Recent studies have revealed the importance of the gut associated lymphoid tissue (GALT) and its interaction with gut commensal bacterial population in the balance of peripheral immunity. We have shown that modifying bacterial populations of the gut can protect against EAE, the experimental model of human multiple sclerosis. Prophylactic and therapeutic oral administration of a highly purified, structurally characterized preparation of the bacterial antigen, polysaccharide A (PSA) derived from the human commensal Bacteroides fragilis can protect against EAE in an IL-10 dependent mechanism. Of note, was a significant increase in both CD103+CD11Chigh GALT derived DC and FoxP3+Treg cells with concurrent downregulation of IL-17 in the CLN of protected mice, when compared to untreated controls. We hypothesize that specific gut commensal antigens, in particular capsular polysaccharide A (PSA) of the human commensal bacteria B. fragilis, when administered per os can protect against CNS demyelinating disease. Protection is mediated via TLR-2 ligation of mucosal DC or B cell populations that are polarized and migrate to the CNS and associated lymphoid tissue whereupon they induce disease-modifying regulatory T cells that control inflammation and demyelination.
The specific aims are: 1) to identify and phenotype the APC associated with PSA immunization in EAE mice, 2) to identify the specific molecules involved in the migration and trafficking by PSA-associated APCs as well as T/B cells to the brain/spinal cord and CNS associated lymphoid tissues and 3) to determine the requirement of TLR2 in the induction of CD39+/- Tregs and B cells by PSA in the CNS and its associated lymphoid tissue. The innovation of this proposal is two-fold. First, it provides novel information on the immune interplay between commensal activated GALT and regulation of CNS inflammatory demyelination and second puts forth a novel probiotic approach as a potential therapeutic against this chronic debilitating disease with broad implications on the treatment of MS and other autoimmune conditions.

Public Health Relevance

The role of the gut microbiome in maintaining immune homeostasis is just being appreciated. This proposal investigates the role of the gut commensal bacteria, in particular B. fragilis, in regulating central nervous system demyelination. We have observed that a single purified bacterial polysaccharide (PSA) can protect against experimental autoimmune encephalomyelitis (EAE), the animal model of human multiple sclerosis. The immunologic mechanism by which this occurs appears related to the induction and polarization of a gut associated dendritic cell population and the amplification of both a T and B regulatory response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI098282-01A1
Application #
8484553
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Esch, Thomas R
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$276,500
Indirect Cost
$104,761
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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Wang, Yan; Begum-Haque, Sakhina; Telesford, Kiel M et al. (2014) A commensal bacterial product elicits and modulates migratory capacity of CD39(+) CD4 T regulatory subsets in the suppression of neuroinflammation. Gut Microbes 5:552-61
Wang, Yan; Telesford, Kiel M; Ochoa-Repáraz, Javier et al. (2014) An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling. Nat Commun 5:4432
Joscelyn, Jennifer; Kasper, Lloyd H (2014) Digesting the emerging role for the gut microbiome in central nervous system demyelination. Mult Scler 20:1553-9
Ochoa-Repáraz, Javier; Kasper, Lloyd H (2014) Gut microbiome and the risk factors in central nervous system autoimmunity. FEBS Lett 588:4214-22