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Unveiling the Role of Sphingolipids in Infection Through Innovative Chemical Probes
At the close of the 19th century, German pathologist Ludwig Thudichum made a significant breakthrough by isolating new fatty substances from the brain, which he named sphingolipids. This term was derived from the Greek mythological creature, the Sphinx, symbolizing the complexities and challenges these compounds presented to researchers.
Since Thudichum’s discovery, researchers have identified a range of diseases stemming from abnormal sphingolipid metabolism in the brain. Conditions such as Fabry’s disease and Gaucher’s disease are notable examples. Moreover, sphingolipids have been implicated in various infectious diseases, with links to viruses such as Ebola, measles, and Covid-19, alongside bacteria like Pseudomonas aeruginosa and Staphylococcus aureus, which can lead to ear infections, skin issues, and respiratory diseases. In these cases, the breakdown of sphingomyelin by sphingomyelinase is often a pivotal factor, yet until recently, visualizing the activity of this enzyme within infection contexts has been a challenge.
A New Chemical Probe to Fill the Gap
In a significant development, researchers from institutions in Würzburg and Berlin have engineered a derivative of sphingomyelin that enables the visualization of sphingomyelin distribution and sphingomyelinase activity during infections.
These scientists are part of the Research Training Group 2581, “Metabolism, topology and compartmentalisation of membrane proximal lipid and signalling components in infection,” which is supported by the German Research Foundation (DFG). This multidisciplinary collaboration bringing together chemists, physicists, and biologists has led to the synthesis and testing of innovative chemical compounds for infection research.
“These new trifunctional sphingomyelins are designed based on the natural sphingomyelin structure and have been modified with three additional functionalities,” explains Professor Jürgen Seibel from the Institute of Organic Chemistry at Julius-Maximilians-Universität (JMU) Würzburg. “Creating such molecules that can be accepted by the metabolic processes like their natural counterparts posed a considerable challenge.”
Sphingomyelin Degradation During the Lifecycle of Chlamydia Bacteria
The research team validated the functionality of their newly created molecules by assessing the activity of bacterial sphingomyelinase on human cell surfaces. They also successfully visualized sphingomyelin breakdown within human cells infected with intracellular Chlamydia bacteria, which are known to infect the genital tract and may play a role in cancer development in affected tissue.
Within infected cells, Chlamydia bacteria create a unique structure known as an inclusion, where the researchers identified that the majority of the trifunctional sphingomyelins were present in their cleaved forms. They employed techniques such as expansion microscopy and click-chemistry to establish that the quantity of metabolized sphingomyelin increased as Chlamydia evolved from non-infectious to infectious particles. This newfound ability to visualize these infection processes paves the way for developing targeted therapeutic strategies against such infections.
“This innovative chemical tool will undoubtedly prove beneficial and can be utilized in many laboratories,” states Professor Seibel. “Our goal is to leverage it to discover new anti-infectious or immunotherapeutic approaches for drug development aimed at addressing infectious diseases by influencing sphingolipid metabolism.”
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