Schistosoma and Leishmania: An Untold Story of Coinfection.

A remarkable characteristic of infectious diseases classified as Neglected Tropical Diseases (NTDs) is the fact that they are mostly transmitted in tropical and subtropical regions with poor conditions of sanitation and low access to healthcare, which makes transmission areas more likely to overlap. Two of the most important NTDs, schistosomiasis and leishmaniasis, despite being caused by very different etiological agents, have their pathogenesis heavily associated with immune-mediated mechanisms, and Schistosoma spp. and Leishmania spp. have been shown to simultaneously infect humans. Still, the consequences of Schistosoma-Leishmania coinfections remain underexplored. As the inflammatory processes elicited by each one of these parasites can influence the other, several changes have been observed due to this coinfection in naturally infected humans, experimental models, and in vitro cell assays, including modifications in susceptibility to infection, pathogenesis, prognostic, and response to treatment. Herein, we review the current knowledge in Schistosoma-Leishmania coinfections in both human populations and experimental models, with special regard to how schistosomiasis affects tegumentary leishmaniasis, discuss future perspectives, and suggest a few steps to further improve our understanding in this model of parasite-host-parasite interaction.

Role of the IL-33/ST2 Activation Pathway in the Development of the Hepatic Fibrosis Induced by Schistosoma mansoni Granulomas in Mice.

Schistosoma mansoni eggs retained in host tissues induce innate cytokine release, contributing to the induction of Type-2 immune responses and granuloma formation, important to restrain cytotoxic antigens, but leading to fibrosis. Interleukin(IL)-33 participates in experimental models of inflammation and chemically induced fibrosis, but its role in S. mansoni-induced fibrosis is still unknown. To explore the role of the IL-33/suppressor of the tumorigenicity 2 (ST2) pathway, serum and liver cytokine levels, liver histopathology, and collagen deposition were comparatively evaluated in S. mansoni-infected wild-type (WT) and IL-33-receptor knockout (ST2-/-) BALB/c mice. Our data show similar egg counts and hydroxyproline in the livers of infected WT and ST2-/- mice; however, the extracellular matrix in ST2-/- granulomas was loose and disorganised. Pro-fibrotic cytokines, such as IL-13 and IL-17, and the tissue-repairing IL-22 were significantly lower in ST2-/- mice, especially in chronic schistosomiasis. ST2-/- mice also showed decreased α-smooth muscle actin (α-SMA) expression in granuloma cells, in addition to reduced Col III and Col VI mRNA levels and reticular fibres. Therefore, IL-33/ST2 signalling is essential for tissue repairing and myofibroblast activation during S. mansoni infection. Its disruption results in inappropriate granuloma organisation, partly due to the reduced type III and VI collagen and reticular fibre formation.

Experimental infection with Schistosoma mansoni isolated from the wild rodent Holochilus sciureus shows a low parasite burden but induces high schistosomiasis severity in BALB/c mice.

Wild mammals, especially rodents, can participate in the life cycle of Schistosoma mansoni; however, the impact of these parasite strains on the severity of schistosomiasis remains unclear. The aim of this study was to comparatively evaluate the parasitological and immunopathological alterations induced by an S. mansoni strain isolated from the wild rodent Holochilus sciureus (HS strain) and a parasite strain isolated from a human (LE strain) in experimentally infected mice. Male BALB/c mice were subcutaneously infected with 50 cercariae/mouse of either the HS or the LE strain and were evaluated for 12 weeks. In the experimental groups, the parasite burden was estimated by worm and egg (feces and tissues) count, and immunopathological alterations were evaluated in the liver and intestines. Compared to experimental infection with the LE parasite strain, HS-infected mice showed reduced number of parasite worms but higher fecundity rate, significant reduction in IL-5, IL-10 and IL-13 concentrations, lower EPO-activity in liver homogenate and higher concentrations of TNF-α, IFN-γ, IL-12 and IL-17 in the small intestine homogenate. Moreover, HS infection resulted in higher concentrations of NO end-products in both the liver and intestine, suggesting a predominance of the Th1/Th17 immune response. HS-infected mice also showed higher plasma transaminase levels, formed larger granulomas, and had a higher mortality rate in comparison with LE-infected mice. Data indicate that BALB/c mice infected with the HS strain of S. mansoni showed reduced susceptibility to the parasite but stronger tissue inflammation and high disease severity.

The IL-33/ST2 pathway is not essential to Th2 stimulation but is key for modulation and survival during chronic infection with Schistosoma mansoni in mice.

Morbidity during chronic schistosomiasis has been associated with the induction and modulation of type-2 granulomatous inflammatory response induced by antigens secreted by the eggs, which become trapped in capillary venules of the host tissues, especially in the liver and intestines. IL-33, an alarmin released after cell damage, binds to its ST2 (suppressor of tumorigenicity 2) receptor, expressed in an variety of immune cells, including ILC2 and macrophages, and stimulates the early production of IL-5 and IL-13, which leads to eosinophil infiltration and activation of a Th2 response. However, the role of IL-33/ST2 activation on Schistosoma-induced granuloma formation and modulation is mostly unknown. In the current work, we comparatively evaluated the immune response and granuloma formation in wild-type BALB/c (WT) and BALB/c mice genetically deficient in the IL-33 receptor (ST2-/-) experimentally infected with Schistosoma mansoni. Mice were infected with 25 or 50 S. mansoni cercariae and followed for up to 14 weeks to assess mortality. Mice from each experimental group were comparatively evaluated for parasite burden, liver immune response, and granuloma appearance during acute and chronic schistosomiasis. Our data showed that the number of circulating worms and eggs retained in the liver and eliminated in the feces was similar in WT and ST2-/- infected mice, but infected ST2-/- mice presented an enhanced rate of mortality. Interestingly, the production of type-2 cytokines by soluble egg antigens (SEA)-stimulated spleen cells, the serum concentrations of IL-5 and Immunoglobulin (Ig)-E, and the level of parasite-reactive IgG1 were similar in infected mice of both experimental groups. The concentrations of IL-4, IL-5, IL-13, and IFN-γ in liver homogenate of infected mice also did not differ between the strains at acute schistosomiasis, but there was a significant increase in IL-17 levels in ST2-/- infected mice at this phase. On the other hand, IL-4, IL-13, IL-10, IL-17, and IFN-γ concentrations were reduced and the ratios of IL-4/IFN-γ and IL-17/IFN-γ were higher in liver homogenate of chronically infected ST2-/- mice, suggesting unbalanced Th2 and Th17 responses. Moreover, liver granulomas of ST2-/- mice were larger and disorganized, showing an intense cellular infiltrate, rich in eosinophils and neutrophils. Our results suggest that the absence of the IL-33/ST2 pathway is not essential for the Schistosoma-induced Th2 response, but is necessary to prevent host mortality by modulating granuloma-mediated pathology.