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. 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. 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.

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. 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. 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. One of the major challenges of schistosomiasis control is that disease prevalence reverts to baseline levels after mass drug administration due to high rate of reinfection. Host factors play a major role in determining resistance or susceptibility to reinfection with schistosomiasis and other diseases. We systematically searched and analyzed studies that identified potential host determinants of reinfection with schistosomes. Among demographic variables, age but not gender was strongly associated with reinfection with schistosomes. Pretreatment infection intensity was also identified as a major determinant of reinfection. Positive association with IgG4 levels and negative association with IgE levels reconfirmed the notion that IgE/IgG4 balance is the major factor controlling protective immunity against schistosomiasis. Other factors were reported by few studies to allow correct inferences. These results contribute to our understanding of host-parasite relationship as it affects reinfection, and will be useful for planning and targeting the limited resources for intervention on high-risk groups.

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. 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). 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. More attention is now shifting towards elimination of some of the neglected tropical diseases, including schistosomiasis. Efficient diagnostics and surveillance tools are the bedrock of planning, implementation, monitoring and evaluation of such disease interventions. We had developed a multiplex immunoassay system for simultaneous detection of several pathogens in a single limited volume of human sample. To include Schistosoma antigen among the panel of pathogen antigens, we assessed the diagnostic value and suitability of selected Schistosoma antigens in multiplex format. S. mansoni serine protease inhibitor (SERPIN) and Sm-RP26 showed good diagnostic value with significant reactivity to patient plasma as compared to the control group. However, S. mansoni Filamin, GAPDH, GST, LAP1, LAP2, Sm31, Sm32 and Tropomyosin did not show disease-specific reactivity to plasma from S. mansoni infected patients. While Sm-RP26 was cross-reactive to plasma from S. haematobium patients, Sm-SERPIN showed species-specific reactivity. There was also significant positive correlation between the number of excreted eggs and fluorescence signals from the multiplex immunoassays for the SERPINs. These findings indicate potentials for utilization of SERPINs in the multiplex system.

Interleukin-4 (IL-4) is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection withSchistosoma haematobiumworms, remains poorly understood due to a historical lack of animal models. The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but associated mechanisms and links to IL-4 are largely unknown.

Chemotherapy‐induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests that IL‐4 alleviates ifosfamide‐induced hemorrhagic cystitis (IHC), but systemically administered IL‐4 causes significant side effects. We hypothesized that the Schistosoma hematobium homolog of IL‐4‐inducing principle from Schistosoma mansoni eggs (H‐IPSE), would reduce IHC and associated bladder pathology. IPSE binds IgE on basophils and mast cells, triggering IL‐4 secretion by these cells. IPSE is also an “infiltrin,” translocating into the host nucleus to modulate gene transcription. Mice were administered IL‐4, H‐IPSE protein or its nuclear localization sequence (NLS) mutant, with or without neutralizing anti‐IL‐4 antibody, or 2‐mercaptoethane sulfonate sodium (MESNA; a drug used to prevent IHC), followed by ifosfamide. Bladder tissue damage and hemoglobin content were measured. Spontaneous and evoked pain, urinary frequency, and bladdergene expression analysis were assessed. Pain behaviors were interpreted in a blinded fashion. One dose of H‐IPSE was superior to MESNA and IL‐4 in suppressing bladder hemorrhage in an IL‐4‐dependent fashion and comparable with MESNA in dampening ifosfamide‐triggered pain behaviors in an NLS‐dependent manner. H‐IPSE also accelerated urothelial repair following IHC. Our work represents the first therapeutic exploitation of a uropathogen‐derived host modulatory molecule in a clinically relevant bladder disease model and indicates that IPSE may be an alternative to MESNA for mitigating CHC.—Mbanefo, E. C., Le, L., Pennington, L. F., Odegaard, J. I., Jardetzky, T. S., Alouffi, A., Falcone, F. H., Hsieh, M. H. Therapeutic exploitation of IPSE, a urogenital parasite‐derived host modulatory protein, for chemotherapy‐induced hemorrhagic cystitis. FASEB J . 32, 4408–4419 (2018). www.fasebj.org