Transcriptional profiling of chronic clinical hepatic schistosomiasis japonica indicates reduced metabolism and immune responses.

Schistosomiasis is a significant cause of human morbidity and mortality. We performed a genome-wide transcriptional survey of liver biopsies obtained from Chinese patients with chronic schistosomiasis only, or chronic schistosomiasis with a current or past history of viral hepatitis B. Both disease groups were compared with patients with no prior history or indicators of any liver disease. Analysis showed in the main, downregulation in gene expression, particularly those involved in signal transduction via EIF2 signalling and mTOR signalling, as were genes associated with cellular remodelling. Focusing on immune associated pathways, genes were generally downregulated. However, a set of three genes associated with granulocytes, MMP7, CLDN7, CXCL6 were upregulated. Differential gene profiles unique to schistosomiasis included the gene Granulin which was decreased despite being generally considered a marker for liver disease, and IGBP2 which is associated with increased liver size, and was the most upregulated gene in schistosomiasis only patients, all of which presented with hepatomegaly. The unique features of gene expression, in conjunction with previous reports in the murine model of the cellular composition of granulomas, granuloma formation and recovery, provide an increased understanding of the molecular immunopathology and general physiological processes underlying hepatic schistosomiasis.

Evaluation of the tuberculosis programme in Ningxia Hui Autonomous region, the People's Republic of China: a retrospective case study.

BACKGROUND: Tuberculosis is a devastating disease due to its rapid transmission and high rate of mortality. Ningxia Hui Autonomous Region (NHAR), located in the North-west, is one of the poorest provinces in China and national surveys have shown TB has been hyper endemic in NHAR for several decades. As no active surveys had been undertaken since the initiation of the DOTS control program across all of NHAR. METHODS: A retrospective study was undertaken of all clinical records of TB patients registered from January 2005 to September 2009. Poisson regression was performed to investigate the change in incidence over time and accounted for age, sex and county. Length of time on treatment, disease severity and patient delay were assessed by county. RESULTS: More than 30% of patients had been on treatment for over 12 months and 10% for over 3 years, reflecting drug-resistance or failure of DOTS. More than 93% of patients had grade III disease at time of diagnosis and >15% of patients had severe disease grade IV-V in some NHAR counties. Further, 8.8% of patients were not diagnosed for over 6 months from the onset of symptoms; this was as high as 20% in some counties. The reported incidence of TB is most likely grossly underestimated and the data indicate TB is a major public health concern in NHAR. CONCLUSIONS: It is clear that active surveillance is necessary to determine the full extent of the burden of TB in NHAR. New control and treatment strategies for TB are required that increase awareness in the health-care system and at the individual and community level.

sTNFR-II and sICAM-1 are associated with acute disease and hepatic inflammation in schistosomiasis japonica.

Soluble intracellular adhesive molecule 1 (sICAM-1) and tumour necrosis factor receptors I (TNFR-1) and II (TNFR-II) have been shown to be associated with numerous liver disorders. Shedding of these membrane proteins can be triggered by the Th1 cytokines, TNF-alpha and IFN-gamma, which are associated with susceptibility or resistance to hepatic schistosomiasis, respectively. Further, TNF-alpha receptors and sICAM-1 have been implicated in periportal fibrosis in advanced human schistosomiasis mansoni and correlate with schistosome granuloma formation in the murine model. We measured serum levels of sICAM-1, TNFR-I and TNFR-II in Chinese patients with different clinically defined stages of schistosomiasis japonica and controls; these included 35 patients with acute schistosomiasis, 45 patients with chronic schistosome infections, 34 advanced patients with evidence of severe morbidity and 20 patients with no known history of exposure to infection. Markedly elevated levels of soluble TNFRs (sTNFRs) and sICAM-1 were observed in the acute and advanced patients compared with the chronic and control groups. Mean sTNFR-II levels were significantly higher in acute patients compared with advanced (P<0.00001) and chronic patients (P<0.00001) and showed the strongest association of the markers with acute disease (odds ratio (OR)=1.099). sTNFR-II and sICAM-1 levels both correlated with infection intensity and there were significant positive correlations observed between eosinophil count and infection intensity (P=0.0072) and sICAM-1 (P=0.0014). Although there were significantly higher levels of antigen-specific IgG4 and total IgG in infected individuals compared with controls, none correlated with infection intensity. Further, no differences in IgG4 and total IgG levels were observed between the acute and chronic groups. The results suggest sTNFRs and sICAM-1 are associated with liver inflammation and disease progression. Measurement of sTNFR-II and sICAM-1 levels in serum could serve as additional markers for the diagnosis of acute stage disease and the monitoring of hepatic inflammation in human schistosomiasis japonica.

Familial aggregation of human susceptibility to co- and multiple helminth infections in a population from the Poyang Lake region, China.

Human helminthiases are common in China, especially in rural areas where sanitation conditions are poor. Co- and multiple infections with helminths are strikingly frequent. A cross-sectional parasitological and questionnaire survey was carried out in a population of 3205 individuals belonging to 498 families from five villages in the Poyang Lake region, Jiangxi Province, China, to assess their helminth infection status and to collect information on risk factors for infection. The prevalences for Ascaris lumbricoides, Schistosoma japonicum and Trichuris trichiura were 30.9%, 15.7% and 47%, respectively. Hookworm infection prevalence was low (0.7%). A significant association was observed between A. lumbricoides and T. trichiura infection, and also between S. japonicum and T. trichiura infection. Variance components analysis was undertaken to investigate the aggregation of S. japonicum and the soil-transmitted helminths, A. lumbricoides and T. trichiura. While A. lumbricoides was found to aggregate only at a household level, T. trichiura was shown to cluster predominantly in families. Both genetic and household effects were found to be important in determining the risk of infection with S. japonicum. Variance components analysis for A. lumbricoides/T. trichiura co-infections indicated a significant domestic environmental effect, attributable for 32.7% of the co-infection risk. Aggregation of S. japonicum/T. trichiura co-infection was also observed at a household level. The risk of infection with multiple helminth species, although mainly environmentally influenced, was also shown to have significant involvement of genetic and household components. The results of this study indicate that a shared household is a major contributing risk factor for helminth co-infections and emphasises the need for increased standards of sanitation and hygiene to prevent parasite transmission. Further, the results suggest that susceptibility to one helminth infection is not completely independent of another, and that there exist common genetic factors underlying infection with multiple helminth species.

Familial aggregation of human infection with Schistosoma japonicum in the Poyang Lake region, China.

Despite the success of extensive control measures that have been implemented in China for over 50 years, the number of individuals infected with Schistosoma japonicum remains high in the existing endemic areas. A variance components analysis was undertaken to estimate the heritable and environmental components that contribute to S. japonicum infection in the Poyang Lake region of Jiangxi Province, PR China. The total target population was 3148 from four separate administrative villages. Two thousand seven hundred and five of these comprised 400 families ranging in size from 3 to 188. After adjustments were made for gender, water contact and past history of having had schistosomiasis, the heritable component was estimated to account for as much as 58% of the phenotype variation under the polygenic model. Household was not shown to be an important environmental factor. Incorporating village effects indicated that the results were valid for the total population. We conclude that genetic heritability in this region is high and plays an important role in determining risk of infection with S. japonicum.

CD4+ T-cell counts, CD4+/CD8+ T-cell count ratios, and antibody levels in migrant fishermen infected with Schistosoma japonicum in the Dongting Lake, China.

In this study, CD4(+) and CD8(+) T cells and antibody levels were measured in 94 migrant fishermen infected with Schistosoma japonicum from Dongting Lake, China. Prevalence among these fishermen was high (63.8%), with a mean infection intensity of 61.4 +/- 3.8 epg, and included a high proportion of individuals (39.4%) with substantial parenchymal fibrosis (stages > or = 2/3). The CD4(+)/CD8(+) ratio in men (1.34 +/- 0.11) was significantly lower than that of women (1.58 +/- 0.15). CD4(+) T cells and the ratio of CD4(+)/CD8(+) were significantly decreased both in subjects infected with S. japonicum and those with parenchymal fibrosis. However, levels of total IgA, IgM, and anti-schistosome egg antigen IgG correlated positively with infection intensity and pathologic lesion number. These results suggest an imbalance between cell-mediated and humoral immunity in these fishermen, the precise cause of which remains undetermined.

Rare variants in MYD88, IRAK4 and IKBKG and susceptibility to invasive pneumococcal disease: a population-based case-control study.

Although rare variants within the Toll-like receptor signalling pathway genes have been found to underlie human primary immunodeficiencies associated with selective predisposition to invasive pneumococcal disease (IPD), the contribution of variants in these genes to IPD susceptibility at the population level remains unknown. Complete re-sequencing of IRAK4, MYD88 and IKBKG genes was undertaken in 164 IPD cases from the UK and 164 geographically-matched population-based controls. 233 single-nucleotide variants (SNVs) were identified, of which ten were in coding regions. Four rare coding variants were predicted to be deleterious, two variants in MYD88 and two in IRAK4. The predicted deleterious variants in MYD88 were observed as two heterozygote cases but not seen in controls. Frequencies of predicted deleterious IRAK4 SNVs were the same in cases and controls. Our findings suggest that rare, functional variants in MYD88, IRAK4 or IKBKG do not significantly contribute to IPD susceptibility in adults at the population level.

Polymorphisms of SP110 are associated with both pulmonary and extra-pulmonary tuberculosis among the Vietnamese.

BACKGROUND: Tuberculosis (TB) is an infectious disease that remains a major cause of morbidity and mortality worldwide, yet the reasons why only 10% of people infected with Mycobacterium tuberculosis go on to develop clinical disease are poorly understood. Genetically determined variation in the host immune response is one factor influencing the response to M. tuberculosis. SP110 is an interferon-responsive nuclear body protein with critical roles in cell cycling, apoptosis and immunity to infection. However association studies of the gene with clinical TB in different populations have produced conflicting results. METHODS: To examine the importance of the SP110 gene in immunity to TB in the Vietnamese we conducted a case-control genetic association study of 24 SP110 variants, in 663 patients with microbiologically proven TB and 566 unaffected control subjects from three tertiary hospitals in northern Vietnam. RESULTS: Five SNPs within SP110 were associated with all forms of TB, including four SNPs at the C terminus (rs10208770, rs10498244, rs16826860, rs11678451) under a dominant model and one SNP under a recessive model, rs7601176. Two of these SNPs were associated with pulmonary TB (rs10208770 and rs16826860) and one with extra-pulmonary TB (rs10498244). CONCLUSION: SP110 variants were associated with increased susceptibility to both pulmonary and extra-pulmonary TB in the Vietnamese. Genetic variants in SP110 may influence macrophage signaling responses and apoptosis during M. tuberculosis infection, however further research is required to establish the mechanism by which SP110 influences immunity to tuberculosis infection.

Immunogenetics of human echinococcosis.

Susceptibility and resistance to human Echinococcus infection and disease, although poorly understood, appear to reflect a complex interaction of parasite and host immunological and genetic factors. Disease stage, progression, and prognosis following treatment appear to be strongly influenced by cytokine and antibody profiles, and more recent evidence has suggested an important role of dendritic cells (DCs) and T regulatory cells (Tregs) in immunomodulation. Microarrays have supported these findings, highlighting both known and novel pathways involved in chronic murine disease. Genetic studies to date have been few and with limited success. Advanced genomic approaches, such as genome-wide association studies (GWAS), may provide further insight to identify the relevant pathways involved, thereby facilitating a new approach for the development of new clinical therapies.

Diagnostic value of non-invasive bio-markers for stage-specific diagnosis of hepatic fibrosis in patients with advanced schistosomiasis japonica.

Hepatic fibrosis caused by schistosome infection can be fatal. Its management depends on the degree of fibrosis present. To assess the diagnostic value of bio-markers in patients with advanced schistosomiasis japonica at different stages of disease progression, 84 advanced schistosomiasis japonica patients and nine controls were recruited in The People's Republic of China. Fibrosis was histologically assessed in wedge liver biopsies using the Chinese criteria for fibrosis (F) Stages. Seven selected hepatic fibrosis bio-markers were assessed and compared between the groups. The method of area under receiver operating characteristic curves (AUROCs) was used as a measurement of diagnostic efficacy. Our results showed that routine laboratory test results were normal for the controls but were significantly elevated or decreased in patients with fibrosis. While serum hyaluronic acid (HA) and matrix metalloproteinase (TIMP)-1 levels were shown to be elevated in patient groups compared with controls, the levels of platelet derived growth factor (PDGF)-BB were markedly lower. To distinguish F≥2 from no fibrosis or mild fibrosis, HA gave a high AUROC of 0.938 (95% confidence interval (CI), 0.886-0.990). Combining the aspartate aminotransferase (AST) to platelet ratio index (APRI) and HA/100 showed an AUROC of 0.958 (95% CI, 0.914-1.000). APRI in combination with TIMP-1/100 provided an AUROC of 0.873 (95% CI, 0.805-0.942) for the diagnosis of fibrosis stages greater than 2. We conclude that AST and APRI levels were reliable and sensitive markers for differentiating significant hepatic fibrosis in patients with advanced schistosomiasis japonica. HA and TIMP-1 show potential as additional markers for the diagnosis of fibrosis and cirrhosis in advanced schistosomiasis patients.

Human cases of simultaneous echinococcosis and tuberculosis - significance and extent in China.

During analysis of retrospective community survey data, we identified two patients from Xiji County, south Ningxia Hui Autonomous Region with simultaneous echinococcosis and tuberculosis (TB), representing the first such reports for China. As the echinococcosis chronicity increased, the immune profile in both subjects changed from a Th1 to Th2 response, as shown by a TB skin test, originally positive, becoming negative. Such an elevated Th2 immune profile, with subsequent suppression of the Th1 immune response, is a common feature of chronic helminth infections. Given the difficulties in definitive diagnosis, and the potential increased susceptibility for TB infection in patients with advanced echinococcosis, we suggest that combined TB/echinococcosis surveys be undertaken in this area in the future. This would allow early diagnosis of both TB and echinococcosis cases with better prognosis for effective and sustainable treatment outcomes, ultimately reducing associated morbidity and mortality, and also the overall financial costs to the individual and the public health care system in this under developed part of China.

Large water management projects and schistosomiasis control, Dongting Lake region, China.

Construction of the Three Gorges Dam across the Yangtze River will substantially change the ecology of the Dongting Lake in southern China. In addition, the Chinese Central and Hunan Provinces' governmental authorities have instigated a Return Land to Lake Program that will extend the Dongting Lake surface area from the current 2,681 km2 to 4,350 km2. The previous construction of embankments and the large silt deposits made by the Yangtze River and other connecting rivers have contributed to frequent disastrous flooding. As a consequence of the 2 water projects, > 2 million persons and their domestic animals are being resettled. This article provides an overview of the historical background of these 2 large water management projects, the associated population movement, and their impact on future transmission and control of schistosomiasis in the Dongting Lake area. The dam will likely substantially extend the range of the snail habitats and increase schistosome transmission and schistosomiasis cases.

Analysis of the 5q31 33 locus shows an association between single nucleotide polymorphism variants in the IL-5 gene and symptomatic infection with the human blood fluke, Schistosoma japonicum.

Genetic studies of human susceptibility to Schistosoma (blood fluke) infections have previously identified a genetic locus determining infection intensity with the African species, Schistosoma mansoni, in the 5q31-33 region of the human genome that is known to contain the Th2 immune response cluster, including the genes encoding the IL-4, IL-5, and IL-13 cytokines. These cytokines are key players in inflammatory immune responses and have previously been implicated in human susceptibility to infection with the Asian species, S. japonicum. In a nested case control study, we genotyped 30 HapMap tagging single nucleotide polymorphisms (SNPs) across these three genes in 159 individuals identified as putatively susceptible to reinfection with S. japonicum and in 133 putatively resistant individuals. A third group comprising 113 individuals demonstrating symptomatic infection was also included. The results provided no significant association at a global level between reinfection predisposition and any of the individual SNPs or haplotype blocks. However, two tagging SNPs in IL-5 demonstrated globally significant association with susceptibility to symptomatic infection. They were in strong linkage disequilibrium with each other and were found to belong to the same haplotype block that also provided a significant association after permutation testing. This haplotype was located in the 3'-untranslated region of IL-5, suggesting that variants in this region of IL-5 may modulate the immune response in these individuals with symptomatic infection.