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

Abstract

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.

Beneficial effects of Strongyloides venezuelensis antigen extract in acute experimental toxoplasmosis

“…As it was previously demonstrated that larval S stercoralis soluble extract itself has the capacity to recruit neutrophils in vivo, 85 we investigated the MPO, an indicative of neutrophil activity in the ileum of infected and SvAg‐treated mice. The SvAg treatment alone was not able to alter the MPO activity in the ileum; however, in accordance with previous studies, 82 T gondii infection increased MPO activity in SvAg‐treated mice. The neutrophils present important mechanisms that are involved in the control of T gondii , such as cytokine and reactive oxygen species (ROS) production, and formation of neutrophil extracellular traps (NETs) (reviewed in 86) 86 .…”

“…Thus, it was verified if the SvAg treatment could improve the inflammatory alterations induced by the parasite. Previous studies demonstrated that experimental T gondii infection reduces goblet numbers 81,82 and eliminates Paneth cells 83,84 in the small intestine. As expected, in the present investigation T gondii infection induced inflammatory lesions in the small intestine, lung and liver of infected mice and reduced intestinal Paneth and goblet cell numbers.…”

Schistosoma mansoni eggs induce Wnt/β-catenin signaling and activate the protooncogene c-Jun in human and hamster colon

“…Furthermore, it has been shown that helminth-derived compounds induced a Th1/Th2 switch that ameliorated experimental colitis 52 , 53 . Other studies reported that the coinfection with S. mansoni attenuated Crohn’s like inflammatory bowel disease, preserving the epithelial barrier function by downregulating the inflammatory response 54 . In a recently published study, the therapeutic effect of autoclaved S. mansoni antigens on toxin induced colon cancer was demonstrated in a murine model 55 .…”

Infection by Leishmania (Leishmania) infantum chagasi causes intestinal changes B‐1 cells dependent

“…On the other hand, considering the Balb/c I and XID I groups, a reduction in the number of Paneth cells occurred, perhaps due to increased degranulation [48][49][50] after infectious conditions. 32,51,52 As previously described, VL causes several intestinal changes, 10,11,38 since the parasite leads to disruption of the intestinal homeostasis. 7,8,12 It can happen due to the presence of the parasite in the organ or as a systemic reaction and could be related to the B-1 cells.…”

“…This cytokine contributes to the Paneth cells development, as observed by the increased number of these cells after the adoption of B‐1 cells that resembled those found in the infected wild group. On the other hand, considering the Balb/c I and XID I groups, a reduction in the number of Paneth cells occurred, perhaps due to increased degranulation after infectious conditions …”