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  • 1
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    IPSE, a parasite-derived, host immunomodulatory infiltrin protein, alleviates resiniferatoxin-induced bladder pain
    SAGE Publications ; 2020
    In:  Molecular Pain Vol. 16 ( 2020-01), p. 174480692097009-
    Details
    In: Molecular Pain, SAGE Publications, Vol. 16 ( 2020-01), p. 174480692097009-
    Abstract: The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-based mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4- and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSE’s analgesic effect. In contrast, IPSE’s analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not significantly affect freezing behaviors. RNA-Seq analysis of resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-κb-related signaling pathway genes. In vitro testing of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSE’s nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms.
    Type of Medium: Online Resource
    ISSN: 1744-8069 , 1744-8069
    URL: Article
    DOI: 10.1177/1744806920970099
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2020
    detail.hit.zdb_id: 2174252-2
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  • 2
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    Onchocerciasis in Anambra State, Southeast Nigeria: clinical and psychological aspects and sustainability of community directed treatment with ivermectin (CDTI)
    Oxford University Press (OUP) ; 2010
    In:  Postgraduate Medical Journal Vol. 86, No. 1020 ( 2010-10-01), p. 573-577
    Details
    In: Postgraduate Medical Journal, Oxford University Press (OUP), Vol. 86, No. 1020 ( 2010-10-01), p. 573-577
    Abstract: A cross-sectional study was performed to determine the psychological impact of onchocerciasis, and assess sustainability of the decade-old community directed treatment with ivermectin (CDTI) in Ayamelum Local Council, Anambra State, Southeast Nigeria. Methods Skin manifestations assessed using the rapid assessment method (RAM) in 894 subjects from 13 communities selected by multi-stage sampling were classified based on the anatomical sites affected. Focus group discussions and in-depth interviews were used to obtain information on the psychological impacts and sustainability of the CDTI programme. Qualitative data were summarised while quantitative data generated were analysed using charts and tables. Results Anatomical distribution showed a preponderance of onchodermatitis on the limbs (the most exposed parts of the body) and buttocks (an area considered ‘private’), thus revealing some reasons for the psychological impacts of the skin disease and the psychosocial inclination of the victims. Itching (40%) and onchocercal skin manifestations (OSDs) (34.3%) were identified as the most troublesome signs and symptoms, while the most worrisome consequence of onchocerciasis was social seclusion (or stigmatisation) (34.3%). Focus group responses revealed the persistence of psychological impacts on the victims, affecting almost all facets of their lives. The CDTI programme has performed creditably well when assessed using the sustainability indicators, yet there are still challenges in the areas of coverage, monitoring, resources, and participation. A ‘quick-win’ was identified whereby the CDTI chain could be utilised to deliver other health interventions. Conclusion It is recommended that onchocerciasis control programmes should include aspects that would address its psychosocial impacts and threats to the sustainability of the CDTI programme.
    Type of Medium: Online Resource
    ISSN: 0032-5473 , 1469-0756
    URL: Article
    DOI: 10.1136/pgmj.2010.100248
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2010
    detail.hit.zdb_id: 2009568-5
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  • 3
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    H-IPSE Is a Pathogen-Secreted Host Nucleus-Infiltrating Protein (Infiltrin) Expressed Exclusively by the Schistosoma haematobium Egg Stage
    American Society for Microbiology ; 2017
    In:  Infection and Immunity Vol. 85, No. 12 ( 2017-12)
    Details
    In: Infection and Immunity, American Society for Microbiology, Vol. 85, No. 12 ( 2017-12)
    Abstract: Urogenital schistosomiasis, caused by the parasitic trematode Schistosoma haematobium , affects over 112 million people worldwide. As with Schistosoma mansoni infections, the pathology of urogenital schistosomiasis is related mainly to the egg stage, which induces granulomatous inflammation of affected tissues. Schistosoma eggs and their secretions have been studied extensively for the related organism S. mansoni , which is more amenable to laboratory studies. Indeed, we have shown that IPSE/alpha-1 (here M-IPSE), a major protein secreted from S. mansoni eggs, can infiltrate host cells. Although the function of M-IPSE is unknown, its ability to translocate to the nuclei of host cells and bind DNA suggests a possible role in immune modulation of host cell tissues. Whether IPSE homologs are expressed in other schistosome species has not been investigated. Here, we describe the cloning of two paralog genes, H03-IPSE and H06-IPSE, which are orthologs of M-IPSE, from egg cDNA of S. haematobium . Using PCR and immunodetection, we confirmed that the expression of these genes is restricted to the egg stage and female adult worms, while the H-IPSE protein is detectable only in mature eggs and not adults. We show that both H03-IPSE and H06-IPSE proteins can infiltrate HTB-9 bladder cells when added exogenously to culture medium. Monopartite C-terminal nuclear localization sequence (NLS) motifs conserved in H03-IPSE, SKRRRKY, and H06-IPSE SKRGRKY, are responsible for targeting the proteins to the nucleus of HTB-9 cells, as demonstrated by site-directed mutagenesis and green fluorescent protein (GFP) tagging. Thus, S. haematobium eggs express IPSE homologs that appear to perform similar functions in infiltrating host cells.
    Type of Medium: Online Resource
    ISSN: 0019-9567 , 1098-5522
    URL: Article
    DOI: 10.1128/IAI.00301-17
    RVK:
    XA 10000
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2017
    detail.hit.zdb_id: 1483247-1
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  • 4
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    Multilevel modelling of the risk of malaria among children aged under five years in Nigeria
    Oxford University Press (OUP) ; 2021
    In:  Transactions of The Royal Society of Tropical Medicine and Hygiene Vol. 115, No. 5 ( 2021-05-08), p. 482-494
    Details
    In: Transactions of The Royal Society of Tropical Medicine and Hygiene, Oxford University Press (OUP), Vol. 115, No. 5 ( 2021-05-08), p. 482-494
    Abstract: Malaria is still a major cause of morbidity and mortality among children aged & lt;5 y (U5s). This study assessed individual, household and community risk factors for malaria in Nigerian U5s. Methods Data from the Nigerian Malaria Health Indicator Survey 2015 were pooled for analyses. This comprised a national survey of 329 clusters. Children aged 6–59 mo who were tested for malaria using microscopy were retained. Multilevel logit model accounting for sampling design was used to assess individual, household and community factors associated with malaria parasitaemia. Results A total of 5742 children were assessed for malaria parasitaemia with an overall prevalence of 27% (95% CI 26 to 28%). Plasmodium falciparum constituted 98% of the Plasmodium species. There was no significant difference in parasitaemia between older children and those aged ≤12 mo. In adjusted analyses, rural living, northwest region, a household size of & gt;7, dependence on river and rainwater as primary water source were associated with higher odds of parasitaemia, while higher wealth index, all U5s who slept under a bed net and dependence on packaged water were associated with lower odds of parasitaemia. Conclusion Despite sustained investment in malaria control and prevention, a quarter of the overall study population of U5s have malaria. Across the six geopolitical zones, the highest burden was in children living in the poorest rural households.
    Type of Medium: Online Resource
    ISSN: 0035-9203 , 1878-3503
    URL: Article
    DOI: 10.1093/trstmh/traa092
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2135136-3
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  • 5
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    IPSE, a urogenital parasite-derived immunomodulatory protein, ameliorates ifosfamide-induced hemorrhagic cystitis through downregulation of pro-inflammatory pathways
    Springer Science and Business Media LLC ; 2019
    In:  Scientific Reports Vol. 9, No. 1 ( 2019-02-07)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-02-07)
    Abstract: Ifosfamide and other oxazaphosphorines can result in hemorrhagic cystitis, a constellation of complications caused by acrolein metabolites. We previously showed that a single dose of IPSE (Interleukin-4-inducing principle from Schistosoma eggs), a schistosome-derived host modulatory protein, can ameliorate ifosfamide-related cystitis; however, the mechanisms underlying this urotoxicity and its prevention are not fully understood. To provide insights into IPSE’s protective mechanism, we undertook transcriptional profiling of bladders from ifosfamide-treated mice, with or without pretreatment with IPSE or IPSE-NLS (a mutant of IPSE lacking nuclear localization sequence). Ifosfamide treatment upregulated a range of proinflammatory genes. The IL-1 β -TNF α -IL-6 proinflammatory cascade via NF κ B and STAT3 pathways was identified as the key driver of inflammation. The NRF2-mediated oxidative stress response pathway, which regulates heme homoeostasis and expression of antioxidant enzymes, was highly activated. Anti-inflammatory cascades, namely Wnt, Hedgehog and PPAR pathways, were downregulated. IPSE drove significant downregulation of major proinflammatory pathways including the IL-1 β -TNF α -IL-6 pathways, interferon signaling, and reduction in oxidative stress. IPSE-NLS reduced inflammation but not oxidative stress. Taken together, we have identified signatures of acute-phase inflammation and oxidative stress in ifosfamide-injured bladder, which are reversed by pretreatment with IPSE. This work revealed several pathways that could be therapeutically targeted to prevent ifosfamide-induced hemorrhagic cystitis.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-018-38274-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2615211-3
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  • 6
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    Interleukin-4 Signaling Plays a Major Role in Urogenital Schistosomiasis-Associated Bladder Pathogenesis
    American Society for Microbiology ; 2020
    In:  Infection and Immunity Vol. 88, No. 3 ( 2020-02-20)
    Details
    In: Infection and Immunity, American Society for Microbiology, Vol. 88, No. 3 ( 2020-02-20)
    Abstract: Interleukin-4 (IL-4) is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection with Schistosoma haematobium worms, 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. We modeled urogenital schistosomiasis by injecting the bladder walls of IL-4 receptor-alpha knockout ( Il4ra −/− ) and wild-type mice with S. haematobium eggs. Readouts included bladder histology and ex vivo assessments of urothelial proliferation, cell cycle, and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial cell proliferation in vitro , including cell cycle status and phosphorylation patterns of major downstream regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of granulomatous responses to bladder-wall-injected S. haematobium eggs in Il4ra −/− versus wild-type mice. S. haematobium egg injection triggered significant urothelial proliferation, including evidence of urothelial hyper-diploidy and cell cycle skewing in wild-type but not Il4ra −/− mice. Urothelial exposure to IL-4 in vitro led to cell cycle polarization and increased phosphorylation of AKT. Our results show that IL-4 signaling is required for key pathogenic features of urogenital schistosomiasis and that particular aspects of this signaling pathway may exert these effects directly on the urothelium. These findings point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis.
    Type of Medium: Online Resource
    ISSN: 0019-9567 , 1098-5522
    URL: Article
    DOI: 10.1128/IAI.00669-19
    RVK:
    XA 10000
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
    detail.hit.zdb_id: 1483247-1
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  • 7
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    Uveitis: Molecular Pathogenesis and Emerging Therapies
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-4-30)
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    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-4-30)
    Abstract: The profound impact that vision loss has on human activities and quality of life necessitates understanding the etiology of potentially blinding diseases and their clinical management. The unique anatomic features of the eye and its sequestration from peripheral immune system also provides a framework for studying other diseases in immune privileged sites and validating basic immunological principles. Thus, early studies of intraocular inflammatory diseases (uveitis) were at the forefront of research on organ transplantation. These studies laid the groundwork for foundational discoveries on how immune system distinguishes self from non-self and established current concepts of acquired immune tolerance and autoimmunity. Our charge in this review is to examine how advances in molecular cell biology and immunology over the past 3 decades have contributed to the understanding of mechanisms that underlie immunopathogenesis of uveitis. Particular emphasis is on how advances in biotechnology have been leveraged in developing biologics and cell-based immunotherapies for uveitis and other neuroinflammatory diseases.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2021.623725
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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  • 8
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    Schistosoma haematobium cercarial infection alters subsequent systemic immune responses to eggs but has minimal impact on immune responses to egg injection of the bladder
    Wiley ; 2019
    In:  Parasite Immunology Vol. 41, No. 1 ( 2019-01)
    Details
    In: Parasite Immunology, Wiley, Vol. 41, No. 1 ( 2019-01)
    Abstract: Mouse bladder wall injection with Schistosoma haematobium eggs has been used to overcome limitations in animal models of urogenital schistosomiasis. However, the effect of the absence of cercarial infection on immune responses to eggs in this model is unknown. We hypothesized that cercarial infection would alter local bladder and systemic immune responses to eggs in this model. Methods and results Mice were infected or not infected with S haematobium cercariae, and then, their bladder walls injected with S haematobium eggs or vehicle 5 weeks following cercarial infection. Three weeks later, mice were bled, sacrificed, perfused and their bladders harvested. Parasitological parameters and gross bladder pathology were not changed in egg‐injected bladders by cercarial exposure. Figure S1 shows no changes in either granulomas or fibrosis. The only bladder cytokine upregulated in egg‐injected bladders by cercarial exposure (vs no exposure) was leptin. Cercarial exposure, compared to no exposure, resulted in increased serum, IL‐1α, IL‐13 and TGF‐β in bladder egg‐injected mice. Conclusion Cercarial exposure altered systemic responses of several cytokines in bladder egg‐injected mice, but surprisingly, only modified leptin expression in bladder tissue. This suggests that depending on the specific application, cercarial exposure may not be strictly necessary to model local immune responses in the bladder wall egg injection mouse model of urogenital schistosomiasis.
    Type of Medium: Online Resource
    ISSN: 0141-9838 , 1365-3024
    URL: Issue
    URL: Article
    DOI: 10.1111/pim.2019.41.issue-1
    DOI: 10.1111/pim.12602
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2020808-X
    SSG: 12
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  • 9
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    Therapeutic exploitation of IPSE, a urogenital parasite‐derived host modulatory protein, for chemotherapy‐induced hemorrhagic cystitis
    Wiley ; 2018
    In:  The FASEB Journal Vol. 32, No. 8 ( 2018-08), p. 4408-4419
    Details
    In: The FASEB Journal, Wiley, Vol. 32, No. 8 ( 2018-08), p. 4408-4419
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v32.8
    DOI: 10.1096/fj.201701415R
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 10
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    IPSE, a parasite-derived host immunomodulatory protein, is a potential therapeutic for hemorrhagic cystitis
    American Physiological Society ; 2019
    In:  American Journal of Physiology-Renal Physiology Vol. 316, No. 6 ( 2019-06-01), p. F1133-F1140
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 316, No. 6 ( 2019-06-01), p. F1133-F1140
    Abstract: Chemotherapy-induced hemorrhagic cystitis is characterized by bladder pain and voiding dysfunction caused by hemorrhage and inflammation. Novel therapeutic options to treat hemorrhagic cystitis are needed. We previously reported that systemic administration of the Schistosomiasis hematobium-derived protein H-IPSE H06 (IL-4-inducing principle from Schistosoma mansoni eggs) is superior to three doses of MESNA in alleviating hemorrhagic cystitis (Mbanefo EC, Le L, Pennington LF, Odegaard JI, Jardetzky TS, Alouffi A, Falcone FH, Hsieh MH. FASEB J 32: 4408–4419, 2018). Based on prior reports by others on S. mansoni IPSE (M-IPSE) and additional work by our group, we reasoned that H-IPSE mediates its effects on hemorrhagic cystitis by binding IgE on basophils and inducing IL-4 expression, promoting urothelial proliferation, and translocating to the nucleus to modulate expression of genes implicated in relieving bladder dysfunction. We speculated that local bladder injection of the S. hematobium IPSE ortholog IPSE H03 , hereafter called H-IPSE H03 , might be more efficacious in preventing hemorrhagic cystitis compared with systemic administration of IPSE H06 . We report that H-IPSE H03 , like M-IPSE and H-IPSE H06 , activates IgE-bearing basophils in a nuclear factor of activated T-cells reporter assay, indicating activation of the cytokine pathway. Furthermore, H-IPSE H03 attenuates ifosfamide-induced increases in bladder wet weight in an IL-4-dependent fashion. H-IPSE H03 relieves hemorrhagic cystitis-associated allodynia and modulates voiding patterns in mice. Finally, H-IPSE H03 drives increased urothelial cell proliferation, suggesting that IPSE induces bladder repair mechanisms. Taken together, H-IPSE H03 may be a potential novel therapeutic to treat hemorrhagic cystitis by basophil activation, attenuation of allodynia, and promotion of urothelial cell proliferation.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00468.2018
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2019
    detail.hit.zdb_id: 1477287-5
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