Nucleotide-oligomerization-domain-2 affects commensal gut microbiota composition and intracerebral immunopathology in acute Toxoplasma gondii induced murine ileitis

• Published in: PloS one 2014-08, Vol.9 (8), p.e105120-e105120
• Main Authors: Heimesaat, Markus M, Dunay, Ildiko R, Alutis, Marie, Fischer, André, Möhle, Luisa, Göbel, Ulf B, Kühl, Anja A, Bereswill, Stefan
• Format: Article
• Language: English
• Subjects: Animals; Bacteria; Bacterial Translocation - immunology; Biology and Life Sciences; Brain; Brain - immunology; Brain - parasitology; Campylobacter; Campylobacter jejuni; Complications; Cysts; Cytokines; Drug dosages; E coli; Encephalitis; Escherichia coli; Female; Gastrointestinal Microbiome - immunology; Gene expression; Genotypes; Hygiene; Ileitis; Ileitis - immunology; Ileitis - microbiology; Ileitis - parasitology; Infections; Inflammation; Inflammation - immunology; Inflammation - microbiology; Inflammation - parasitology; Interferon-gamma - immunology; Intestinal microflora; Intestine; Intestine, Small - immunology; Intestine, Small - microbiology; Intestine, Small - parasitology; Kidneys; Kinases; Liver; Lymphocytes T; Macrophages; Medicine; Mice; Mice, Inbred C57BL; Microbiota; Microglia; NOD2 protein; Nod2 Signaling Adaptor Protein - immunology; Oligomerization; Parasite Load; Parasites; Protozoa; RNA, Ribosomal, 16S - immunology; Rodents; rRNA 16S; Signaling; Spleen; Toxoplasma - immunology; Toxoplasma - pathogenicity; Toxoplasma gondii; Toxoplasmosis - immunology; Toxoplasmosis - microbiology; Toxoplasmosis - parasitology; Translocation; Tumor Necrosis Factor-alpha - immunology; Tumor necrosis factor-α; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0105120

Within one week following peroral high dose infection with Toxoplasma (T.) gondii, susceptible mice develop non-selflimiting acute ileitis due to an underlying Th1-type immunopathology. The role of the innate immune receptor nucleotide-oligomerization-domain-2 (NOD2) in mediating potential extra-intestinal inflammatory sequelae including the brain, however, has not been investigated so far. Following peroral infection with 100 cysts of T. gondii strain ME49, NOD2-/- mice displayed more severe ileitis and higher small intestinal parasitic loads as compared to wildtype (WT) mice. However, systemic (i.e. splenic) levels of pro-inflammatory cytokines such as TNF-α and IFN-γ were lower in NOD2-/- mice versus WT controls at day 7 p.i. Given that the immunopathological outcome might be influenced by the intestinal microbiota composition, which is shaped by NOD2, we performed a quantitative survey of main intestinal bacterial groups by 16S rRNA analysis. Interestingly, Bifidobacteria were virtually absent in NOD2-/- but not WT mice, whereas differences in remaining bacterial species were rather subtle. Interestingly, more distinct intestinal inflammation was accompanied by higher bacterial translocation rates to extra-intestinal tissue sites such as liver, spleen, and kidneys in T. gondii infected NOD2-/- mice. Strikingly, intracerebral inflammatory foci could be observed as early as seven days following T. gondii infection irrespective of the genotype of animals, whereas NOD2-/- mice exhibited higher intracerebral parasitic loads, higher F4/80 positive macrophage and microglia numbers as well as higher IFN-γ mRNA expression levels as compared to WT control animals. NOD2 signaling is involved in protection of mice from T. gondii induced acute ileitis. The parasite-induced Th1-type immunopathology at intestinal as well as extra-intestinal sites including the brain is modulated in a NOD2-dependent manner.