AUTHOR=Pêgo Beatriz , Martinusso Cesonia A. , Bernardazzi Claudio , Ribeiro Beatriz Elias , de Araujo Cunha Aline Fernandes , de Souza Mesquita Jacilene , Nanini Hayandra F. , Machado Marcelo Pelajo , Castelo-Branco Morgana T. L. , Cavalcanti Marta Guimarães , de Souza Heitor S. P. 

TITLE=Schistosoma mansoni Coinfection Attenuates Murine Toxoplasma gondii-Induced Crohn's-Like Ileitis by Preserving the Epithelial Barrier and Downregulating the Inflammatory Response

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00442

DOI=10.3389/fimmu.2019.00442

ISSN=1664-3224

ABSTRACT=<p><bold>Background and aims:</bold> Mice orally infected with <italic>T. gondii</italic> 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 <italic>S. mansoni</italic> in <italic>T. gondii</italic>-induced CD-like enteritis has not been elucidated. Our study investigated the mechanisms underlying <italic>T. gondii</italic>-induced ileitis and the potential therapeutic effect of <italic>S. mansoni</italic> coinfection.</p><p><bold>Methods:</bold> C57BL/6 mice were infected by subcutaneous injection of cercariae of the BH strain of <italic>S. mansoni</italic>, and 7–9 weeks later, they were orally infected with cysts of the ME49 strain of <italic>T. gondii</italic>. 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.</p><p><bold>Results:</bold><italic>T. gondii</italic>-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 <italic>S. mansoni</italic>-infected or coinfected animals. Coinfection preserved goblet cells and Paneth cells, remarkably depleted in <italic>T. gondii</italic>-infected mice. Densities of CD4- and CD11b-positive cells were increased in <italic>T. gondii</italic>- compared to <italic>S. mansoni</italic>-infected mice and controls. MPO was significantly increased among <italic>T. gondii</italic>-mice, while attenuated in coinfected animals. In <italic>T. gondii</italic>-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 <italic>IL-1 beta, NOS2, HMOX1, MMP3</italic>, and <italic>MMP9</italic> and activation of NF-kappa B and p38 MAPK signaling, all of which were counterregulated by <italic>S. mansoni</italic> coinfection.</p><p><bold>Conclusion:</bold><italic>S. mansoni</italic> coinfection attenuates <italic>T. gondii</italic>-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 <italic>S. mansoni</italic> infection suggests the involvement of innate immune mechanisms and supports a conceptually new approach to the treatment of chronic inflammatory diseases, including CD.</p>