Land use impacts on parasitic infection: a cross-sectional epidemiological study on the role of irrigated agriculture in schistosome infection in a dammed landscape

Background Water resources development promotes agricultural expansion and food security. But are these benefits offset by increased infectious disease risk? Dam construction on the Senegal River in 1986 was followed by agricultural expansion and increased transmission of human schistosomes. Yet the mechanisms linking these two processes at the individual and household levels remain unclear. We investigated the association between household land use and schistosome infection in children. Methods We analyzed cross-sectional household survey data (n = 655) collected in 16 rural villages in August 2016 across demographic, socio-economic and land use dimensions, which were matched to Schistosoma haematobium (n = 1232) and S. mansoni (n = 1222) infection data collected from school-aged children. Mixed effects regression determined the relationship between irrigated area and schistosome infection presence and intensity. Results Controlling for socio-economic and demographic risk factors, irrigated area cultivated by a household was associated with an increase in the presence of S. haematobium infection (odds ratio [OR] = 1.14; 95% confidence interval [95% CI]: 1.03–1.28) but not S. mansoni infection (OR = 1.02; 95% CI: 0.93–1.11). Associations between infection intensity and irrigated area were positive but imprecise (S. haematobium: rate ratio [RR] = 1.05; 95% CI: 0.98–1.13, S. mansoni: RR = 1.09; 95% CI: 0.89–1.32). Conclusions Household engagement in irrigated agriculture increases individual risk of S. haematobium but not S. mansoni infection. Increased contact with irrigated landscapes likely drives exposure, with greater impacts on households relying on agricultural livelihoods.

Schistosome infection promotes osteoclast-mediated bone loss

Infection with schistosome results in immunological changes that might influence the skeletal system by inducing immunological states affecting bone metabolism. We investigated the relationships between chronic schistosome infection and bone metabolism by using a mouse model of chronic schistosomiasis, affecting millions of humans worldwide. Results showed that schistosome infection resulted in aberrant osteoclast-mediated bone loss, which was accompanied with an increased level of receptor activator of nuclear factor-κB (NF-κB) Ligand (RANKL) and decreased level of osteoprotegerin (OPG). The blockade of RANKL by the anti-RANKL antibody could prevent bone loss in the context of schistosome infection. Meanwhile, both B cells and CD4+ T cells, particularly follicular helper T (Tfh) cell subset, were the important cellular sources of RANKL during schistosome infection. These results highlight the risk of bone loss in schistosome-infected patients and the potential benefit of coupling bone therapy with anti-schistosome treatment.

Schistosome Infection and Schistosome-Derived Products as Modulators for the Prevention and Alleviation of Immunological Disorders

Parasitic helminths, comprising the flatworms (tapeworms and flukes) and nematodes (roundworms), have plagued humans persistently over a considerable period of time. It is now known that the degree of exposure to these and other pathogens inversely correlates with the incidence of both T helper 1 (Th1)-mediated autoimmunity and Th2-mediated allergy. Accordingly, there has been recent increased interest in utilizing active helminth worm infections and helminth-derived products for the treatment of human autoimmune and inflammatory diseases and to alleviate disease severity. Indeed, there is an accumulating list of novel helminth derived molecules, including proteins, peptides, and microRNAs, that have been shown to exhibit therapeutic potential in a variety of disease models. Here we consider the blood-dwelling schistosome flukes, which have evolved subtle immune regulatory mechanisms that promote parasite survival but at the same time minimize host tissue immunopathology. We review and discuss the recent advances in using schistosome infection and schistosome-derived products as therapeutics to treat or mitigate human immune-related disorders, including allergic asthma, arthritis, colitis, diabetes, sepsis, cystitis, and cancer.

Loss of natural resistance to schistosome in T cell deficient rat

Schistosomiasis is among the major neglected tropical diseases and effective prevention by boosting the immune system is still not available. T cells are key cellular components governing adaptive immune response to various infections. While common laboratory mice, such as C57BL/6, are highly susceptible to schistosomiasis, the SD rats are extremely resistant. However, whether adaptive immunity is necessary for such natural resistance to schistosomiasis in rats remains to be determined. Therefore, it is necessary to establish genetic model deficient in T cells and adaptive immunity on the resistant SD background, and to characterize liver pathology during schistosomiasis. In this study we compared experimental schistosomiasis in highly susceptible C57BL/6 (B6) mice and in resistant SD rats, using cercariae of Schistosoma japonicum. We observed a marked T cell expansion in the spleen of infected B6 mice, but not resistant SD rats. Interestingly, CD3e−/− B6 mice in which T cells are completely absent, the infectious burden of adult worms was significantly higher than that in WT mice, suggesting an anti-parasitic role for T cells in B6 mice during schistosome infection. In further experiments, we established Lck deficient SD rats by using CRISPR/Cas9 in which T cell development was completely abolished. Strikingly, we found that such Lck deficiency in SD rats severely impaired their natural resistance to schistosome infection, and fostered parasite growth. Together with an additional genetic model deficient in T cells, the CD3e−/− SD rats, we confirmed the absence of T cell resulted in loss of natural resistance to schistosome infection, but also mitigated liver immunopathology. Our further experiments showed that regulatory T cell differentiation in infected SD rats was significantly decreased during schistosomiasis, in contrast to significant increase of regulatory T cells in infected B6 mice. These data suggest that T cell mediated immune tolerance facilitates persistent infection in mice but not in SD rats. The demonstration of an important role for T cells in natural resistance of SD rats to schistosomiasis provides experimental evidences supporting the rationale to boost T cell responses in humans to prevent and treat schistosomiasis.

Interleukin (IL)-33 is dispensable for Schistosoma mansoni worm maturation and the maintenance of egg-induced pathology in intestines of infected mice

Background: Schistosomes are trematode worms that dwell in their definitive host’s blood vessels, where females lay eggs that need to be discharged into the environment with host excreta to maintain their life cycle. Both worms and eggs require type 2 immunity for their maturation and excretion, respectively. However, immune molecules that orchestrate such immunity remain unclear. IL-33 is one of the epithelium-derived cytokines that induce type 2 immunity in tissues. This study aimed at determining its role in the maturation, reproduction, and excretion of S. mansoni eggs, and in the maintenance of egg-induced pathology in the intestines of mice.Methods: Using S. mansoni-infected IL-33-deficient (IL-33-/-) and wild-type (WT) mice, the morphology of worms and the number of eggs in intestinal tissues were studied at different time points of infection. IL-5 and IL-13 production in spleens and mesenteric lymph nodes were measured. Tissue histology was performed on the terminal ilea of infected and non-infected mice.Results: Morphology-wise, worms from IL-33-/- and WT mice at the fourth and sixth weeks of infection did not differ. The number of eggs in intestinal tissues did not differ much between IL-33-/- and WT mice. In the sixth week of infection, IL-33-/- mice presented impaired type 2 immunity in intestines, characterized by decreased production of IL-5 and IL-13 in mesenteric lymph nodes and fewer inflammatory infiltrates with fewer eosinophils in the ilea. Otherwise there was no difference between IL-33-/- and WT mice in the levels of IL-25 and thymic stromal lymphopoietin (TSLP) in intestinal tissues.Conclusions: Despite its ability to initiate type 2 immunity in tissues, IL-33 alone seems dispensable for S. mansoni maturation and its absence may not affect much the accumulation of eggs in intestinal tissues. The transient impairment of type 2 immunity observed in the intestines, but not spleens, highlights the importance of IL-33 over IL-25 and TSLP in initiating, but not maintaining, locally-induced type 2 immunity in intestinal tissues during schistosome infection. Further studies are needed to decipher the role of each of them in schistosomiasis and clarify the possible interactions that might exist between them.

A Cross Sectional Assessment on Distribution of Snail and Risk Factors of Schistosoma Mansoni Infection in Proximity to Water Contact Points in Gorgora Town, Western Dembia District, Northwest Ethiopia.

Background: Schistosomiasis is one of the great neglected tropical diseases with socio-economic and health problem worldwide. In Ethiopia numerous studies reported S. mansoni is high among school-age and preschool age children. Though intensive prevalence studies are conducted the snail distribution and infectivity status and human infection rate dynamics in Ethiopian context remains poorly understood. Thus the purpose of the current study was to assess distribution of snail and risk factors of Schistosoma mansoni infection in proximity to water contact points in Gorgora town, Western Dembia District, Northwest Ethiopia. Method: A Community based cross-sectional study was conducted in Gorgora Town from March to May 2020. A total of 385 study participants were selected by systematic random sampling technique. Stool sample was collected and examined by Kato-Katz technique. Malacological survey was done from sampling sites showing signs of human activity near Lake Tana shoreline. Live snails collected in plastic bucket containing water and weed were transported within four hours to the University of Gondar, Medical parasitology laboratory for identification and determination of infection. Data was entered with EPI Data version 4.4.2.1. Data analysis was carried out using SPSS version 20.0 and STATA version 15.0. p-value ≤ 0.05 was reported as statistically significant. Spatial distribution analysis was done using ArcGIS system for Geographical Information System (GIS). Result: The overall prevalence of S. mansoni infection was 36.6% (CI: 32-41.9) with intensity of 30.5%, 27.0% and 42.6% for light, moderate, and heavy, respectively. Among the different fresh water snails collected on the basis of shell morphology 546(%) were Biomphalaria pfeifferi, 310(28.1%) were Bulinus spp, 101(9.1%) were Lymnaea, and 147(13.3%) were Bivalve. Schistosome infection in Biomphalaria spp. was 0.0%. Swimming frequency and proximity to water body were observed to be the most associated risk factor to S. mansoni infection. Conclusion: The study showed that S. mansoni is an ongoing health problem in Gorgora. Different fresh water snails with a potential of transmitting diseases of human and veterinary importance that requires attention had been identified. Longitudinal and molecular study on Biomphalaria pfeifferi infection rate as well as susceptibility to schistosome infection is recommended.

STAT3 Promotes Schistosome-Induced Liver Injury by Inflammation, Oxidative Stress, Proliferation and Apoptosis Signal Pathway

Schistosomiasis is a parasitic helminth disease that can cause organ lesions leading to health damage. During a schistosome infection, schistosome eggs can flow into the liver along the portal vein. Numerous inflammatory cells gather around the eggs, causing granulomas and fibrosis in the liver. In this process, many molecules are involved in the initiation and regulation of the fibrous scar formation. However, the precise molecular mechanisms that explain the progression of granuloma formation and fibrosis initiation caused by schistosome infection have not been extensively studied. In this study, C57BL/6 wild-type mice and signal transducer and activator of transcription 3 (Stat3)flox/flox Alb-Cre mice were infected with cercariae of Schistosoma japonicum. Liver injury, effector molecule levels and RNA transcriptome resequencing of liver were detected at 4, 5, and 6 weeks postinfection. We investigated the role of STAT3 in Schistosoma-induced liver injury in mice. After 6 weeks postinfection, there has obvious liver fibrosis. A sustained pathological process such as inflammation, oxidative stress, proliferation and apoptosis occurred in S. japonicum-induced liver fibrosis initiation. Meanwhile, we found the activation of the STAT3 pathway in hepatic injury during S. japonicum infection by RNA transcriptome resequencing. Liver p-STAT3 deficiency alleviated infection-induced liver dysfunction, hepatic granuloma formation and fibrosis initiation. It also promoted STAT3-dependent apoptosis and reduced liver inflammation, oxidative stress and proliferation. Our results suggest that STAT3 signal pathway and its mediating inflammation, oxidative stress, proliferation and apoptosis are involved in S. japonicum-induced liver injury and may be a new potential guideline for the treatment of schistosomiasis.