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Tuberculosis (TB) remains a major global health challenge, responsible for over a million deaths each year. The disease is caused by the bacterium Mycobacterium tuberculosis, which has developed a sophisticated outer structure that helps it evade the immune responses of those it infects. In a recent study published in ACS Infectious Diseases, scientists have created a chemical probe aimed at investigating a critical element of this protective envelope, marking a significant step toward developing new strategies to combat the bacterium.
Given that effective treatment for TB often necessitates prolonged antibiotic use, there’s a risk of the bacteria developing resistance. This has led researchers to seek alternative therapeutic approaches, particularly targeting the bacterium’s mycomembrane—the outermost layer that shields it from various stressors. When M. tuberculosis encounters immune cells from the host, specifically macrophages, the mycomembrane produces substances that can dampen the host’s immune response. Previous work by Ben Swarts, Sloan Siegrist, and their team introduced light-activated chemical probes designed to replicate some of these suppressive compounds and analyze their potential interactions with immune cells. Their latest development focuses on a different component of the mycomembrane called mycolic acid, a probe that captures proteins interacting with it in immune cells, potentially providing insights into the bacterium’s survival mechanisms within the host.
In laboratory tests using enzyme immunoassays, the mycolic acid probe elicited an immune response analogous to that of actual mycolic acid in cultured mouse macrophage cells. The researchers employed fluorescence scanning to document that this probe successfully photo-labeled proteins in the macrophages. Subsequent analysis through an immunoblotting technique revealed its interaction with a specific receptor on macrophage cells known as TREM2, which plays a role in suppressing the activation of immune cells.
Swarts and his colleagues assert that their methodology offers a novel means to explore the function of mycolic acids in the pathogenicity of M. tuberculosis. “Chemical probes are essential tools for uncovering and characterizing the interactions between hosts and pathogens that might otherwise remain elusive,” notes Swarts. “Understanding the molecular intricacies of how components of the M. tuberculosis cell envelope influence host responses could guide the development of innovative TB treatment strategies, including immunotherapies focused on host proteins.”
The research has received support from the National Science Foundation and the National Institutes of Health.
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