Abstract
BackgroundThe immunopathological impact of human Arcobacter (A.) infections is under current debate. Episodes of gastroenteritis with abdominal pain and acute or prolonged watery diarrhea were reported for A. butzleri infected patients. Whereas adhesive, invasive and cytotoxic capacities have been described for A. butzleri in vitro, only limited information is available about the immunopathogenic potential and mechanisms of infection in vivo.Methodology/Principal FindingsGnotobiotic IL-10-/- mice were generated by broad-spectrum antibiotic treatment and perorally infected with the A. butzleri strains CCUG 30485 and C1 shown to be invasive in cell culture assays. Bacterial colonization capacities, clinical conditions, intestinal, extra-intestinal and systemic immune responses were monitored at day six and 16 postinfection (p.i.). Despite stable intestinal A. butzleri colonization at high loads, gnotobiotic IL-10-/- mice were virtually unaffected and did not display any overt symptoms at either time point. Notably, A. butzleri infection induced apoptosis of colonic epithelial cells which was paralleled by increased abundance of proliferating cells. Furthermore A. butzleri infection caused a significant increase of distinct immune cell populations such as T and B cells, regulatory T cells, macrophages and monocytes in the colon which was accompanied by elevated colonic TNF, IFN-γ, nitric oxide (NO), IL-6, IL-12p70 and MCP-1 concentrations. Strikingly, A. butzleri induced extra-intestinal and systemic immune responses as indicated by higher NO concentrations in kidney and increased TNF, IFN-γ, IL-12p70 and IL-6 levels in serum samples of infected as compared to naive mice. Overall, inflammatory responses could be observed earlier in the course of infection by the CCUG 30485 as compared to the C1 strain.Conclusion/SignificancePeroral A. butzleri infection induced not only intestinal but also extra-intestinal and systemic immune responses in gnotobiotic IL-10-/- mice in a strain-dependent manner. These findings point towards an immunopathogenic potential of A. butzleri in vertebrate hosts.
Highlights
The motile and spiral-shaped gram-negative Arcobacter (A.) species belong to the family of Campylobacteraceae and can be isolated from a broad range of habitats
Given that mice can exhibit a strong colonization resistance against pathogens such as C. jejuni due to their host- and age-specific microbiota composition [16], we first addressed the question whether different A. butzleri strains were able to stably establish intestinal colonization in wildtype mice with a conventional microbiota
Survey of A. butzleri loads in fecal samples revealed that following infection with 109 viable A. butzleri strains CCUG 30485 or C1, gnotobiotic IL-10-/- mice could be stably colonized with pathogenic loads of 108 colony forming units (CFU) per gram fecal sample (Fig 1)
Summary
The motile and spiral-shaped gram-negative Arcobacter (A.) species belong to the family of Campylobacteraceae and can be isolated from a broad range of habitats. The barrier dysfunction caused by A. butzleri infection in monolayers of the human colon cell line HT-29/B6 highlights potential mechanisms by which diarrhea is induced in susceptible human hosts [15]. In order to study the pathogenic potential of A. butzleri in more detail in vivo, we monitored the colonization properties of two A. butzleri strains, for which invasive capacities have been shown in in vitro assays [8], and the subsequent host responses following peroral infection. In previous infection studies with enteric pathogens such as Campylobacter (C.) jejuni we could demonstrate that the physiological colonization resistance exerted by mice harboring a conventional microbiota prevented the animals from infection and could be overcome following eradication of the murine intestinal microbiota [16]. Invasive and cytotoxic capacities have been described for A. butzleri in vitro, only limited information is available about the immunopathogenic potential and mechanisms of infection in vivo
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