Interkingdom Communication of a Bacterial Mutualist and its Mammalian Host

Citation

Shen, Yue (2012) Interkingdom Communication of a Bacterial Mutualist and its Mammalian Host. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/56YV-8J33. https://resolver.caltech.edu/CaltechTHESIS:06062012-145546209

Abstract

Microbial molecules have evolved to promote transient and/or permanent associations with mammals. Although numerous examples of secretion systems employed by pathogens during infection have been described, mechanisms by which commensal bacteria export molecules during symbiosis remain unknown. The human gut mutualist Bacteroides fragilis produces a capsular polysaccharide (PSA) that directs host immune development. We reveal herein that outer membrane vesicles (OMVs) deliver PSA to dendritic cells (DCs), promoting development of regulatory T cells and inducing anti-inflammatory cytokines during in vivo protection of intestinal disease. OMV mediated regulatory responses required the Growth Arrest and DNA-Damage-Inducible protein (Gadd45α) in DCs. DCs treated with OMVs containing PSA protect mice from experimental colitis, whereas Gadd45α-/- DCs are unable to support T cell regulatory response and are defective in suppressing proinflammatory cytokine production and host pathology. Our findings demonstrate DC-induced protection from disease via interaction with a beneficial microbial molecule delivered by OMVs, uncovering a novel paradigm for interkingdom communication between the microbiota and mammals. In another effort to test the immunomodulatory activity of PSA outside of the gut, we found systemic treatment with PSA protects animals from experimental sepsis, a model for systemic inflammatory disease. More interestingly, this protection is mediated by B cells but not T cells because Rag-/- mice reconstituted with B cells gained the protection by PSA while those reconstituted with T cells were not protected. We further showed that a subset of B cells, marginal B cells, which are known to produce natural antibodies against bacterial antigens, were sufficient in mediating this protection. Preliminary data also suggested that secretion of IgM and/ or expression of type II Interleukin 1 receptor (IL-1R2) from marginal zone B cells might be critical for the suppression of the excessive inflammation during disease. This study will help to uncover the systemic effect of PSA, a microbial molecule from a gut commensal, and its potential as a novel therapy for human sepsis.

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