Article

Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression.

Section of Neurology, Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA.
The Journal of Immunology (Impact Factor: 5.36). 10/2010; 185(7):4101-8. DOI: 10.4049/jimmunol.1001443
Source: PubMed

ABSTRACT The importance of gut commensal bacteria in maintaining immune homeostasis is increasingly understood. We recently described that alteration of the gut microflora can affect a population of Foxp3(+)T(reg) cells that regulate demyelination in experimental autoimmune encephalomyelitis (EAE), the experimental model of human multiple sclerosis. We now extend our previous observations on the role of commensal bacteria in CNS demyelination, and we demonstrate that Bacteroides fragilis producing a bacterial capsular polysaccharide Ag can protect against EAE. Recolonization with wild type B. fragilis maintained resistance to EAE, whereas reconstitution with polysaccharide A-deficient B. fragilis restored EAE susceptibility. Enhanced numbers of Foxp3(+)T(reg) cells in the cervical lymph nodes were observed after intestinal recolonization with either strain of B. fragilis. Ex vivo, CD4(+)T cells obtained from mice reconstituted with wild type B. fragilis had significantly enhanced rates of conversion into IL-10-producing Foxp3(+)T(reg) cells and offered greater protection against disease. Our results suggest an important role for commensal bacterial Ags, in particular B. fragilis expressing polysaccharide A, in protecting against CNS demyelination in EAE and perhaps human multiple sclerosis.

Download full-text

Full-text

Available from: Javier Ochoa-Repáraz, May 01, 2014
0 Followers
 · 
97 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Commensal bacteria impact host health and immunity through various mechanisms, including the production of immunomodulatory molecules. Bacter-oides fragilis produces a capsular polysaccharide (PSA), which induces regulatory T cells and mucosal tolerance. However, unlike pathogens, which employ secretion systems, the mechanisms by which commensal bacteria deliver molecules to the host remain unknown. We reveal that Bacteroides fragilis releases PSA in outer membrane vesicles (OMVs) that induce immunomodulatory effects and prevent experimental colitis. Dendritic cells (DCs) sense OMV-associated PSA through TLR2, resulting in enhanced regulatory T cells and anti-inflammatory cytokine production. OMV-induced signaling in DCs requires growth arrest and DNA-damage-induc-ible protein (Gadd45a). DCs treated with PSA-containing OMVs prevent experimental colitis, whereas Gadd45a À/À DCs are unable to promote regulatory T cell responses or suppress proinflam-matory cytokine production and host pathology. These findings demonstrate that OMV-mediated delivery of a commensal molecule prevents disease, uncovering a mechanism of interkingdom communication between the microbiota and mammals.
    Cell Host & Microbe 10/2012; DOI:10.1016/j.chom.2012.08.004 · 12.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: An estimated 100 trillion microbes colonize human beings, with the majority of organisms residing in the intestines. This microbiota impacts host nutrition, protection, and gut development. Alterations in microbiota composition are associated with susceptibility to various infectious and inflammatory gut diseases. The mucosal surface is not a static barrier that simply prevents microbial invasion but a critical interface for microbiota-immune system interactions. Recent work suggests that dynamic interactions between microbes and the host immune system at the mucosal surface inform immune responses both locally and systemically. This review focuses on intestinal microbiota-immune interactions leading to intestinal homeostasis, and show that these interactions at the GI mucosal surface are critical for driving both protective and pathological immune responses systemically.
    Current opinion in microbiology 10/2010; 14(1):99-105. DOI:10.1016/j.mib.2010.09.018 · 7.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Infectious agents have intimately co-evolved with the host immune system, acquiring a portfolio of highly sophisticated mechanisms to modulate immunity. Among the common strategies developed by viruses, bacteria, protozoa, helminths, and fungi is the manipulation of the regulatory T cell network in order to favor pathogen survival and transmission. Treg activity also benefits the host in many circumstances by controlling immunopathogenic reactions to infection. Interestingly, some pathogens are able to directly induce the conversion of naive T cells into suppressive Foxp3-expressing Tregs, while others activate pre-existing natural Tregs, in both cases repressing pathogen-specific effector responses. However, Tregs can also act to promote immunity in certain settings, such as in initial stages of infection when effector cells must access the site of infection, and subsequently in ensuring generation of effector memory. Notably, there is little current information on whether infections selectively drive pathogen-specific Tregs, and if so whether these cells are also reactive to self-antigens. Further analysis of specificity, together with a clearer picture of the relative dynamics of Treg subsets over the course of disease, should lead to rational strategies for immune intervention to optimize immunity and eliminate infection.
    Advances in Immunology 01/2011; 112:73-136. DOI:10.1016/B978-0-12-387827-4.00003-6 · 5.53 Impact Factor