Dataset Information

Comprehensive Kinetic Survey of Intestinal, Extra-Intestinal and Systemic Sequelae of Murine Ileitis Following Peroral Low-Dose Toxoplasma gondii Infection.

ABSTRACT: We have recently shown that following peroral low-dose Toxoplasma gondii infection susceptible mice develop subacute ileitis within 10 days. Data regarding long-term intestinal and extra-intestinal sequelae of infection are scarce, however. We therefore challenged conventional C57BL/6 mice with one cyst of T. gondii ME49 strain by gavage and performed a comprehensive immunopathological survey 10, 36, and 57 days later. As early as 10 days post-infection, mice were suffering from subacute ileitis as indicated by mild-to-moderate histopathological changes of the ileal mucosa. Furthermore, numbers of apoptotic and proliferating/regenerating epithelial cells as well as of T and B lymphocytes in the mucosa and lamina propria of the ileum were highest at day 10 post-infection, but declined thereafter, and were accompanied by enhanced pro-inflammatory mediator secretion in ileum, colon and mesenteric lymph nodes that was most pronounced during the early phase of infection. In addition, subacute ileitis was accompanied by distinct shifts in the commensal gut microbiota composition in the small intestines. Remarkably, immunopathological sequelae of T. gondii infection were not restricted to the intestines, but could also be observed in extra-intestinal tissues including the liver, kidneys, lungs, heart and strikingly, in systemic compartments that were most prominent at day 10 post-infection. We conclude that the here provided long-term kinetic survey of immunopathological sequalae following peroral low-dose T. gondii infection provides valuable corner stones for a better understanding of the complex interactions within the triangle relationship of (parasitic) pathogens, the host immunity and the commensal gut microbiota during intestinal inflammation. The low-dose T. gondii infection model may be applied as valuable gut inflammation model in future pre-clinical studies in order to test potential treatment options for intestinal inflammatory conditions in humans.

SUBMITTER: Heimesaat MM

PROVIDER: S-EPMC6474322 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Comprehensive Kinetic Survey of Intestinal, Extra-Intestinal and Systemic Sequelae of Murine Ileitis Following Peroral Low-Dose Toxoplasma gondii Infection.

Heimesaat Markus M MM Dunay Ildiko R IR Bereswill Stefan S

Frontiers in cellular and infection microbiology 20190412

We have recently shown that following peroral low-dose Toxoplasma gondii infection susceptible mice develop subacute ileitis within 10 days. Data regarding long-term intestinal and extra-intestinal sequelae of infection are scarce, however. We therefore challenged conventional C57BL/6 mice with one cyst of T. gondii ME49 strain by gavage and performed a comprehensive immunopathological survey 10, 36, and 57 days later. As early as 10 days post-infection, mice were suffering from su ...[more]

PMID: 31032232

Similar Datasets

Project description:BackgroundWithin seven days following peroral high dose infection with Toxoplasma gondii susceptible conventionally colonized mice develop acute ileitis due to an underlying T helper cell (Th) -1 type immunopathology. We here addressed whether mice harboring a human intestinal microbiota developed intestinal, extra-intestinal and systemic sequelae upon ileitis induction.Methodology/principal findingsSecondary abiotic mice were generated by broad-spectrum antibiotic treatment and associated with a complex human intestinal microbiota following peroral fecal microbiota transplantation. Within three weeks the human microbiota had stably established in the murine intestinal tract as assessed by quantitative cultural and culture-independent (i.e. molecular 16S rRNA based) methods. At day 7 post infection (p.i.) with 50 cysts of T. gondii strain ME49 by gavage human microbiota associated (hma) mice displayed severe clinical, macroscopic and microscopic sequelae indicating acute ileitis. In diseased hma mice increased numbers of innate and adaptive immune cells within the ileal mucosa and lamina propria and elevated intestinal secretion of pro-inflammatory mediators including IFN-γ, IL-12 and nitric oxide could be observed at day 7 p.i. Ileitis development was accompanied by substantial shifts in intestinal microbiota composition of hma mice characterized by elevated total bacterial loads and increased numbers of intestinal Gram-negative commensals such as enterobacteria and Bacteroides / Prevotella species overgrowing the small and large intestinal lumen. Furthermore, viable bacteria translocated from the inflamed ileum to extra-intestinal including systemic compartments. Notably, pro-inflammatory immune responses were not restricted to the intestinal tract as indicated by increased pro-inflammatory cytokine secretion in extra-intestinal (i.e. liver and kidney) and systemic compartments including spleen and serum.Conclusion/significanceWith respect to the intestinal microbiota composition "humanized" mice display acute ileitis following peroral high dose T. gondii infection. Thus, hma mice constitute a suitable model to further dissect the interactions between pathogens, human microbiota and vertebrate host immunity during acute intestinal inflammation.

Project description:The globally rising incidences of multidrug-resistant (MDR) Pseudomonas aeruginosa (Psae) in humans and live-stock animals has prompted the World Health Organization to rate MDR Psae as serious threat for human health. Only little is known, however, regarding factors facilitating gastrointestinal Psae-acquisition by the vertebrate host and subsequently induced inflammatory sequelae. In the present study, we addressed whether subacute ileitis predisposed mice harboring a human gut microbiota for intestinal MDR Psae carriage and whether inflammatory responses might be induced following peroral challenge with the opportunistic pathogen. To accomplish this, secondary abiotic mice were associated with a human gut microbiota by fecal microbiota transplantation. Ten days later (i.e., on day 0), subacute ileitis was induced in human microbiota associated (hma) mice by peroral low-dose Toxoplasma gondii infection. On day 5 post-infection, mice were perorally challenged with 109 colony forming units of a clinical MDR Psae isolate by gavage and the fecal bacterial loads surveyed thereafter. Four days post-peroral challenge, only approximately one third of mice with a human gut microbiota and subacute ileitis harbored the opportunistic pathogen in the intestinal tract. Notably, the gut microbiota composition was virtually unaffected by the Psae-carriage status during subacute ileitis of hma mice. The Psae challenge resulted, however, in more pronounced intestinal epithelial apoptotic cell and T lymphocyte responses upon ileitis induction that were not restricted to the ileum, but also affected the large intestines. Higher Psae-induced abundances of T cells could additionally be observed in extra-intestinal compartments including liver, kidney, lung, and heart of hma mice with subacute ileitis. Furthermore, higher apoptotic cell numbers, but lower anti-inflammatory IL-10 concentrations were assessed in the liver of Psae as compared to mock treated mice with ileitis. Remarkably, Psae-challenge was accompanied by even more pronounced systemic secretion of pro-inflammatory cytokines such as TNF and IL-6 at day 9 post ileitis induction. In conclusion, whereas in one third of hma mice with subacute ileitis Psae could be isolated from the intestines upon peroral challenge, the opportunistic pathogen was responsible for inflammatory sequelae in intestinal, extra-intestinal, and even systemic compartments and thus worsened subacute ileitis outcome irrespective of the Psae-carrier status.

Project description:Background and aims: Mice orally infected with T. gondii develop Crohn's disease (CD)-like enteritis associated with severe mucosal damage and a systemic inflammatory response, resulting in high morbidity and mortality. Previously, helminthic infections have shown therapeutic potential in experimental colitis. However, the role of S. mansoni in T. gondii-induced CD-like enteritis has not been elucidated. Our study investigated the mechanisms underlying T. gondii-induced ileitis and the potential therapeutic effect of S. mansoni coinfection. Methods: C57BL/6 mice were infected by subcutaneous injection of cercariae of the BH strain of S. mansoni, and 7-9 weeks later, they were orally infected with cysts of the ME49 strain of T. gondii. After euthanasia, the ileum was removed for histopathological analysis; staining for goblet cells; immunohistochemistry characterizing mononuclear cells, lysozyme expression, apoptotic cells, and intracellular pathway activation; and measuring gene expression levels by real-time PCR. Cytokine concentrations were measured in the serial serum samples and culture supernatants of the ileal explants, in addition to myeloperoxidase (MPO) activity. Results: T. gondii-monoinfected mice presented dense inflammatory cell infiltrates and ulcerations in the terminal ileum, with abundant cell extrusion, apoptotic bodies, and necrosis; these effects were absent in S. mansoni-infected or coinfected animals. Coinfection preserved goblet cells and Paneth cells, remarkably depleted in T. gondii-infected mice. Densities of CD4- and CD11b-positive cells were increased in T. gondii- compared to S. mansoni-infected mice and controls. MPO was significantly increased among T. gondii-mice, while attenuated in coinfected animals. In T. gondii-infected mice, the culture supernatants of the explants showed increased concentrations of TNF-alpha, IFN-gamma, and IL-17, and the ileal tissue revealed increased expression of the mRNA transcripts for IL-1 beta, NOS2, HMOX1, MMP3, and MMP9 and activation of NF-kappa B and p38 MAPK signaling, all of which were counterregulated by S. mansoni coinfection. Conclusion: S. mansoni coinfection attenuates T. gondii-induced ileitis by preserving mucosal integrity and downregulating the local inflammatory response based on the activation of NF-kappa B and MAPK. The protective function of prior S. mansoni infection suggests the involvement of innate immune mechanisms and supports a conceptually new approach to the treatment of chronic inflammatory diseases, including CD.

Dataset Information

Comprehensive Kinetic Survey of Intestinal, Extra-Intestinal and Systemic Sequelae of Murine Ileitis Following Peroral Low-Dose Toxoplasma gondii Infection.

Publications

Comprehensive Kinetic Survey of Intestinal, Extra-Intestinal and Systemic Sequelae of Murine Ileitis Following Peroral Low-Dose <i>Toxoplasma gondii</i> Infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets