Commensal Microbiota-Induced Interferon-Beta Mediates Host Immune System Modulation and Natural Resistance to Virus Infection
Stefan, Kailyn Louise
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CitationStefan, Kailyn Louise. 2020. Commensal Microbiota-Induced Interferon-Beta Mediates Host Immune System Modulation and Natural Resistance to Virus Infection. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractThe type I interferon (IFN-I) response is a crucial mediator of antiviral immunity and homeostatic immune system regulation. Despite this importance, the source of IFN-I signaling under homeostatic conditions has yet to be identified. We have found that one of the IFN-Is, IFNβ, is expressed by colonic lamina propria dendritic cells in response to the commensal microbiota. Moreover, commensal-induced IFNβ was found to be required for local and systemic expression of interferon-stimulated genes, and thus for regulation of the IFN-I response, under steady-state conditions. Having identified that the IFN-I response is regulated by the commensal microbiota, we proceeded to investigate the mechanism of this interaction and identified a single commensal microbial molecule, the lipooligosaccharide (LOS) of the human intestinal commensal Bacteroides fragilis, that is capable of inducing IFNβ secretion by dendritic cells in vitro and in vivo through the TLR4 signaling pathway. Since Bacteroidetes are a very prominent bacterial phylum in the gut microbiota, we examined outer membrane extracts from several different Bacteroides species that are rich in LOS reported to have similar structure to the LOS of B. fragilis and found that they are also potent IFNβ inducers. The physiological relevance of commensal-induced IFNβ in immunoregulation and in virus infection was next investigated. We discovered that IFNβ signaling is important for induction of tolerogenic mechanisms by B. fragilis capsular polysaccharide A, which is also comprised in part by an LOS-like molecule, and for protection in an experimental autoimmune disease model, EAE. Importantly, we found using vesicular stomatitis virus infection as a model, that commensal-induced IFNβ regulates the natural resistance of the host to virus infection.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365141
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