Researchers have introduced a new molecule designed for visualizing how sphingomyelin is metabolized, paving the way for potential advancements in infection research.
In the late 1800s, German pathologist Ludwig Thudichum discovered new types of fatty substances, called lipids, in the brain. He coined the term sphingolipids, inspired by the Greek mythological Sphinx due to the “many puzzles it posed to scientists.”
Since Thudichum’s time, various diseases linked to abnormal sphingolipid metabolism in the brain have been identified, including Fabry’s disease and Gaucher’s disease. Additionally, sphingolipids are associated with infectious diseases, such as viral infections with Ebola, measles, or Covid-19, as well as bacterial infections caused by Pseudomonas aeruginosa and Staphylococcus aureus, which can lead to middle ear infections, skin infections, lung infections, and more. In these cases, the breakdown of sphingomyelin by the enzyme sphingomyelinase is often a critical factor, but previously, it was impossible to visualize this enzyme’s activity.
A New Chemical Probe to Address This Challenge
Scientists from Würzburg and Berlin have successfully created a sphingomyelin derivative that allows for the visualization of sphingomyelin distribution and sphingomyelinase activity during infections.
These researchers are part of the Research Training Group 2581 “Metabolism, topology and compartmentalisation of membrane proximal lipid and signalling components in infection,” supported by the German Research Foundation (DFG). This group involves collaboration among chemists, physicists, and biologists to develop new chemical compounds and evaluate their use in infection research.
“The newly developed molecules are trifunctional sphingomyelins derived from natural sphingomyelin, enhanced with three additional features. It was a challenge to create such molecules that the metabolism would accept as if they were their natural source,” explains Professor Jürgen Seibel from the Institute of Organic Chemistry at Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany.
Visualizing Sphingomyelin Breakdown During Chlamydia Infection
The team not only assessed bacterial sphingomyelinase activity on human cell surfaces but also visualized the degradation of sphingomyelin within human cells during infections with intracellular Chlamydia bacteria, known for affecting the human genital tract and potentially leading to cancer in the affected tissues.
Within host cells, Chlamydia creates a structure known as an inclusion, which the researchers found primarily contains metabolized forms of the trifunctional sphingomyelins. Utilizing techniques like expansion microscopy and click-chemistry, they observed that the amount of broken-down sphingomyelin molecules increased as Chlamydia transitioned from a non-infectious to an infectious state. This new ability to visualize infection processes opens up possibilities for targeted strategies against these infections.
“This innovative chemical tool will undoubtedly be beneficial and can easily be utilized in numerous laboratories,” remarks Professor Seibel. “Our goal is to leverage it to discover new anti-infectious or immunotherapeutic strategies in drug development aimed at combating infectious diseases by modifying sphingolipid metabolism.”
