Schistosoma japonicum Infection in Treg-Specific USP21 Knockout Mice.

The E3 deubiquitinating enzyme ubiquitin-specific proteolytic enzyme 21 (USP21) plays vital roles in physiological activities and is required for Treg-cell-mediated immune tolerance. Using a murine model infected with Schistosoma japonicum, we observed that there were more cercariae developed into adults and more eggs deposited in the livers of the USP21fl/flFOXP3Cre (KO) mice. However, immunohistochemistry showed that the degree of egg granuloma formation and liver fibrosis was reduced. In USP21fl/flFOXP3Cre mice, levels of IFN-gamma, IL-4, anti-soluble egg antigen (SEA) IgG and anti-soluble worm antigen preparation (SWAP) IgG increased in blood, as determined using ELISAs and multiplex fluorescent microsphere immunoassays, while the levels of IL-10, lL-17A, IL-23, IL-9, and anti-SEA IgM decreased. In addition, the levels of the USP21 protein and mRNA in the liver and spleen of KO mice decreased. We further observed increased Th1 responses amplified by Tregs (regulatory T cells) and compromised Th17 responses, which alleviated the liver immunopathology. We speculated that these changes were related to polarization of Th1-like Tregs. Our results revealed the roles of USP21 in Treg-cell-mediated regulation of immune interactions between Schistosoma and its host. USP21 may have potential for regulating hepatic fibrosis in patients with schistosomiasis.

Human Mobility Associated With Risk of Schistosoma japonicum Infection in Sichuan, China.

Urbanization increases human mobility in ways that can alter the transmission of classically rural, vector-borne diseases like schistosomiasis. The impact of human mobility on individual-level Schistosoma risk is poorly characterized. Travel outside endemic areas may protect against infection by reducing exposure opportunities, whereas travel to other endemic regions may increase risk. Using detailed monthly travel- and water-contact surveys from 27 rural communities in Sichuan, China, in 2008, we aimed to describe human mobility and to identify mobility-related predictors of S. japonicum infection. Candidate predictors included timing, frequency, distance, duration, and purpose of recent travel as well as water-contact measures. Random forests machine learning was used to detect key predictors of individual infection status. Logistic regression was used to assess the strength and direction of associations. Key mobility-related predictors include frequent travel and travel during July-both associated with decreased probability of infection and less time engaged in risky water-contact behavior, suggesting travel may remove opportunities for schistosome exposure. The importance of July travel and July water contact suggests a high-risk window for cercarial exposure. The frequency and timing of human movement out of endemic areas should be considered when assessing potential drivers of rural infectious diseases.

Soluble egg antigen of Schistosoma japonicum induces pyroptosis in hepatic stellate cells by modulating ROS production.

BACKGROUND: Inflammation-induced dysfunction of hepatic stellate cells (HSCs) is involved in schistosomiasis-associated liver fibrosis, and soluble egg antigen (SEA) is a crucial pathogen-associated molecular pattern associated with liver injury in schistosomiasis. In addition, numerous studies have shown that caspase-1-mediated pyroptosis participates in the development of multiple inflammation-related diseases. However, whether pyroptotic cell death of HSCs is involved in SEA-mediated liver damage is not well understood. METHODS: Primary cultured HSCs and Schistosoma japonicum-infected mouse liver tissue were analysed for histological changes and caspase-1 activation, and the role of pyroptosis in the mechanisms underlying SEA-induced HSC death was investigated. Accumulation of reactive oxygen species (ROS) in infected livers and SEA-stimulated HSCs was measured by flow cytometry and immunofluorescence. RESULTS: Caspase-1 activity was elevated in both liver tissues and HSCs of S. japonicum-infected mice. Furthermore, SEA stimulation increased the proportion of pyroptotic HSCs, as shown by lactate dehydrogenase (LDH) release assays and by flow cytometric analysis of propidium iodide (PI) and caspase-1 double staining in cells. In addition, ROS generation was elevated in infected liver tissues and SEA-stimulated HSCs, and ROS inhibition downregulated SEA-induced caspase-1 activation and pyroptosis in HSCs. CONCLUSIONS: Our present study demonstrates that pyroptotic cell death in HSCs induced by SEA via ROS-mediated caspase-1 activation may serve as a significant mechanism to initiate the inflammatory response and thereby exacerbate liver injury during S. japonicum infection.

Dynamics of Th9 cells and their potential role in immunopathogenesis of murine schistosomiasis.

BACKGROUND: Th1, Th2, Th17, Treg and Tfh cells play important roles in schistosomiasis. Th9 cells secrete IL-9 as a signature cytokine and contribute to several classes of inflammatory disease. However, the effects of Th9 cells in schistosomiasis are unknown. We aimed to explore the dynamic changes and potential roles of Th9 cells in the pathogenesis of hepatic egg granulomatous inflammation in mice infected with Schistosoma japonicum. METHODS: Twenty mice with S. japonicum infection and five normal controls (NC) were used as models. The average areas of egg granulomas were estimated by hematoxylin-eosin (H & E) staining. Hepatic IL-9 and transcription factor PU.1 levels were detected by immunohistochemistry. Flow cytometry techniques were used to analyze the proportions of Th9 cells. With the help of ELISA, serum levels of IL-9 were examined. RESULTS: The egg granulomas began to form from four weeks after infection and continued to develop. In parallel with the development of egg granulomas, the hepatic levels of IL-9 and PU.1 increased very slowly during the first four weeks post-infection and increased rapidly thereafter. Moreover, the proportions of splenic Th9 cells and levels of serum IL-9 had similar developmental trends with the egg granulomas. CONCLUSION: The proliferation of Th9 cells and levels of IL-9 were significantly higher in S. japonicum-infected mice compared to NC. In addition, dynamic changes of Th9 and IL-9 were synchronous with the developmental trend of hepatic egg granulomatous inflammation, suggesting that Th9 cells might be a new subset in the pathogenesis of schistosomiasis.

[Investigation on prevalence and risk factors of HIV/AIDS and Schistosoma japonicum, Ascaris lumbricoides and Trichuris trichiura infections in a rural community of southwestern China].

OBJECTIVE: To investigate the prevalence and risk factors of helminthic infections including Schistosoma japonicum, Ascaris lumbricoides and Trichuris trichiura and human immunodeficiency virus (HIV), and find out the association among them in a rural community of southwestern China. METHODS: A community-based cross sectional study was conducted. One town was selected randomly; the infections of S.japonicum, A.lumbricoides and T.trichiura were detected with the modified Kato-Katz thick smear method and HIV infection with the diagnostic Test Kit among all residents. A questionnaire survey was conducted to investigate the related risk factors. RESULTS: Among the participants, the infection rates of HIV, S.japonicum, A.lumbricoides and T.trichiura were 2.33%, 2.05%, 13.47% and 30.59% respectively; 7.08% (31/438) were infected with both A.lumbricoides and T.trichiura; 0.23% (1/438) were co-infected with HIV and A.lumbricoides, and the same with HIV and T.trichiura. The multivariate logistic regression analysis showed that sex (male, OR=3.26, 95% CI：0.97, 10.95) and drug abuse (OR=72.86, 95% CI：18.51, 286.76) were significantly associated with HIV infection. Home toilet was negatively related to A.lumbricoides infection (OR=0.52, 95% CI：0.27, 0.98) and T.trichiura infection (OR=0.48, 95% CI：0.28, 0.80). Compared with the people in Villages Four, the people living in Village One were at a higher risk for A.lumbricoides infection (OR=3.14, 95% CI：1.35, 7.27), and compared with the people living in Village Four, the people living in Village Two and Village Three were more likely to be infected with T.trichiura (OR=3.73, 95% CI：1.92, 7.26; OR=4.53, 95% CI：2.12, 9.68). The people aged between 11 and 20 years had a higher T.trichiura infection risk than the people aged more than 50 years (OR = 3.72, 95% CI：1.59, 8.67). There was a significant association between A.lumbricoides and T.trichiura infections (OR = 3.11, 95% CI：1.63, 5.93). There was no association between S.japonicum infection and related factors above mentioned. CONCLUSIONS: The infection rates of HIV, S.japonicum, A.lumbricoides and especially T.trichiura were rather high in this area, and therefore, the prevention and treatment of these diseases should be strengthened. Further studies on the relationship between HIV and the infections of helminths, especially S.japonicum are needed.

Exploring the contribution of host susceptibility to epidemiological patterns of Schistosoma japonicum infection using an individual-based model.

We recently reported the analysis of epidemiological data suggesting variability in individual susceptibility to infection by Schistosoma japonicum among rural villagers who reside in Sichuan Province of southwestern China. By supplementing the data used in the earlier analysis from other studies we have reported from this region, we presented improved estimates of cercarial exposure, which in turn, result in stronger evidence of susceptibility. This analysis was conducted using an individual-based mathematical model (IBM) whose use was motivated by the nature and extent of field data from the low-transmission environments exemplified by one of our datasets and typical of the current situation in most endemic areas of China. In addition to individual susceptibility and water contact, the model includes stochastic aspects of cercarial exposure as well as of diagnostic procedures, the latter being particularly relevant to the low-transmission environment. The simulation studies show that, to produce key aspects of the epidemiological findings, the distribution of susceptibility ranges over several orders of magnitude and is highly right skewed. We found no compelling evidence that the distribution of susceptibility differed between the two populations that underlie both the epidemiological and simulation results.

Schistosomiasis japonica identified by laparoscopic and colonoscopic examination.

A 45-year-old Philippine woman who came from Mindanao Island was admitted to our hospital with a complaint of epigastric discomfort. Abdominal ultrasonography and computed tomography demonstrated a network pattern and linear calcification in the liver. Laparoscopic examination showed numerous yellowish, small speckles over the liver surface. The liver surface was separated into many small blocks by groove-like depressions, demonstrating a so-called tortoise shell pattern. Conventional colonoscopy and narrow-band imaging showed irregular areas of yellowish mucosa, and diminished vascular network and increased irregular microvessels extending from the descending colon to the rectum. Liver biopsy showed many Schistosoma japonicum eggs in Glisson's capsule and colon biopsy showed many S. japonicum eggs in the submucosal layer. These findings established a diagnosis of schistosomiasis japonica. The present case is imported schistosomiasis japonica. Even though new cases have not occurred recently in Japan, we should remain aware of schistosomiasis japonica for patients who came from foreign epidemic areas.

Conquering 'snail fever': schistosomiasis and its control in China.

Schistosomiasis japonica is a serious parasitic disease and a major health risk for more than 60 million people living in the tropical and subtropical zones of south China. The disease is a zoonosis and its cause, the parasitic trematode Schistosoma japonicum, has a range of mammalian reservoirs, making control efforts difficult. Current control programs are heavily based on community chemotherapy with a single dose of the highly effective drug praziquantel. However, vaccines (for use in bovines and in humans) in combination with other control strategies are needed to eliminate the disease. In this review, we provide an overview of the transmission, clinical features, pathogenesis, diagnosis, treatment, genetics and susceptibility, epidemiology, and prospects for control of schistosomiasis japonica in China. The threat posed by the Three Gorges Dam may undermine control efforts because it will change the local ecology and associated schistosomiasis transmission risks over the next decade and beyond.

Genetic and household risk factors for Schistosoma japonicum infection in the presence of larger scale environmental differences in the mountainous transmission areas of China.

Schistosoma japonicum egg excretion and kinship relationship data from 13 endemic villages in the mountainous transmission area near Xichang, in Sichuan province, China, were analyzed via a variance components methodology to assess the relative contribution of kinship, shared household, and shared village to the risk of infection. Large intervillage differences in egg counts exist in this region due to differences in transmission potential related to environmental differences in snail density and agricultural practices. After accounting for these intervillage differences, there was no kinship or household effect on egg excretion. This reinforces earlier findings that suggest environmental factors dominate risk in this region.

[A case-control study on risk factors for advanced schistosomiasis japonica].

OBJECTIVE: To investigate risk factors for the development of advanced schistosomiasis. METHODS: The case-control study was designed with a match of 1:1 and 1:2. Healthy persons and chronic schistosomiasis patients were used as control. Each group was composed of 213 cases. Items investigated included: history of schistosomiasis and treatment, exposure to the contaminated water, social-economical condition and nutritional status, other concomitant diseases. Cellular and humoral immunity, HBVMs and ABO blood groups were also detected. Statistical analysis was performed by 1:1 and 1:2 matched single and stepwise conditional logistic regression analysis with SAS software. RESULTS: By stepwise conditional logistic regression analysis, it was revealed that number of schistosomiasis examination (OR = 1.168-1.311), interval from first infection to last treatment(OR = 1.142), interval from first infection to this investigation (OR = 1.089), HBsAg+ (OR = 4.683-10.759), HBcAb+ (OR = 2.873), HBsAg+ + HBeAb+ + HBcAb+ (OR = 7.64) were risk factors of developing advanced schistosomiasis. The average living space and cellular immunity were lower in advanced schistosomiasis patients than others. No association was found between advanced schistosomiasis and ABO blood groups. CONCLUSION: The development of advanced schistosomiasis is associated with repeated infections, and delayed or incomplete treatment. Combined infection with hepatitis B, poor socio-economic conditions and impaired cellular immunity may increase the pathogenetic risk of schistosomiasis.

Measuring exposure to S. japonicum in China. I. Activity diaries to assess water contact and comparison to other measures.

We introduce a new method, activity diaries, in order to evaluate human water contact among fishing communities in an area moderately endemic for Schistosoma japonicum in the Dongting Lake region of Southern China. Two hundred and forty-nine subjects (76% male) were followed prospectively over a 9-month-period in order to verify exposure and reinfection. Exposure was determined crudely with questionnaires, direct 12-h water observations, and more precisely with activity diaries and an adjusted exposure model which took into account the time of day, the duration of contact and the percent body surface area in contact with water. Cohort subjects filled in activity diaries for an average of 85 days as compared with 2 days for the direct water observations. The typical unadjusted mean daily water contact (duration) based on the activity diaries was 53 min with 62% of this time spent in fishing. In contrast, the direct water observations revealed an average daily duration of 149 min with 53% of the time spent in fishing. Human water contact patterns (min/day) by site, activity and body part exposed were examined with the activity diaries. Individuals in the 36-49-year-old age range had the highest degree of water contact. Most of this daily contact occurred by males on the hands (mean+/-S.D.; 83.53+/-67.80 min/day) while fishing (mean+/-S.D.; 87.84+/-8.88 min/day) on the lake (mean+/-S.D.; 85.98+/-69.90 min/day). There was a strong positive log correlation (r=0.95) between the crude and adjusted (based on our derived exposure model) diary outcomes for the entire study sample, however, at higher exposure levels this relationship was differentially weaker (r=0.70). Results from this study suggest that current methods used in evaluating schistosomiasis exposure in China may overestimate and bias measures of the risk of infection. Activity diaries adjusted for the time of day, duration and the percent body surface area exposed are cost-effective and practical instruments to accurately quantify human exposure in the vast lake regions of Southern China where most of the endemic schistosomiasis japonica occurs.

Schistosomal glomerulopathy: selection factors.

Of several hundreds of millions of people infested with schistosomiasis, only a few hundreds have, so far, been documented to have one or other of the three schistosoma-associated immune-mediated glomerulopathies, namely proliferative glomerulonephritis, focal and segmental sclerosis, and amyloidosis. Regardless of undoubted under-reporting, some factors must be involved in the selection of those who develop such glomerulopathies. On the basis of experimental and clinical evidence, this review highlights the importance of parasitic species, associated salmonellosis, genetic predisposition and impaired hepatic macrophage activity. It also discusses the potential pathogenic role of the prevailing parasite 'strains', intensity of infestation, associated infections with hepatitis B, and common urinary pathogens and impairment of hepatocellular function. Selection ultimately seems to be multifactorial, but there is evidence that inefficiency of the hepatic macrophage system plays a key role by allowing both schistosomal antigens and IgA polymers to escape hepatic clearance and/or modulation.