Association of glucose-6-phosphate dehydrogenase deficiency and malaria: a systematic review and meta-analysis.

Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency overlaps with malaria endemicity although it predisposes carriers to hemolysis. This fact supports the protection hypothesis against malaria. The aim of this systematic review is to assess the presence and the extent of protective association between G6PD deficiency and malaria. Thirteen databases were searched for papers reporting any G6PD alteration in malaria patients. Twenty-eight of the included 30 studies were eligible for the meta-analysis. Results showed absence of negative association between G6PD deficiency and uncomplicated falciparum malaria (odds ratio (OR), 0.77; 95% confidence interval (CI), 0.59-1.02; p = 0.07). However, this negative association happened in Africa (OR, 0.59; 95% CI, 0.40-0.86; p = 0.007) but not in Asia (OR, 1.24; 95% CI, 0.96-1.61; p = 0.10), and in the heterozygotes (OR, 0.70; 95% CI, 0.57-0.87; p = 0.001) but not the homo/hemizygous (OR, 0.70; 95% CI, 0.46-1.07; p = 0.10). There was no association between G6PD deficiency and total severe malaria (OR, 0.82; 95% CI, 0.61-1.11; p = 0.20). Similarly, there was no association with other malaria species. G6PD deficiency can potentially protect against uncomplicated malaria in African countries, but not severe malaria. Interestingly, this protection was mainly in heterozygous, being x-linked thus related to gender.

High-Throughput Screening and Prediction Model Building for Novel Hemozoin Inhibitors Using Physicochemical Properties.

It is essential to continue the search for novel antimalarial drugs due to the current spread of resistance against artemisinin by Plasmodium falciparum parasites. In this study, we developed in silico models to predict hemozoin inhibitors as a potential first-step screening for novel antimalarials. An in vitro colorimetric high-throughput screening assay of hemozoin formation was used to identify hemozoin inhibitors from 9,600 structurally diverse compounds. The physicochemical properties of positive hits and randomly selected compounds were extracted from the ChemSpider database; they were used for developing prediction models to predict hemozoin inhibitors using two different approaches, i.e., traditional multivariate logistic regression and Bayesian model averaging. Our results showed that a total of 224 positive-hit compounds exhibited the ability to inhibit hemozoin formation, with 50% inhibitory concentrations (IC50s) ranging from 3.1 µM to 199.5 µM. The best model according to traditional multivariate logistic regression included the three variables octanol-water partition coefficient, number of hydrogen bond donors, and number of atoms of hydrogen, while the best model according to Bayesian model averaging included the three variables octanol-water partition coefficient, number of hydrogen bond donors, and index of refraction. Both models had a good discriminatory power, with area under the curve values of 0.736 and 0.781 for the traditional multivariate model and Bayesian model averaging, respectively. In conclusion, the prediction models can be a new, useful, and cost-effective approach for the first screen of hemozoin inhibition-based antimalarial drug discovery.

Species-Specific Serological Detection for Schistosomiasis by Serine Protease Inhibitor (SERPIN) in Multiplex Assay.

BACKGROUND: Both Schistosoma mansoni and Schistosoma haematobium cause schistosomiasis in sub-Saharan Africa. We assessed the diagnostic value of selected Schistosoma antigens for the development of a multiplex serological immunoassay for sero-epidemiological surveillance. METHODOLOGY/PRINCIPAL FINDINGS: Diagnostic ability of recombinant antigens from S. mansoni and S. haematobium was assessed by Luminex multiplex immunoassay using plasma from school children in two areas of Kenya, endemic for different species of schistosomiasis. S. mansoni serine protease inhibitor (SERPIN) and Sm-RP26 showed significantly higher reactivity to patient plasma as compared to the control group. Sm-Filamin, Sm-GAPDH, Sm-GST, Sm-LAP1, Sm-LAP2, Sm-Sm31, Sm-Sm32 and Sm-Tropomyosin did not show difference in reactivity between S. mansoni infected and uninfected pupils. Sm-RP26 was cross-reactive to plasma from S. haematobium patients, whereas Sm-SERPIN was species-specific. Sh-SEPRIN was partially cross-reactive to S. mansoni infected patients. ROC analysis for Sm-RP26, Sm-SERPIN and Sh-SERPIN showed AUC values of 0.833, 0.888 and 0.947, respectively. Using Spearman's rank correlation coefficient analysis, we also found significant positive correlation between the number of excreted eggs and median fluorescence intensity (MFI) from the multiplex immunoassays for Sm-SERPIN (ρ = 0.430, p-value = 0.003) and Sh-SERPIN (ρ = 0.433, p-value = 0.006). CONCLUSIONS/SIGNIFICANCE: Sm-SERPIN is a promising species-specific diagnostic antigen. Sh-SEPRIN was partially cross-reactive to S. mansoni infected patients. SERPINs showed correlation with the number of excreted eggs. These indicate prospects for inclusion of SERPINs in the multiplex serological immunoassay system.

Molecular markers and Schistosoma-associated bladder carcinoma: A systematic review and meta-analysis.

BACKGROUND: Molecular mechanisms and pathogenesis of schistosomal-associated bladder cancer (SABC), one of the most common malignancies in Africa and parts of the Middle East, is still unclear. Identification of host molecular markers involved in schistosomal related bladder carcinogenesis is of value in prediction of high-risk group, early detection and timely intervention. METHODS: PubMed, Scopus, Google Scholar, Cochrane Library and African Journals Online databases were systematically searched and reviewed. A total of 63 articles reporting 41 host molecular factors were included in the meta-analysis. RESULTS: Pooled odds ratio demonstrated associations of p53 expression, telomerase activity and sFas with SABC as compared to other schistosomal patients (p53 expression: OR=9.46, 95%CI=1.14-78.55, p=0.04; telomerase by TERT: OR=37.38, 95%CI=4.17-334.85, p=0.001; telomerase by TRAP: OR=10.36, 95%CI=6.08-17.64, p<0.00001; sFas: OR=34.37, 95%CI=3.32-355.51, p=0.003). In comparison to bladder cancers of other etiology, positive associations were found between SABC and p15 deletion, p16 deletion, telomerase activity and sFas (p15 deletion: OR=4.20, 95%CI=2.58-6.82, p<0.00001; p16 deletion: OR=4.93, 95%CI=2.52-9.65, p<0.00001; telomerase by TERT: OR=3.01, 95%CI=1.51-5.97, p=0.002; telomerase by TRAP: OR=2.66, 95%CI=1.18-6.01, p=0.02; sFas: OR=4.50, 95%CI=1.78-11.40, p=0.001). Other identified associations were reported by few numbers of studies to enable reliable interpretation. CONCLUSIONS: Variations in gene expression or genomic alterations of some molecular markers in SABC as compared to non-SABC or other schistosomal patients were identified. These suggest minute differences in the pathogenesis and physiological profile of SABC, in relation to non-SABC.

Immunogenicity and anti-fecundity effect of nanoparticle coated glutathione S-transferase (SjGST) DNA vaccine against murine Schistosoma japonicum infection.

There is still urgent need for a vaccine against schistosomiasis, especially in Schistosoma japonicum endemic areas where even a vaccine that will interrupt zoonotic transmission will be potentially effective as an intervention tool. We had developed a novel nanoparticle gene delivery system, which has proven efficacious in gene transfection to target immune cells with complementary adjuvant effect and high protective efficacy in several diseases. Here, we applied this nanoparticle system in combination with S. japonicum glutathione S-transferase (SjGST) DNA vaccine to show the immunogenicity and anti-fecundity effect of the nanoparticle coated vaccine formulation against murine schistosomiasis. The nanoparticle-coated DNA vaccine formulation induced desired immune responses. In comparison with the nanoparticle coated empty vector, it produced significantly increased antigen-specific humoral response, T-helper 1 polarized cytokine environment, higher proportion of IFN-γ producing CD4(+) T-cells and the concomitant decrease in IL-4 producing CD4(+) T-cells. Although there was no effect on worm burden, we recorded a marked reduction in tissue egg burden. There was up to 71.3% decrease in tissue egg burden and 55% reduction in the fecundity of female adult worms. Our data showed that SjGST DNA vaccine, delivered using the nanoparticle gene delivery system, produced anti-fecundity effect on female adult schistosomes as previously described by using conventional subunit vaccine with adjuvant, proving this DNA vaccine formulation as a promising candidate for anti-pathology and transmission blocking application.

Host determinants of reinfection with schistosomes in humans: a systematic review and meta-analysis.

BACKGROUND: Schistosomiasis is still a major public health burden in the tropics and subtropics. Although there is an effective chemotherapy (Praziquantel) for this disease, reinfection occurs rapidly after mass drug administration (MDA). Because the entire population do not get reinfected at the same rate, it is possible that host factors may play a dominant role in determining resistance or susceptibility to reinfection with schistosomes. Here, we systematically reviewed and meta-analyzed studies that reported associations between reinfection with the principal human-infecting species (S. mansoni, S. japonicum and S. haematobium) and host socio-demographic, epidemiological, immunological and genetic factors. METHODOLOGY/PRINCIPAL FINDINGS: PubMed, Scopus, Google Scholar, Cochrane Review Library and African Journals Online public databases were searched in October 2013 to retrieve studies assessing association of host factors with reinfection with schistosomes. Meta-analysis was performed to generate pooled odds ratios and standardized mean differences as overall effect estimates for dichotomous and continuous variables, respectively. Quality assessment of included studies, heterogeneity between studies and publication bias were also assessed. Out of the initial 2739 records, 109 studies were included in the analyses, of which only 32 studies with 37 data sets were eligible for quantitative data synthesis. Among several host factors identified, strong positive association was found with age and pre-treatment intensity, and only slightly for gender. These factors are major determinants of exposure and disease transmission. Significant positive association was found with anti-SWA IgG4 level, and a negative overall effect for association with IgE levels. This reconfirmed the concept that IgE/IgG4 balance is a major determinant of protective immunity against schistosomiasis. Other identified determinants were reported by a small number of studies to enable interpretation. CONCLUSIONS: Our data contribute to the understanding of host-parasite interaction as it affects reinfection, and is a potential tool to guide planning and tailoring of community interventions to target high-risk groups.

Characterization of a gene family encoding SEA (sea-urchin sperm protein, enterokinase and agrin)-domain proteins with lectin-like and heme-binding properties from Schistosoma japonicum.

BACKGROUND: We previously identified a novel gene family dispersed in the genome of Schistosoma japonicum by retrotransposon-mediated gene duplication mechanism. Although many transcripts were identified, no homolog was readily identifiable from sequence information. METHODOLOGY/PRINCIPAL FINDINGS: Here, we utilized structural homology modeling and biochemical methods to identify remote homologs, and characterized the gene products as SEA (sea-urchin sperm protein, enterokinase and agrin)-domain containing proteins. A common extracellular domain in this family was structurally similar to SEA-domain. SEA-domain is primarily a structural domain, known to assist or regulate binding to glycans. Recombinant proteins from three members of this gene family specifically interacted with glycosaminoglycans with high affinity, with potential implication in ligand acquisition and immune evasion. Similar approach was used to identify a heme-binding site on the SEA-domain. The heme-binding mode showed heme molecule inserted into a hydrophobic pocket, with heme iron putatively coordinated to two histidine axial ligands. Heme-binding properties were confirmed using biochemical assays and UV-visible absorption spectroscopy, which showed high affinity heme-binding (K D = 1.605×10(-6) M) and cognate spectroscopic attributes of hexa-coordinated heme iron. The native proteins were oligomers, antigenic, and are localized on adult worm teguments and gastrodermis; major host-parasite interfaces and site for heme detoxification and acquisition. CONCLUSIONS: The results suggest potential role, at least in the nucleation step of heme crystallization (hemozoin formation), and as receptors for heme uptake. Survival strategies exploited by parasites, including heme homeostasis mechanism in hemoparasites, are paramount for successful parasitism. Thus, assessing prospects for application in disease intervention is warranted.

The association of cytokines with severe dengue in children.

BACKGROUND: Dengue virus infection is a major public health problem. A hypothesis put forward for severe dengue is the cytokine storm, a sudden increase in cytokines that induces vascular permeability. Previous studies and our recent meta-analysis showed that IL-6, IL-8, IFNγ, TNFα, VEGF-A and VCAM-1 are associated with dengue shock syndrome. Therefore, in this study we aim to validate the association of these cytokines with severe dengue. METHODS & FINDINGS: In a hospital based-case control study in Vietnam, children with dengue fever, other febrile illness and healthy controls were recruited. Dengue virus infection was confirmed by several diagnostic tests. Multiplex immunoassay using Luminex technology was used to measure cytokines simultaneously. A positive association with dengue shock syndrome was found for VCAM-1, whereas a negative association was found for IFNγ. Furthermore, multivariate logistic analysis also showed that VCAM-1 and IFNγ were independently correlated with dengue shock syndrome. CONCLUSION: IFNγ and VCAM-1 were associated with dengue shock syndrome, although their role in the severe dengue pathogenesis remains unclear. Additional studies are required to shed further light on the function of these cytokines in severe dengue.

Origin of a novel protein-coding gene family with similar signal sequence in Schistosoma japonicum.

BACKGROUND: Evolution of novel protein-coding genes is the bedrock of adaptive evolution. Recently, we identified six protein-coding genes with similar signal sequence from Schistosoma japonicum egg stage mRNA using signal sequence trap (SST). To find the mechanism underlying the origination of these genes with similar core promoter regions and signal sequence, we adopted an integrated approach utilizing whole genome, transcriptome and proteome database BLAST queries, other bioinformatics tools, and molecular analyses. RESULTS: Our data, in combination with database analyses showed evidences of expression of these genes both at the mRNA and protein levels exclusively in all developmental stages of S. japonicum. The signal sequence motif was identified in 27 distinct S. japonicum UniGene entries with multiple mRNA transcripts, and in 34 genome contigs distributed within 18 scaffolds with evidence of genome-wide dispersion. No homolog of these genes or similar domain was found in deposited data from any other organism. We observed preponderance of flanking repetitive elements (REs), albeit partial copies, especially of the RTE-like and Perere class at either side of the duplication source locus. The role of REs as major mediators of DNA-level recombination leading to dispersive duplication is discussed with evidence from our analyses. We also identified a stepwise pathway towards functional selection in evolving genes by alternative splicing. Equally, the possible transcription models of some protein-coding representatives of the duplicons are presented with evidence of expression in vitro. CONCLUSION: Our findings contribute to the accumulating evidence of the role of REs in the generation of evolutionary novelties in organisms' genomes.

Onchocerciasis in Anambra State, Southeast Nigeria: endemicity and clinical manifestations.

BACKGROUND: A cross-sectional study was performed to determine the current endemicity of onchocerciasis in Ayamelum Local Council, Anambra State, Southeast Nigeria, where community-directed treatment with ivermectin has been implemented for over a decade. METHODS: An estimate of the endemicity of onchocerciasis was obtained using the rapid assessment method in 894 subjects from 13 communities selected by multistage sampling. Dermatological and ocular manifestations were analysed and classified using standard criteria. RESULTS: Onchocerca volvulus nodules were recorded in 86 (9.6 ± 1.9%) of the subjects, and 186 (20.8 ± 3.7%) had one or more of the various classes of onchocercal skin diseases (OSD). Prevalence was dependent on age (p = 0.001), but not on sex (p = 0.31). There was a total absence of symptoms in the youngest age group and a low prevalence among subjects in their second decade of life. Pearson's correlation showed a strong positive correlation between nodular rate and prevalence of chronic papular onchodermatitis (r = 0.943) and a poor correlation with acute papular onchodermatitis (r = 0.259). Age-dependent analysis of various classes of OSDs showed that the rate of acute papular onchodermatitis increased with age up to the third decade of life and decreased steadily thereafter, while the chronic forms of OSD increased with age for both sexes. Infection was dependent on occupation and proximity of the village to the vector breeding sites. CONCLUSIONS: Generally low prevalence in the population and absence of symptoms among the youngest age group emphasise the success of the intervention, but the persistent occurrence of acute disease may suggest a shortfall due to low coverage or non-compliance with the mass chemotherapeutic regimen.