Correction: Novel Murine Infection Models Provide Deep Insights into the “Ménage à Trois” of Campylobacter jejuni, Microbiota and Host Innate Immunity

Abstract

Background: Although Campylobacter jejuni-infections have a high prevalence worldwide and represent a significant socioeconomic burden, it is still not well understood how C. jejuni causes intestinal inflammation. Detailed investigation of C. jejuni-mediated intestinal immunopathology is hampered by the lack of appropriate vertebrate models. In particular, mice display colonization resistance against this pathogen. Methodology/Principal Findings:To overcome these limitations we developed a novel C. jejuni-infection model using gnotobiotic mice in which the intestinal flora was eradicated by antibiotic treatment. These animals could then be permanently associated with a complete human (hfa) or murine (mfa) microbiota. After peroral infection C. jejuni colonized the gastrointestinal tract of gnotobiotic and hfa mice for six weeks, whereas mfa mice cleared the pathogen within two days. Strikingly, stable C. jejuni colonization was accompanied by a pro-inflammatory immune response indicated by increased numbers of T-and B-lymphocytes, regulatory T-cells, neutrophils and apoptotic cells, as well as increased concentrations of TNF-a, IL-6, and MCP-1 in the colon mucosa of hfa mice. Analysis of MyD88 2/2 , TRIF 2/2 , TLR4 2/2 , and TLR9 2/2 mice revealed that TLR4-and TLR9-signaling was essential for immunopathology following C. jejuni-infection. Interestingly, C. jejuni-mutant strains deficient in formic acid metabolism and perception induced less intestinal immunopathology compared to the parental strain infection. In summary, the murine gut flora is essential for colonization resistance against C. jejuni and can be overcome by reconstitution of gnotobiotic mice with human flora. Detection of C. jejuni-LPS and -CpG-DNA by host TLR4 and TLR9, respectively, plays a key role in immunopathology. Finally, the host immune response is tightly coupled to bacterial formic acid metabolism and invasion fitness. Conclusion/Significance:We conclude that gnotobiotic and ''humanized'' mice represent excellent novel C. jejuni-infection and -inflammation models and provide deep insights into the immunological and molecular interplays between C. jejuni, microbiota and innate immunity in human campylobacteriosis.

Novel Clinical Campylobacter jejuni Infection Models Based on Sensitization of Mice to Lipooligosaccharide, a Major Bacterial Factor Triggering Innate Immune Responses in Human Campylobacteriosis

“…This can be attributed to the fact that mice are approximately 10,000-fold less responsive to Toll-like receptor (TLR)-4 ligands, mainly LOS and LPS [44] (Figure 3). Furthermore, the gastrointestinal microbiota of conventional mice mediates a strong colonization resistance (CR) to C. jejuni [45][46][47]. In line with other investigators, we have recently shown that conventional mice bred in our specific pathogen-free (SPF) facilities are protected from stable gastrointestinal C. jejuni colonization even upon peroral infection with high doses.…”

“…In line with other investigators, we have recently shown that conventional mice bred in our specific pathogen-free (SPF) facilities are protected from stable gastrointestinal C. jejuni colonization even upon peroral infection with high doses. Upon modifying the murine gut microbiota (i.e., its virtual depletion) following broad-spectrum antibiotic treatment, and also upon re-association with human as opposed to murine gut microbiota by fecal microbiota transplantation, these mice can be effectively colonized by the pathogen upon peroral challenge and display typical histopathologic pro-inflammatory features of campylobacteriosis in their intestines [46][47][48][49], whereas the classic symptoms such as abdominal cramps, watery, or bloody diarrhea seen in infected humans were missing in conventional wildtype mice without genetic manipulations [46] (Figure 4).…”

“…However, each animal model showed strong limitations in terms of employing or comparing with human conditions upon C. jejuni infection [54]. The use of mice as a model for C. jejuni infection was banned in the early 2000s, given that conventional wildtype mice are highly resistant to C. jejuni colonization due to the physiological colonization resistance (CR) exerted by the murine gut microbiota composition [43,46,50].…”

Fecal Microbiota Transplantation in Neurological Disorders

“…Antibiotic-treated and gnotobiotic mice display increased colonization and gastrointestinal inflammation after C. jejuni inoculation (Chang and Miller, 2006;Stahl et al, 2014;O'Loughlin et al, 2015), with a potential protective role for Enterococcus faecalis (O'Loughlin et al, 2015). Furthermore, a considerably decreased C. jejuni clearance time is observed in mice that receive antibiotics and gavage with murine microbiota compared to human microbiota-receiving mice and gnotobiotic mice, that showed a more pro-inflammatory immune response (Bereswill et al, 2011).…”

The Probiotic Compound VSL#3 Modulates Mucosal, Peripheral, and Systemic Immunity Following Murine Broad-Spectrum Antibiotic Treatment

“…The microbiota has been shown to be involved in numerous physiological processes, including vitamin synthesis (LeBlanc et al, 2013), food digestion (Hooper et al, 2002), fat metabolism (Backhed et al, 2004), intestinal angiogenesis (Stappenbeck et al, 2002), enteric nerve function (Husebye et al, 1994), protection from pathogens (Sekirov et al, 2008; Bereswill et al, 2011), and immune system development (Cebra, 1999). Moreover, perturbations of the complex host resident intestinal ecologic system, termed dysbiosis, have been linked to a wide range of pathological conditions including intestinal disorders such as inflammatory bowel diseases (IBD; Baumgart and Carding, 2007), irritable bowel syndrome (IBS; Carroll et al, 2010), and coeliac disease (De Palma et al, 2010), as well as extra-intestinal pathologies such as allergy and asthma (Noverr and Huffnagle, 2004), arthritis (Taurog et al, 1994), type 1 diabetes mellitus (Wen et al, 2008), obesity (Backhed et al, 2007), multiple sclerosis (Ochoa-Reparaz et al, 2009), and distinct cardiovascular diseases (Serino et al, 2014).…”