Interplay of host and pathogen factors determines immunity and clinical outcome following Campylobacter jejuni infection in mice
"Campylobacter jejuni is a common cause of bacterial enteritis worldwide, and is associated with the post-infectious neuropathy Guillain-Barré syndrome (GBS). The currently accepted pathogenesis of C. jejuni-associated GBS involves generation of cross-reactive antibodies to the C. jejuni LOS and structurally similar gangliosides enriched in peripheral nerves. Complex host-pathogen interactions determine innate and adaptive immunity and corresponding disease outcomes. The overarching aim of this study was to determine how these interactions underlie contrasting immune responses to C. jejuni in mice, beginning with the initial interaction of C. jejuni with dendritic cells (DCs) in vitro and assessing the impact on development of adaptive immunity and disease outcome in vivo. The model system was developed to exploit both C. jejuni strain differences and immunogenetic biases reported for C57BL/6 and BALB/c mice. C. jejuni strains associated with colitis (C. jejuni 11168) and GBS (C. jejuni 260.94) were used in combination with C57BL/6 mice, a reportedly Th1-biased strain, and BALB/c mice, a reportedly Th2-biased strain. C. jejuni strains were evaluated for invasion efficiency, intracellular survival, and elicitation of pro-inflammatory and Th-polarizing cytokine production in vitro using bone marrow-derived DCs (BMDCs) from C57BL/6 and BALB/c mice. In vivo models were used to assess how local and systemic adaptive immunity, leading to disease outcomes including colitis and production of anti-ganglioside antibodies, vary by both C. jejuni strain and mouse genetic background. BALB/c wild-type and IL-10-/- mice infected with C. jejuni 260.94 were first assessed as a potential GBS model. C57BL/6 IL-10-/- mice infected with C. jejuni 260.94 were previously shown to mount Th2-mediated immunity and produce anti-ganglioside antibodies, and BALB/c mice are reportedly Th2-biased. BALB/c mice were therefore expected to mount strong Th2-mediated responses, produce anti-ganglioside antibodies, and develop neurological deficits. Instead, infected BALB/c mice developed systemic Th1/Th17-mediated immunity, and did not develop anti-ganglioside antibodies or neurological disease. The contrasting immune response to C. jejuni 260.94 demonstrated by mice of two different genetic backgrounds highlights the important and incompletely understood role of host factors in determining immunity to C. jejuni. The second in vivo study was designed to further explore these contrasting immune responses. Both C57BL/6 IL-10-/- and BALB/c IL-10-/- mice were orally infected with colitogenic C. jejuni 11168 or GBS-associated C. jejuni 260.94. Immunity and disease outcome were C. jejuni strain-specific in BALB/c IL-10-/- mice: C. jejuni 11168 stimulated strong Th1/Th17-mediated immunity and colitis with greater transmigration of C. jejuni through intestinal layers and higher numbers of intracellular organisms. C. jejuni 260.94 was less invasive and induced less robust Th1/Th17 responses, without colitis or antiganglioside antibody production. These findings were mirrored in vitro, as C. jejuni 11168 demonstrated higher invasion efficiency, intracellular survival ability, and stimulated more robust production of IL-6 by BALB/c IL-10-/- BMDCs than C. jejuni 260.94. The findings in BALB/c IL-10-/- mice indicate that outcome of infection is dependent upon the infecting C. jejuni strain, and that DCs have a potential early role in driving the immune response. Interestingly, infected C57BL/6 IL-10-/- mice in this study colonized with C. jejuni but developed neither the previously reported severe colitis following C. jejuni 11168 infection nor the Th2-mediated immunity and anti-ganglioside antibody production after C. jejuni 260.94 infection. Lactobacillus murinus was cultured from all C57BL/6 IL-10-/- mice, but no BALB/c IL-10-/- mice, at the end of the study. Further studies evaluating L. murinus as a potential probiotic candidate are warranted. Results of the current studies demonstrate that immunity and disease outcome following C. jejuni infection depend upon the characteristics of both the infecting C. jejuni strain and host genetic background, and implicate DCs as early contributors to adaptive immunity."--Pages ii-iii.
Read
- In Collections
-
Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
-
Theses
- Authors
-
Brudvig, Jean Marie
- Thesis Advisors
-
Mansfield, Linda S.
- Committee Members
-
Hoag, Kathleen
Manning, Shannon
Moeser, Adam
Patterson, Jon
- Date
- 2018
- Program of Study
-
Comparative Medicine and Integrative Biology - Doctor of Philosophy
- Degree Level
-
Doctoral
- Language
-
English
- Pages
- xvii, 236 pages
- ISBN
-
9780355867060
0355867060
- Permalink
- https://doi.org/doi:10.25335/M54X54K18