Poster - Bacterial capnine blocks transcription of human antimicrobial peptides

Type: Poster presentation
Presented by: Trevor Marshall, PhD
Conference: Third International Conference on Metagenomics
Location: University of California, San Diego
Date: July 11-13, 2007
Additional content: poster (includes a number of Wirostko photographs); post at Nature Precedings

The US CDC believes that 65% of all infections in developed countries may be caused by pathogens in biofilms A structured community of microorganisms encapsulated within a self-developed protective matrix and living together.. Electron Microscopy has shown that these bacterial communities can evade phagocytosis, and persist in the cytoplasm of monocytes, macrophages, lymphocytes and neutrophils. Three decades ago, Wirostko, et al, found such intraphagocytic communities in Crohn’s disease, Juvenile Rheumatoid Arthritis and Sarcoidosis¹⁾. However, the mechanism(s) by which such persistent bacteria could evade the immune system have remained elusive. Recently, 16S RNA from species of gliding bacteria never thought to be able to survive in-vivo, have been found in surgically removed biofilms.²⁾ This study set out to identify whether the genomes of these gliding bacteria might yield insight into mechanisms by which such persistent pathogens could evade phagocytosis.

A single Type 1 Nuclear ReceptorIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affects transcription., the VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response. (commonly known as the ‘Vitamin D ReceptorA nuclear receptor located throughout the body that plays a key role in the innate immune response.’), is responsible for transcription of LL-37, the human Cathelicidin Family of antimicrobial peptides found primarily in immune cells and transcribed by the Vitamin D Receptor. antimicrobial peptide, as well as the beta Defensin anti-microbial peptides defB2/defB4³⁾. Disabling transcription by the VDR would allow a pathogen to persist inside phagocytes without threat from these anti-microbial peptides. Static molecular modeling (primarily using AutoDock) was used to screen a number of proteins and peptides known to be produced by the genomes of the gliding bacteria.

A candidate bacterial sulfonolipid, Capnine, was identified to have a nanomolar Ki for the ligand binding pocket (LBP) of the VDR. Molecular Dynamics simulation of the human VDR in complex with Capnine confirmed that this substance is indeed stable in the VDR LBP, and that its action is that of a strong transcriptional antagonist.

Medical Metagenomics has demonstrated the ability to deliver important results in silicoExperiment technique performed on computer or via computer emulation., potentially underpinning an infectious pathogenesis for idiopathicnic illness.⁴⁾⁵⁾