Probiotics are live organisms that confer a benefit to their host in some fashion. Bacteroides fragilis is one such probiotic by virtue of the immunomodulatory properties of its capsular polysaccharide PSA, the founding member of a novel class of MHC class II-presented carbohydrate T cell antigens (glycoantigens). Oral exposure to PSA in gnotobiotic mice restores the Th1/Th2 balance and immune homeostasis while rendering these animals less susceptible to inflammatory diseases through the induction of regulatory T cells. Our published and preliminary data further demonstrate that the nature of the N-linked glycans decorating antigen presenting cells, and specifically MHCII, is a critical aspect of the mechanism by which glycoantigens are presented and recognized by T cells. These innovative and unexpected findings suggest that immune homeostasis could be regulated by cellular glycosylation by virtue of the impact host glycans have on the induction of commensal-specific Treg cells. Here, we propose three specific aims to obtain a complete mechanistic and structural understanding of how host glycosylation modulates glycoantigen presentation, peripheral inflammation, and ultimately immune homeostasis at the molecular, cellular, and organismal levels. The results from our proposed experiments will reveal regulatory connections between inflammation and glycosylation through carbohydrate antigen activity and could lead to drug target identification to prevent and/or treat ongoing inflammation in diseases as diverse as asthma, IBD, atherosclerosis, and cancer.

Public Health Relevance

Our findings during the previous funding period show there is interplay between protein glycosylation, protective anti-inflammatory immune responses, and the prevention of inflammatory diseases by commensal bacteria-derived polysaccharide antigens. This proposal seeks to provide an in depth analysis of the mechanism underlying this interplay in order to understand and manipulate these relationships to improve the outcome for patients with diseases where underlying inflammation is a causative force for disease progression and pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM082916-04
Application #
8600289
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Marino, Pamela
Project Start
2009-08-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2014
Total Cost
$288,153
Indirect Cost
$106,353
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Johnson, Jenny L; Jones, Mark B; Cobb, Brian A (2015) Bacterial capsular polysaccharide prevents the onset of asthma through T-cell activation. Glycobiology 25:368-75
Ryan, Sean O; Leal Jr, Sixto M; Abbott, Derek W et al. (2014) Mgat2 ablation in the myeloid lineage leads to defective glycoantigen T cell responses. Glycobiology 24:262-71
Taylor, Patricia R; Roy, Sanhita; Leal Jr, Sixto M et al. (2014) Activation of neutrophils by autocrine IL-17A-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORýýt and dectin-2. Nat Immunol 15:143-51
Ryan, Sean O; Abbott, Derek W; Cobb, Brian A (2014) Myeloid glycosylation defects lead to a spontaneous common variable immunodeficiency-like condition with associated hemolytic anemia and antilymphocyte autoimmunity. J Immunol 192:5561-70
Bloem, Karien; Garcia-Vallejo, Juan J; Vuist, Ilona M et al. (2013) Interaction of the Capsular Polysaccharide A from Bacteroides fragilis with DC-SIGN on Human Dendritic Cells is Necessary for Its Processing and Presentation to T Cells. Front Immunol 4:103
Ryan, Sean O; Johnson, Jenny L; Cobb, Brian A (2013) Neutrophils confer T cell resistance to myeloid-derived suppressor cell-mediated suppression to promote chronic inflammation. J Immunol 190:5037-47
Johnson, Jenny L; Jones, Mark B; Ryan, Sean O et al. (2013) The regulatory power of glycans and their binding partners in immunity. Trends Immunol 34:290-8
Rabinovich, Gabriel A; van Kooyk, Yvette; Cobb, Brian A (2012) Glycobiology of immune responses. Ann N Y Acad Sci 1253:1-15
Kreisman, Lori Sc; Cobb, Brian A (2012) Infection, inflammation and host carbohydrates: a Glyco-Evasion Hypothesis. Glycobiology 22:1019-30
Ryan, Sean O; Bonomo, Jason A; Zhao, Fan et al. (2011) MHCII glycosylation modulates Bacteroides fragilis carbohydrate antigen presentation. J Exp Med 208:1041-53

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