H-IPSE Is a Pathogen-Secreted Host Nucleus-Infiltrating Protein (Infiltrin) Expressed Exclusively by the Schistosoma haematobium Egg Stage

Pennington, Luke F.; Alouffi, Abdulaziz; Mbanefo, Evaristus C.; Ray, Debalina; Heery, David M.; Jardetzky, Theodore S.; Hsieh, Michael H.; Falcone, Franco H.

doi:10.1128/iai.00301-17

Cited by 39 publications

(65 citation statements)

References 40 publications

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“…The response in this setting was rapid in onset and localized, including induction of IL-4. In other studies, we also showed that S. haematobium egg antigens induce IL-4 release from non-lymphocyte populations [20], mainly by activation via their surface Fcε receptors. Herein we sought to use our micro-injection technique to define the role of IL-4 in schistosomal bladder pathogenesis.…”

Section: Discussionmentioning

confidence: 66%

“…Other Fcε receptor negative non-lymphocyte sources of IL-4 have also been reported [17, 18]. The most abundant IL-4 inducing egg antigen has since been identified and characterized from S. mansoni and S. haematobium [2, 15, 19, 20]. The interleuking-4 inducing principle from Schistosoma eggs (IPSE) binds to IgE on the surface of these non-T-cell sources, inducing massive IL-4 release that subsequently drive type-2 response [2, 15, 19, 20].…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

Mbanefo

et al. 2019

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19IL-4 is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection with 20 Schistosoma haematobium worms, remains poorly understood due to a historical lack of animal models. 21The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in 22 the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but 23 associated mechanisms and links to IL-4 are largely unknown. We modeled urogenital schistosomiasis 24 by injecting the bladder walls of IL-4 receptor-alpha knockout(Il4ra -/-) and wild type mice with S. 25 haematobium eggs. Readouts included bladder histology and ex vivo assessments of urothelial 26 proliferation, cell cycle and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial 27 cell proliferation in vitro, including cell cycle status and phosphorylation patterns of major downstream 28 regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of 29 granulomatous responses to bladder-wall injected S. haematobium eggs in Il4ra -/versus wild type mice. 30 S. haematobium egg injection triggered significant urothelial proliferation, including evidence of 31 urothelial hyperdiploidy and cell cycle skewing in wild type but not Il4ra -/mice. Urothelial exposure to 32 IL-4 in vitro led to cell cycle polarization and increased phosphorylation of AKT. Our results show IL-4 33 signaling is required for key pathogenic features of urogenital schistosomiasis, and that particular 34 aspects of this signaling pathway may exert these effects directly on the urothelium. These findings 35 point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis. 36 37 unfortunately sets the stage for the characteristic fibrotic response. For intestinal schistosomiasis, 48 hepatosplenomegaly and portal hypertension may result, or bladder cancer in the case of urogenital 49 schistosomiasis. 50The exact underlying mechanism by which schistosome eggs induce IL-4 production/release is still 51 uncertain [2]. The major sources of IL-4 have also been shown to include other sources beyond the Th2 52 cells themselves [14]. Parasite egg crude extract has been shown to stimulate enormous IL-4 release 53 from basophils [2, 15], mast cells and other non-T-cell, non-B-cell populations [16], which may indeed 54 represent constitutive sources of IL-4, apart from the Th2 cells. Other Fcε receptor negative non-55 lymphocyte sources of IL-4 have also been reported [17, 18]. The most abundant IL-4 inducing egg 56 antigen has since been identified and characterized from S. mansoni and S. haematobium [2, 15, 19, 20]. 57The interleuking-4 inducing principle from Schistosoma eggs (IPSE) binds to IgE on the surface of these 58 non-T-cell sources, inducing massive IL-4 release that subsequently drive type-2 response [2, 15, 19, 59 20]. 60Although the role of IL-4 in driving schistosomiasis-induced pathogenesis is widely studied for hepato-61 splenic schistosomi...

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

Mbanefo

et al. 2019

Preprint

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“…Another explanation for the different phenotypes observed between H-IPSE H03 and H-IPSE H06 is that variations in the sequence, and therefore, function of IPSE proteins have evolved such that different orthologs of H-IPSE are secreted to perform different host-modulatory functions. Both orthologs of H-IPSE are homologous to M-IPSE in that they both conserve the C-terminal nuclear localization sequence as well as 7 cysteines which are responsible for forming disulfide bonds to create a homodimeric structure (19). Characterization of sequence/structure-function relationships of individual orthologs of H-IPSE is the subject of continued investigation.…”

Section: Discussionmentioning

confidence: 99%

“…One alternative may be the interleukin-4 inducing principle from Schistosoma mansoni eggs (IPSE), the most abundant protein secreted by S. mansoni eggs. IPSE attenuates inflammation via multiple mechanisms, including binding immunoglobulins to stimulate IL-4 release, sequestering chemokines, and translocating to the nucleus to modulate transcription (17, 19). We have previously reported that similar to the S. mansoni ortholog of IPSE, M-IPSE, several S. haematobium orthologs, referred hereafter as H-IPSE, bind to IgE on mast cells and basophils and upregulate the expression of IL-4 (19).…”

Section: Introductionmentioning

confidence: 99%

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IPSE, a parasite-derived host immunomodulatory protein, is a promising therapeutic for hemorrhagic cystitis

Zee

Mbanefo

et al. 2018

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1Chemotherapy-induced hemorrhagic cystitis is characterized by bladder pain and 2 voiding dysfunction caused by hemorrhage and inflammation. Of currently available 3 therapies, prophylactic 2-mercaptoethanesulfonic acid (MESNA) has limited efficacy 4 and cannot treat pre-existing lesions. Therefore, novel therapeutic options to treat 5 hemorrhagic cystitis are needed. We previously reported that systemic administration of 6 the Schistosomiasis haematobium-derived protein H-IPSE H06 (IL-4-inducing principle 7 from Schistosoma mansoni eggs), is superior to 3 doses of MESNA in alleviating 8 hemorrhagic cystitis. Based on prior reports by others on S. mansoni IPSE and 9 additional work by our group, we reasoned that H-IPSE H06 mediates its effects on 1 0 hemorrhagic cystitis by binding IgE on basophils and inducing IL-4 expression, 1 1promoting urothelial proliferation, and translocating to the nucleus to modulate 1 2 expression of genes implicated in relieving bladder dysfunction. We speculated that 1 3 local bladder injection of the S. haematobium IPSE ortholog IPSE H03 , hereafter called H-1 4 IPSE H03 , might be more efficacious in preventing hemorrhagic cystitis compared to 1 5 systemic administration of IPSE H06 . We demonstrate herein that H-IPSE H03 is a 1 6promising therapeutic for the treatment of voiding dysfunction and bladder pain in 1 7 hemorrhagic cystitis. Namely, it attenuates ifosfamide-induced increases in bladder wet 1 8 weight in an IL-4-dependent fashion. H-IPSE H03 relieves hemorrhagic cystitis-associated 1 9 allodynia. Finally, H-IPSE H03 drives increased urothelial cell proliferation. This indicates 2 0that IPSE induces bladder healing mechanisms, which suggests that it may be a novel 2 1 non-opioid analgesic to treat bladder pain syndromes. 2 2 4 1 demonstrated fewer spontaneous pain behaviors and had a higher threshold for evoked 4 2pain responses. We speculated that direct injection of IPSE into the bladder wall would 4 3 have multiple advantages over intravenous injection, including avoidance of side effects 4 4 caused by systemic administration (although none have been identified to date), and 4 5 potentially decreased dosage to achieve a therapeutic effect. The aim of this work was 4 6

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Schistosoma mansoni Egg–Secreted Antigens Activate Hepatocellular Carcinoma–Associated Transcription Factors c‐Jun and STAT3 in Hamster and Human Hepatocytes

et al. 2019

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Clinical data have provided evidence that schistosomiasis can promote hepatocellular carcinogenesis. c-Jun and STAT3 are critical regulators of liver cancer development and progression. The aim of the present study was to investigate the hepatocellular activation of c-Jun and STAT3 by Schistosoma mansoni-infection. Expression and function of c-Jun, STAT3 as well as proliferation and DNA repair were analyzed by Western blotting, electrophoretic mobility shift assay, and immunohistochemistry in liver of S. mansoni-infected hamsters, Huh7 cells, primary hepatocytes, and human liver biopsies. Hepatocellular activation of c-Jun was demonstrated by nuclear translocation of c-Jun, enhanced phosphorylation (Ser73), and AP-1/DNA-binding in response to S. mansoni infection. Nuclear c-Jun staining pattern around lodged eggs without ambient immune reaction, and directionally from granuloma to the central veins suggested that substances released from schistosome eggs were responsible for the observed effects. In addition, hepatocytes with c-Jun activation, show cell activation and DNA double-strand breaks. These findings from the hamster model were confirmed by analyses of human biopsies from patients with schistosomiasis. Cell culture experiments finally demonstrated that activation of c-Jun and STAT3 as well as DNA repair were induced by an extract from schistosome eggs (soluble egg antigens (SEA) and culture supernatants of live schistosome egg (egg-conditioned medium (ECM)), and in particular by IPSE/alpha-1, the major component secreted by live schistosome eggs. The permanent activation of hepatocellular carcinoma-associated proto-oncogenes such as c-Jun and associated transcription factors including STAT3 by substances released from tissue-trapped schistosome eggs may be important factors contributing to the development of liver cancer in S. mansoni-infected patients. Therefore, identification and therapeutic targeting of the underlying pathways is a useful strategy to prevent schistosomiasis associated carcinogenesis. This article is protected by copyright. All rights reserved.

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H-IPSE Is a Pathogen-Secreted Host Nucleus-Infiltrating Protein (Infiltrin) Expressed Exclusively by the Schistosoma haematobium Egg Stage

Cited by 39 publications

References 40 publications

Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

IPSE, a parasite-derived host immunomodulatory protein, is a promising therapeutic for hemorrhagic cystitis

Schistosoma mansoni Egg–Secreted Antigens Activate Hepatocellular Carcinoma–Associated Transcription Factors c‐Jun and STAT3 in Hamster and Human Hepatocytes

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