Scientists at Cambridge University in England have discovered that the rare genetic mutations that cause Gaucher disease protect against tuberculosis (TB), the leading infectious killer internationally (with the exception of the last few years during the COVID pandemic).
Gaucher, an autosomal recessive lysosomal disorder, is far more common in Jews than in the rest of the global population. According to a study published by the National Institutes of Health, it affects 1 in 500-1000 individuals of Ashkenazi Jewish heritage, as opposed to 1 in 50,000- 100,000 people in the general population.
People with Gaucher are missing an enzyme that breaks down lipids. These fatty substances start to build up in certain organs such as the spleen and liver. There is no cure for the disease, but it generally does not shorten average lifespans and its symptoms can be managed.
The findings that a person with Gaucher is less susceptible to tuberculosis were made by Prof. Lalita Ramakrishnan and her group at Cambridge and published earlier this year in the peer-reviewed Proceedings of the National Academy of Sciences of the United States of America (PNAS).
“We made this discovery while working with zebrafish in our lab. We have been studying TB using zebrafish because their immune systems are similar to those of humans. It is also possible to manipulate their genes,” Ramakrishnan told The Times of Israel.
Ramakrishnan is world-renowned for her tuberculosis research and is the sister of Venkatraman Ramakrishnan, who won the 2009 Nobel Prize in Chemistry together with Thomas A. Steitz and Israeli scientist Ada Yonath for their research on ribosomes.
For Ramakrishnan, this pursuit is not merely academic. She has personally seen people succumb to TB, which is spread through the air and usually affects the lungs, but can make its way into other parts of the body. When Ramakrishnan was a child, her mother was ill three times with spinal TB. Later, when she was a medical student working at a general hospital in Baroda, India, she had to check every patient for the rampant disease by putting them behind a fluoroscope.
“We do our experiments using an organism called Mycobacterium marinum. It’s a natural pathogen of cold-blooded animals, including fish, in which it gives a TB-like disease. The pathology looks like TB in humans,” Ramakrishnan said.
Ramakrishnan further explained that while Mycobacterium marinum can cause systemic infection in cold-blooded animals, it can generally go only skin-deep in humans.
“Therefore, it can be worked with under standard lab conditions and does not require respiratory containment measures,” she said.
Ramakrishnan and her group had been engineering genetic mutations to enzymes in the lysosomes within the zebrafish’s cells. Lysosomes break down unwanted proteins and fats. If a lysosomal disorder exists and the production of the enzymes is reduced, there is a buildup of unwanted material in the cell.
The scientists found that lysosomal disorders made white blood cells called macrophages bloated and sluggish. Unable to move quickly, they could not properly do their job of surrounding and killing the invading TB-like bacteria. This was bad news for the zebrafish.
“So then we decided to look at Gaucher. It’s a common lysosomal disorder and the accumulated substrate in it is not a protein, but rather a lipid,” Ramakrishnan said.
“We were sure the animals would be susceptible to the bacteria, because it was the same mechanism. We engineered Gaucher-mutant fish. We see that the macrophages have the storage, their lysosomes are packed. They look just like human Gaucher macrophages and we can see that they don’t move very much. And so we thought okay, let’s do the experiment to see if they are susceptible to TB,” she said.
To everyone’s surprise, the Gaucher fish were resistant to the TB-like bacteria once it was introduced.
“[My student] Jingwen Fan does the experiment again and again — and they are resistant! And the funny thing is that in our screen, it’s been much easier for us to find susceptible mutants than resistant mutants. And so this is the holy grail,” Ramakrishnan said.
The Gaucher fish were resistant to the bacteria because of what happens with the substrates that accumulate in the macrophages in Gaucher disease. One is glucosylceramide, which is a neutral lipid. That gets converted to glucosylsphingosine, which is a charged lipid.
“That’s very similar to the quaternary ammonium compounds. These are the things that are found in disinfectants and sterilizing liquids. And we realized that that was probably the reason the bugs were dying. So we tested this, and we showed that in vitro, the glucosylsphingosine killed the bugs. It also kills the human TB bug and other disease-causing bacteria, as well. It simply inserts itself into the bacteria’s cell’s membrane and quickly disintegrates it,” Ramakrishnan explained.
Once she and her group conducted experiments using the N370S allele (the most common Gaucher-related genetic mutation in Ashkenazi Jews), they were ready to submit their paper for publication.
TB in humans can be traced back to 9,000 years ago at Atlit Yam, a city now under the Mediterranean Sea, off the coast of Israel. Ramakrishnan surmised that the Gaucher genetic mutation is likely to have protected a significant portion of Jews who were historically often forced to live in the kinds of crowded conditions where TB flourishes.
Ramakrishnan’s group’s discovery could lead to a new approach to treating TB. This is incredibly important given the fact that half a million people become infected with drug-resistant TB globally every year.
“No one wants to have Gaucher disease, but ironically this bad disease has helped us understand another ancient disease. It is just possible that this research will help develop new therapies for TB, which sickens 10.6 million and kills 1.5 people annually,” Ramakrishnan said.