Virulent and Antimicrobial Amyloids in Infections and Neurodegeneration
Amyloids are protein fibers with robust structures, which are known mainly in the context of neurodegenerative diseases yet are secreted by species across kingdoms of life to carry out physiological function and help survival and activity. For example, several microbial amyloids serve as key “weapons” making infections more aggressive. Thereby, they exposed new routes for the development of novel antivirulence drugs, which may elicit less resistance as the evolutionary pressure on the microbe is less profound compared to bactericidal drugs. Our laboratory published the first structures of bacterial amyloid fibrils involved in virulent activities. Our findings thus far exposed an extreme structural diversity, extending beyond canonical amyloid cross-β structures, and encoding different activities. In particular, the discovery of a novel class of cross-α amyloid fibrils of toxic peptides presented a unique protein architecture, offered drug targets and leads, and opened a fresh perspective to study amyloid-related toxicity. Moreover, we revealed that amyloids secreted by bacteria highly abundant in the microbiome and food sources show similarities in molecular structures to human amyloids involved in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. This might raise concerns about the involvement of microbes in facilitating these diseases, similar to prion proteins transmitted by contaminated meat that elicit the Creutzfeldt-Jakob disease. In addition, we identified peptides produced across species that provide antimicrobial protection that form amyloid fibrils and determined their first high resolution structures. This amyloid-antimicrobial link signifies a physiological role in neuroimmunity for human amyloids. Such antimicrobial fibrils can facilitate the design of functional and stable nanostructures to serve as a stable coating for medical devices or implants, industrial equipment, food packing and more.
Atomic structures of amyloid fibrils determined by X-ray crystallography and cryogenic electron microscopy (cryo-EM) of microbial and antimicrobial amyloids. A scanning electron micrograph shows cells damaged by a cytotoxic bacterial amyloid peptide, and transmission electron micrographs display fibrils of antimicrobial peptides covering bacterial cells, and of massive fibrils formed by biofilm-associated amyloids.
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