Mucosal sugars delineate pyrazine vs pyrazinone autoinducer signaling in Klebsiella oxytoca

• Published in: Nature communications Vol. 15; no. 1; pp. 8902 - 17
• Main Authors: Hamchand, Randy, Wang, Kevin, Song, Deguang, Palm, Noah W., Crawford, Jason M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 140/131; 140/58; 45/91; 631/326/41; 631/45; 639/638/60; 639/638/92/349; 82/16; 82/80; Bacteria - chemistry; Bacteria - genetics; Biosynthesis; Carbohydrate metabolism; Carbohydrates; Enterobactin; Histamine receptors; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Immune response; Iron - metabolism; Klebsiella; Klebsiella Infections - immunology; Klebsiella Infections - metabolism; Klebsiella Infections - microbiology; Klebsiella oxytoca; Klebsiella oxytoca - chemistry; Klebsiella oxytoca - genetics; Klebsiella oxytoca - metabolism; Klebsiella oxytoca - pathogenicity; Leupeptin; Leupeptins - metabolism; Lungs; Metabolism; Microorganisms; multidisciplinary; N-Acetylneuraminic Acid - metabolism; Pathogenesis; Protease inhibitors; Proteinase inhibitors; Pyrazine; Pyrazines; Pyrazines - metabolism; Pyrroles - metabolism; Receptors, Histamine - metabolism; Science; Science (multidisciplinary); Signal transduction; Sugar; Virulence; Virulence factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53185-6

Virulent Klebsiella oxytoca strains are associated with gut and lung pathologies, yet our understanding of the molecular signals governing pathogenesis remains limited. Here, we characterized a family of K. oxytoca pyrazine and pyrazinone autoinducers and explored their roles in microbial and host signaling. We identified the human mucin capping sugar Neu5Ac as a selective elicitor of leupeptin, a protease inhibitor prevalent in clinical lung isolates of K. oxytoca , and leupeptin-derived pyrazinone biosynthesis. Additionally, we uncovered a separate pyrazine pathway, regulated by general carbohydrate metabolism, derived from a broadly conserved PLP-dependent enzyme. While both pyrazine and pyrazinone signaling induce iron acquisition responses, including enterobactin biosynthesis, pyrazinone signaling enhances yersiniabactin virulence factor production and selectively activates the proinflammatory human histamine receptor H4 (HRH4). Our findings suggest that the availability of specific carbohydrates delineates distinct autoinducer pathways in K. oxytoca that may have differential effects on bacterial virulence and host immune responses. Differential carbohydrate metabolism elicits distinct pyrazine and pyrazinone autoinducer signalling pathways in Klebsiella oxytoca , which impact bacterial virulence programs.