Scientists use zebrafish to study Jewish immune response to tuberculosis

A gene that causes Gaucher disease, common in Ashkenazi Jews, could help protect them against contracting tuberculosis (TB). 

Researchers at Cambridge University in the UK as well as in Europe and the US may have solved the question of why Ashkenazi Jews are significantly more susceptible to the rare genetic disorder known as Gaucher disease – and the answer could help settle the debate about whether they are less susceptible to TB.

In research published today in the Proceedings of the [US] National Academy of Sciences (PNAS) under the title “Gaucher Disease Protects Against Tuberculosis,” Cambridge scientists, with colleagues in the Netherlands, Spain and Pennsylvania, show that the same biological mechanisms that underlie Gaucher disease are also effective at reducing the risk of TB infection.

What is Gaucher?

Gaucher is a metabolic disease caused by the accumulation of fatty substances in certain organs, particularly the liver and spleen, causing them to enlarge and affecting their function. The fatty substances can also build up in bone tissue, weakening the bone and increasing the risk of fractures. Among the symptoms are an enlarged liver, yellow spots in the eyes, anemia, fatigue, bruising, eye-movement disorder and lung problems.

It is a rare inherited disorder. People who suffer from it have an abnormal GBA gene and are missing an enzyme that breaks down lipids (fats) that accumulate. It is an autosomal recessive disorder: Each parent must pass along an abnormal GBA gene for their child to get Gaucher. A child who gets a defective GBA gene from only one parent won’t show any signs of the disease, but are carriers.

Type-1 Gaucher disease, which is the kind that occurs in nine out of 10 patients, is most commonly found among Ashkenazi Jews who have a high number of carriers of the defective GBA gene.

The discovery was made while studying TB susceptibility in tiny, transparent zebrafish. It suggests that genetic variants that increase the risk of Gaucher also help protect against TB, giving them a selective advantage – that is, making the variants more likely to be passed down from generation to generation.

Asked to comment, Prof. Ari Zimran – founder, former director and now senior physician in the Gaucher Disease Center in Jerusalem’s Shaare Zedek Medical Center (SZMC), told The Jerusalem Post that he actually thought of this possibility in the 1990s.

“My first doctoral student Dr. Ruth Kalai and I wanted to understand why so many autosomal diseases occur in Ashkenazi Jews,” he said. “They married in for centuries, and there are founders whose abnormal genes are passed down. We thought that Ashkenazi Jews may have a selective advantage and found that people with sickle-cell disease are better protected against malaria.”

Gaucher disease affects about one in 40,000 to 60,000 births in the general population, but rates are significantly higher among Ashkenazi Jews: about one in 800 births – 50 to 75 times as often. In most cases, the disease is relatively mild. And two-thirds of people carrying two copies of the most common genetic variant are unaware they are carriers. The late, great biblical scholar Prof. Adin Steinsaltz suffered from a serious case of Gaucher, but benefited from an enzyme named glucocerebrosidase that helped control the disease after it was given to him by Zimran, the world’s leading expert on the disorder.

“We looked at TB and found that Jews locked away by the Nazis in European ghettos who were carriers of Tay-Sachs diseases – which is a ‘sister’ disease of Gaucher – were less likely to get TB, despite the overcrowding,” Zimran said. “We did a study of TB survivors to see if they included fewer carriers of Gaucher that we wrote 15 years ago, entitling it as ‘Gaucher’s: TB or not TB.’ I liked the title, but we didn’t actually find the selective advantage that actual Gaucher sufferers seemed to have.”

Zimran, whose center is the largest in the world with over 900 Gaucher patients, is in touch with the researchers at Cambridge and was well aware of this new study. “It’s true in zebrafish and it’s an interesting concept: that an advantage exists in patients and not carriers. But I’m not sure if the new study is relevant to human patients.”

The professor is now working on a connection between being a Gaucher carrier and developing Parkinson’s disease.

“About 25% of Ashkenazi Jews and 10% of the world’s population are carriers of Gaucher, and they have a higher risk of developing Parkinson’s disease,” he said. “TB is not a major disease in the developed world, but Parkinson’s is. We think it would be worthwhile for Gaucher carriers to be tested for Parkinson’s to find out if they are at risk for Parkinson’s and then give treatment to slow down progression. In fact, I am setting up a small start-up company named Agyany Pharma to develop clinical tests and eventually drugs to prevent Parkinson’s or early Parkinson in Jerusalem.”

In 2021, an estimated 10.6 million people worldwide fell ill with TB and 1.6 million people died from the disease. Most people manage to recover from the infection themselves, however – and only around one in 10 to 20 people will go on to develop the disease.

Prof. Lalita Ramakrishnan and colleagues from the University of Cambridge and the Medical Research Council Laboratory of Molecular Biology, Cambridge, wanted to know what makes some people susceptible to TB while others appear to be protected. She used zebrafish to model Gaucher’s and other human diseases 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.

“Macrophages need to move quickly to attack invading bacteria and viruses,” Ramakrishnan said. “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 she and her team modeled Gaucher, a lysosomal storage disease, they found something very unexpected – increased 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, in this case an unusual type of fat (called sphingolipids) rather than protein. But when the team exposed the fish to TB, they discovered unexpectedly that they were resistant to infection, not susceptible.

“We’d unknowingly landed in a debate that’s been going on in human genetics for decades,” Ramakrishnan said: “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.”

Ashkenazi Jews are no strangers to genetic mutations

The Ashkenazi Jewish Diaspora had experienced centuries of persecution, often forced to live in ghettos and migrate from country to country. They would almost certainly have been exposed to TB, which spreads more widely among poorer living conditions and densely-populated urban areas, the team wrote.

Unlike the example of sickle-cell anemia, however, only people who carry two copies of the Gaucher genetic variant – one from each parent – are likely to be protected against TB. That’s because the one ‘healthy’ gene generates enough of the enzyme to clear the macrophages of their accumulating material – and hence gets rid of the antimicrobial substrate.

“Our discovery may provide clues to possible new treatments for TB,” according to Prof. Timothy Cox from the University of Cambridge, a co-author of the paper. “Drugs that mimic the effects of Gaucher disease – specifically the build-up of glucosylsphingosine – might offer antimicrobial effects against TB.”