N-Acyl Amides from Neisseria meningitidis and Their Role in Sphingosine Receptor Signaling

Area of Science:

• Microbiology
• Immunology
• Metabolomics

Background:

• Neisseria meningitidis is a dangerous pathogen causing meningitis and septicemia.
• Its virulence mechanisms, including immune evasion and barrier translocation, are not fully understood.
• N-acyl amides are bioactive small molecules involved in bacterial signaling, but many remain unidentified in the human microbiota.

Purpose of the Study:

• To identify novel N-acyl amides produced by Neisseria meningitidis.
• To investigate the immunomodulatory functions of these identified N-acyl amides.
• To explore the role of these metabolites in pathogen virulence and host immune response.

Main Methods:

• Heterologous expression of an N-acyltransferase from N. meningitidis.
• Identification and characterization of N-acyl amides using mass spectrometry.
• Assays to determine the effects of metabolites on immune cell signaling pathways (e.g., IL-10, IL-17A).

Main Results:

• Identified 30 novel N-acyl amides from N. meningitidis.
• Characterized two mammalian N-acyl amides from bovine medium.
• Demonstrated that these N-acyl amides act as agonists for the G-protein coupled receptor S1PR4.
• Showed suppression of anti-inflammatory IL-10 signaling in macrophages.
• Observed suppression of pro-inflammatory IL-17A+ population in CD4+ T cells.

Conclusions:

• N. meningitidis synthesizes diverse N-acyl amides with significant immunomodulatory activities.
• These metabolites can suppress both pro- and anti-inflammatory immune responses.
• The identified N-acyl amides represent potential virulence factors and targets for therapeutic intervention.