by Tuberculosis, the biggest infectious killer of humanity, is caused by bacteria that usually affect the lungs, but can affect many other organs in the body as well. In 2021, around 10.6 million people worldwide fell ill with tuberculosis (TB) and 1.6 million people died from the disease.
However, about 95% of people who are infected with the bacteria that cause TB do not get sick. Your immune system manages to successfully destroy the bug.
My colleagues and I are interested in what makes some people susceptible to TB, while others appear to be protected. We used zebrafish to study the disease, since their immune system shares many similarities with that of humans, and it is possible to manipulate their genes in the laboratory. In our latest study, published in the online journal PNAS, we have used this type of manipulation to show that genes carried by many Ashkenazi Jews that put them at increased risk of contracting a rare disease also help protect them against tuberculosis.
Our team had previously found that zebrafish with genetic mutations in certain enzymes in their cells became more susceptible to TB. These enzymes are found in the cells’ lysosomes, components that break down unwanted material, including proteins and fats. When the production of these enzymes is reduced, it can lead to a buildup of toxic material.
One type of cell that is vulnerable to this buildup is the macrophage, a cell that “eats” toxic material, including bacteria and waste products. In lysosomal disorders, macrophages move slowly and enlarge because they accumulate undigested material in their lysosomes, making them less able to fight infection.
Macrophages need to move quickly to attack invading bacteria and viruses. Their name means “great eater,” and that’s exactly what they do. But with lysosomal disorders, they can’t break down the food they eat, leaving them bloated and sluggish, unable to perform their functions.
resistant to infection
However, when our group genetically engineered zebrafish to model one of these lysosomal disorders, called Gaucher disease (pronounced go-SHAY), we found something highly unexpected: These fish were resistant to TB rather than susceptible.
Gaucher disease is a rare disease that can affect anyone, but the rates are significantly high among Ashkenazi Jews: around one in 800 births. In most cases, the disease can be relatively mild, with symptoms including an enlarged spleen and liver and anemia. About two-thirds of people who carry two copies of the most common genetic variant don’t know they are carriers.
We made zebrafish with genetic variants that cause Gaucher disease in Ashkenazi Jews, and as expected, their macrophages became enlarged and unable to break down an unusual type of fat called sphingolipids. However, when the fish were exposed to TB, we were surprised to find that they were resistant to infection.
The reason for this resistance to infection was due to the fatty chemical that accumulates in the macrophages in Gaucher disease. This fatty chemical was found to act like a solvent that can kill TB bacteria in a matter of minutes by disrupting their cell walls.
These fish unknowingly led us into a debate that has been going on in human genetics for decades: Are Ashkenazi Jews, who we know are at much higher risk of Gaucher disease, somehow less likely to get it? TB infection? The answer seems to be yes.
The Ashkenazi Jewish diaspora has experienced centuries of persecution, often forced to live in ghettos and migrate from one country to another. They would have been highly exposed to tuberculosis, which spreads most widely among the poorest living conditions and densely populated urban areas.
These gene variants may increase the risk of Gaucher disease, but they also help protect against TB, giving them a selective advantage, i.e. making the variants more likely to be passed down from generation to generation and thus therefore spread within the population. A similar phenomenon is seen in groups where people carry gene variants that protect them from malaria, but when more than one copy is present, it causes harmful anemia or even sickle cell disease.
Unlike the sickle cell example, however, only people who carry two copies of the Gaucher gene variant, one from each parent, are likely to be protected from tuberculosis. This is because having a “healthy” gene makes enough enzyme to remove the fatty chemical that kills bacteria so it doesn’t build up.
This discovery may provide clues to possible new treatments for TB. Drugs that mimic the effects of Gaucher disease, specifically the buildup of the fatty chemical that acts as a solvent, could be useful in the global fight against tuberculosis.
This article is republished from The Conversation under a Creative Commons license. Read the original article.
Lalita Ramakrishnan receives funding from the Wellcome Trust, UK and the National Institutes of Health, USA.
Laura Whitworth does not work for, consult with, own shares in, or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond her academic position.
