It kills TB mycobacteria within minutes and could make people resistant to Tuberculosis infection, not susceptible.

Why do some people become susceptible to TB infection while others, particularly Ashkenazi Jews, seem to have protection against it?

Scientists found something very unexpected in Ashkenazi Jews: TB resistance rather than susceptibility.

Researchers from Cambridge, along with collaborators from the Netherlands, Spain, and Pennsylvania, USA, demonstrate in a study published today in Proceedings of the National Academy of Sciences (PNAS) that the same biological mechanisms that cause Gaucher disease also work well to eliminate TB infection.

The finding, which came about as a result of research on TB susceptibility in zebrafish, suggests that genetic variants that increase the risk of Gaucher disease also work to protect against TB, giving them a selective advantage—making the variants more likely to be passed down from one generation to the next.

In 2021, around 10.6 million cases of TB were reported globally, leading to 1.6 million deaths. Although the majority of infected individuals are able to fight off the infection on their own, approximately 1 in 10 to 20 will progress to full-blown TB.

What factors make some individuals vulnerable to tuberculosis while others seem to be protected is of interest to Professor Lalita Ramakrishnan and her colleagues at the University of Cambridge and the Medical Research Council Laboratory of Molecular Biology, Cambridge. She models human diseases in zebrafish due to their genetic manipulability and similarities in immune systems with humans.

Her team had previously shown that zebrafish with mutations that compromised the lysosomes’ ability to break down proteins were more vulnerable to TB. Lysosomes are components of our cells that use enzymes to degrade waste materials such as proteins and lipids. Lysosomes are found in all of our cells. When a mutation interferes with the synthesis of these enzymes, it may result in an accumulation of compounds that are toxic to the body.

The immune cell known as the macrophage, which “eats” harmful materials such as bacteria and waste products, is one kind of cell that is susceptible to this build-up. Because of the buildup of undigested material in their lysosomes, macrophages suffering from lysosomal diseases expand, move slowly and are less able to combat infection.

Macrophages need to respond fast to combat intruding bacteria and viruses, according to Professor Ramakrishnan. They are precisely what their name implies—big eaters. However, those who have lysosomal illnesses are unable to digest their meals, which causes bloating and lethargy and renders them unable of doing their tasks.

Instead of susceptibility, Ramakrishnan and colleagues discovered TB resistance when they mimicked the lysosomal storage disorder known as Gaucher disease.

In the general community, Gaucher disease affects one in 40,000 to 60,000 newborns, while rates are much higher among Ashkenazi Jews, where they affect one in 800 births. Two-thirds of those who possess two copies of the most common genetic mutation are unaware they are carriers, and the condition may often be very mild with symptoms including anaemia and enlarged spleen and liver.

As expected, when the researchers genetically modified zebrafish with Gaucher disease-causing genetic variants that are prevalent among Ashkenazi Jews, their macrophages grew larger and were unable to break down the toxic substances, which in this case were unusual fats (called sphingolipids) rather than proteins.

However, the team surprisingly found that the fish were resistant to TB infection, not vulnerable when they were exposed to TB.

The glucosylsphingosine, a fatty substance that builds up within the macrophages in Gaucher illness, was the origin of this resistance to infection. It was discovered that glucosylsphingosine functions as a microbicide similar to a detergent that quickly kills TB mycobacteria by rupturing 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,” adds Professor Ramakrishnan.

The Ashkenazi Jewish diaspora has been subjected to persecution for generations, and its members were sometimes compelled to live in ghettos and move from one nation to another. They very probably were exposed to tuberculosis, which is more common in low-income and heavily populated locations like cities.

The fitness cost of having this genetic mutation, which is linked to Gaucher disease, is likely to have been balanced by the benefit of increased TB resistance. This would have boosted the transmission of the mutation among the population as more afflicted people passed on their genes to subsequent generations. Some people have genetic variations that protect them against malaria but, when present in higher than normal numbers, lead to severe anemia or possibly sickle cell disease.

Contrary to the case of sickle cell anemia, people are only likely to be protected against TB if they have two copies of the Gaucher genetic variation, one from each parent. This is due to the fact that the one “healthy” gene produces enough of the enzyme to cleanse the macrophages of the material that has accumulated inside of them, eliminating the antibacterial substrate in the process.

“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,” remarks co-author Professor Timothy Cox.

Professor Hans Aerts of Leiden University, who is also a co-author on the research, has already designed many such medications. The brief duration of treatment with these medications means that any potential adverse effects should be short-lived.

Image Credit: Getty