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Author (presenter): Trevor G Marshall
Email: trevor.m@AutoimmunityResearch.org
1. School of Biological Sciences and Biotechnology, Murdoch University, Western Australia
2. Autoimmunity Research Foundation, Thousand Oaks, CA, USA
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Bacterial Capnine Blocks Transcription of Human Antimicrobial Peptides

The US CDC believes that 65% of all infections in developed countries may be caused by
pathogens in biofilms. 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 Sarcoidosis [1]. 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.
METHODS: A single Type 1 Nuclear Receptor, the VDR (commonly known as the `Vitamin D
Receptor'), is responsible for transcription of LL-37, the human Cathelicidin antimicrobial
peptide, as well as the beta-Defensin anti-microbial peptides defB2/defB4 [3]. 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.
RESULTS: 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.
CONCLUSION: Medical Metagenomics has demonstrated the ability to deliver important
results in-silico, potentially underpinning an infectious pathogenesis for idiopathic chronic
illness [4,5].

References:
1. Wirostko E, Johnson LA, Wirostko BM, Farris RL: Mycoplasma-like organisms and ophthalmic
disease. Trans Am Ophthalmol Soc. 1993;91:85-94; discussion 95-8.
2. Dempsey KE, Riggio MP, Lennon A, Hannah VE, Ramage G, Allan D, Bagg J. Identification of
bacteria on the surface of clinically infected and non-infected prosthetic hip joints removed
during revision arthroplasties by 16S rRNA gene sequencing and by microbiological culture.
Arthritis Res Ther. 2007 May 14;9(3):R46
3. Wang TT, et al: Large-scale in silico and microarray-based identification of direct 1,25-
dihydroxyvitamin-D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
4. Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G: High levels of active 1,25-
dihydroxyvitamin D despite low levels of the 25-hydroxyvitamin D precursor - Implications of
dysregulated vitamin D for diagnosis and treatment of Chronic Disease. In Vitamin D: New
Research. Volume 1. Edited by: Stoltz VD. New York: Nova Science Publishers; 2006. ISBN: 1-
60021-000-7
5.
Marshall TG: VDR Nuclear Receptor Competence is the Key to Recovery from Chronic
Inflammatory and Autoimmune Disease. Abstract presentation, DMM2006, Karolinska Institute,
May 2006. Copy available from URL http://autoimmunityresearch.org/karolinska-handout.pdf
Nature Precedings : doi:10.1038/npre.2007.164.1 : Posted 21 Jun 2007