Abstract
BackgroundWithin 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.Methodology/Principal FindingsFollowing 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.Conclusion/SignificanceNOD2 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.
Highlights
The obligate intracellular parasite Toxoplasma (T.) gondii belongs to the Apicomplexa phylum and is widely used in distinct murine models of infection [1]
In order to investigate the role of NOD2 in T. gondii infection and induced acute ileitis, NOD2-/- and WT control mice were perorally infected with 100 cysts of T. gondii ME49 strain by gavage at day 0
It is well established that NOD2 plays an important role in the innate host defense against intestinal bacterial pathogens such as Salmonella enteritidis, Listeria monocytogenes, and Streptococcus pneumoniae [17,28,29,30]
Summary
The obligate intracellular parasite Toxoplasma (T.) gondii belongs to the Apicomplexa phylum and is widely used in distinct murine models of infection [1]. Molecular mechanisms underlying resistance of mice against oral T. gondii infection and small intestinal inflammation, for instance, are commonly studied in high dose infection with 50 to 100 cysts of a type II strain [1,6,7]. Within one week following peroral infection with 100 cysts of the T. gondii ME49 strain, susceptible animals such as C57BL/6 mice (with H-2b haplotype) develop a panileitis and succumb to the infection [1,2,8]. The high dose infection model mimics some key features of human inflammatory bowel diseases (IBD) such as Crohn’s disease in the acute stage [1,10,11]. 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, has not been investigated so far
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