpectedly, when the genetically engineered fish were exposed to TB, the researchers found that they were resistant to TB.

“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,” says Ramakrishnan.

In the zebrafish model, a fatty chemical called glucosylsphingosine accumulates in the macrophages where it acts as a “detergent-like” microbicide, killing TB bacteria. The researchers believe this molecular mechanism confers TB disease resistance. They add that the protection against TB could ultimately outweigh the effect of Gaucher disease that occurs in mild forms. 

Characteristic large, rounded macrophages with accumulated fat in zebrafish with Gaucher disease. Arrows, fat-filled macrophages. Arrowheads, normal macrophages. Credit: Jingwen Fan.

“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 Professor Timothy Cox from the University of Cambridge, who is a co-author on the paper. These drugs would be administered for a short period of time, meaning any associated side-effects would be short-lived.

Dr. Hans Aerts, professor of medical biochemistry at Leiden University, is another co-author of the study. His laboratory aims to improve the diagnosis and therapy options for inherited lysosomal disorders, and has already designed drugs that mimic the effect of glucosylsphingosine, according to the researchers.

This article is a rework of a press release issued by the University of Cambridge. Material has been edited for length and content.

Reference: Fan J, Hale V, Lelieveld L, et al. Gaucher disease protects against tuberculosis. PNAS. 2023. doi: 10.1073/pnas.2217673120.