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home:publications:marshall_metagenomics_2007 [04.24.2009]
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home:publications:marshall_metagenomics_2007 [01.03.2012] (current)
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 + 
 +~~NOTOC~~
 +====== Poster - Bacterial capnine blocks transcription of human antimicrobial peptides ======
  
 +
 +**Type:** Poster presentation\\
 +**Presented by:**  Trevor Marshall, PhD\\
 +**Conference:​** ​ [[http://​metagenomics.calit2.net/​2007/​index.php|Third International Conference on Metagenomics]]\\
 +**Location:​** ​ University of California, San Diego\\
 +**Date:​** ​ July 11-13, 2007\\
 +**Additional content:** [[http://​autoimmunityresearch.org/​transcripts/​metagenomics2007.pdf|poster]] (includes a number of Wirostko photographs);​ [[http://​precedings.nature.com/​documents/​164/​version/​1|post at Nature Precedings]]\\
 +
 + 
 +
 +===== Abstract =====
 +
 +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(({{pubmed>​long:​8140710}})).
 +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.(({{pubmed>​long:​17501992}})) 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(({{pubmed>​long:​16002434}})). 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 idiopathicnic
 +illness.((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))((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))
 +
 +{{tag>​posters Trevor_Marshall_PhD Metagenomics capnine antimicrobial_peptides 2007}}
 +
 +===== References =====
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