Composition of gut microbiota affects C. jejuni-mediated inflammation and autoimmunity in murine models
Campylobacter jejuni is the leading antecedent infection to the acute peripheral neuropathy Guillain-Barre Syndrome (GBS). GBS is debilitating, often causes paralysis, and can require several months or more for recovery. Most concerning is that GBS patients are frequently left with long-term neurologic disabilities. Because a vaccine for Campylobacter is lacking there are no viable approaches for preventing this form of GBS. Currently, therapeutic approaches for GBS include plasma exchange and intravenous immunoglobulin but they require specialized equipment, pose significant financial burden, and produce mixed results. These strategies lack a strong rationale because GBS is poorly defined mechanistically. While new working mouse models of GBS may lead to alternative therapies, confirmation of C. jejuni’s specific role in precipitating GBS and the mechanism(s) through which this occurs remain elusive. Thus far, evidence gathered from murine models demonstrates that multiple factors influence C. jejuni pathogenesis, including host genetics and C. jejuni genetics, particularly the genetic plasticity of this pathogen. Notably, the gut microbiota can modulate C. jejuni colonization- and colitis- resistance; however, its role in modulating C. jejuni-triggered autoimmunity remains unknown. The overarching goal of this study is to determine if the composition of gut microbiota affects C. jejuni-triggered autoimmunity in murine models. The chapters of this thesis present the following data addressing this goal; mice infected with antimicrobial resistant Campylobacter strains from Guillain-Barré syndrome patients produced severe colitis and type 2 autoimmune responses when their microbiota were depleted by antibiotics. Furthermore, we demonstrated that transplanted human fecal microbiota alters the immune response to Campylobacter jejuni infection in C57BL/6 mice, potentially increasing the risk of autoimmune sequelae. Finally, comparative genomic analysis of passaged C. jejuni populations revealed genetic variation in multidrug transporter genes cmeB and cmeR in Campylobacter jejuni populations from antibiotic treated mice. CmeR regulates expression of C. jejuni cell surface molecules, again potentially impacting the risk of autoimmune sequelae. Taken together, our results demonstrate that composition of gut microbiota is a critical determinant of inflammatory and autoimmune outcomes in C. jejuni murine models.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Brooks, Phillip Tremaine
- Thesis Advisors
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Mansfield, Linda S.
- Committee Members
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Waters, Christopher
Ganey, Patricia
Brooks, C T.
- Date
- 2016
- Subjects
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Gastrointestinal system--Microbiology
Campylobacter jejuni
Mechanism of action (Biochemistry)
Genetics
Guillain-Barré syndrome
- Program of Study
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Comparative Medicine and Integrative Biology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- xii, 190 pages
- ISBN
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9781369431636
1369431635
- Permalink
- https://doi.org/doi:10.25335/47nb-7d92