scholarly journals IPSE, an abundant egg-secreted protein of the carcinogenic helminth Schistosoma haematobium, promotes proliferation of bladder cancer cells and angiogenesis

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Evaristus C. Mbanefo ◽  
Chinwike Terry Agbo ◽  
Yuanlong Zhao ◽  
Olivia K. Lamanna ◽  
Kim H. Thai ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Schistosoma Haematobium ◽  
Causal Link ◽  
Urothelial Cell ◽  
Cell Uptake ◽  
Interleukin 4 ◽  
Nuclear Localization Sequence ◽  
Urothelial Cells ◽  
Cell Nuclei ◽  
Urogenital Schistosomiasis

Abstract Background Schistosoma haematobium, the helminth causing urogenital schistosomiasis, is a known bladder carcinogen. Despite the causal link between S. haematobium and bladder cancer, the underlying mechanisms are poorly understood. S. haematobium oviposition in the bladder is associated with angiogenesis and urothelial hyperplasia. These changes may be pre-carcinogenic events in the bladder. We hypothesized that the Interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE), an S. haematobium egg-secreted “infiltrin” protein that enters host cell nuclei to alter cellular activity, is sufficient to induce angiogenesis and urothelial hyperplasia. Methods: Mouse bladders injected with S. haematobium eggs were analyzed via microscopy for angiogenesis and urothelial hyperplasia. Endothelial and urothelial cell lines were incubated with recombinant IPSE protein or an IPSE mutant protein that lacks the native nuclear localization sequence (NLS-) and proliferation measured using CFSE staining and real-time monitoring of cell growth. IPSE’s effects on urothelial cell cycle status was assayed through propidium iodide staining. Endothelial and urothelial cell uptake of fluorophore-labeled IPSE was measured. Findings: Injection of S. haematobium eggs into the bladder triggers angiogenesis, enhances leakiness of bladder blood vessels, and drives urothelial hyperplasia. Wild type IPSE, but not NLS-, increases proliferation of endothelial and urothelial cells and skews urothelial cells towards S phase. Finally, IPSE is internalized by both endothelial and urothelial cells. Interpretation: IPSE drives endothelial and urothelial proliferation, which may depend on internalization of the molecule. The urothelial effects of IPSE depend upon its NLS. Thus, IPSE is a candidate pro-carcinogenic molecule of S. haematobium. Summary Schistosoma haematobium acts as a bladder carcinogen through unclear mechanisms. The S. haematobium homolog of IPSE, a secreted schistosome egg immunomodulatory molecule, enhances angiogenesis and urothelial proliferation, hallmarks of pre-carcinogenesis, suggesting IPSE is a key pro-oncogenic molecule of S. haematobium.

scholarly journals IPSE, an Abundant Egg-Secreted Protein of the Carcinogenic Helminth Schistosoma haematobium, Promotes Proliferation of Bladder Cancer Cells and Angiogenesis

2020 ◽  
Author(s):  
Evaristus C. Mbanefo ◽  
Chinwike Terry Agbo ◽  
Yuanlong Zhao ◽  
Olivia K. Lamanna ◽  
Kimberly H. Thai ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Schistosoma Haematobium ◽  
Causal Link ◽  
Urothelial Cell ◽  
Cell Uptake ◽  
Interleukin 4 ◽  
Nuclear Localization Sequence ◽  
Urothelial Cells ◽  
Cell Nuclei ◽  
Urogenital Schistosomiasis

Abstract Background: Schistosoma haematobium, the helminth causing urogenital schistosomiasis, is a known bladder carcinogen. Despite the causal link between S. haematobium and bladder cancer, the underlying mechanisms are poorly understood. S. haematobium oviposition in the bladder is associated with angiogenesis and urothelial hyperplasia. These changes may be pre-carcinogenic events in the bladder. We hypothesized that the Interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE), an S. haematobium egg-secreted “infiltrin” protein that enters host cell nuclei to alter cellular activity, is sufficient to induce angiogenesis and urothelial hyperplasia. Methods: Mouse bladders injected with S. haematobium eggs were analyzed via microscopy for angiogenesis and urothelial hyperplasia. Endothelial and urothelial cell lines were incubated with recombinant IPSE protein or an IPSE mutant protein that lacks the native nuclear localization sequence (NLS-) and proliferation measured using CFSE staining and real-time monitoring of cell growth. IPSE’s effects on urothelial cell cycle status was assayed through propidium iodide staining. Endothelial and urothelial cell uptake of fluorophore-labeled IPSE was measured. Findings: Injection of S. haematobium eggs into the bladder triggers angiogenesis, enhances leakiness of bladder blood vessels, and drives urothelial hyperplasia. Wild type IPSE, but not NLS-, increases proliferation of endothelial and urothelial cells and skews urothelial cells towards S phase. Finally, IPSE is internalized by both endothelial and urothelial cells. Interpretation: IPSE drives endothelial and urothelial proliferation, which may depend on internalization of the molecule. The urothelial effects of IPSE depend upon its NLS. Thus, IPSE is a candidate pro-carcinogenic molecule of S. haematobium.

scholarly journals IPSE, an Abundant Egg-Secreted Protein of the Carcinogenic Helminth Schistosoma haematobium, Promotes Proliferation of Bladder Cancer Cells and Angiogenesis

2020 ◽  
Author(s):  
Evaristus C. Mbanefo ◽  
Chinwike Terry Agbo ◽  
Yuanlong Zhao ◽  
Olivia K. Lamanna ◽  
Kimberly H. Thai ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Schistosoma Haematobium ◽  
Causal Link ◽  
Urothelial Cell ◽  
Cell Uptake ◽  
Interleukin 4 ◽  
Nuclear Localization Sequence ◽  
Urothelial Cells ◽  
Cell Nuclei ◽  
Urogenital Schistosomiasis

Abstract Background: Schistosoma haematobium, the helminth causing urogenital schistosomiasis, is a known bladder carcinogen. Despite the causal link between S. haematobium and bladder cancer, the underlying mechanisms are poorly understood. S. haematobium oviposition in the bladder is associated with angiogenesis and urothelial hyperplasia. These changes may be pre-carcinogenic events in the bladder. We hypothesized that the Interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE), an S. haematobium egg-secreted “infiltrin” protein that enters host cell nuclei to alter cellular activity, is sufficient to induce angiogenesis and urothelial hyperplasia.Methods: Mouse bladders injected with S. haematobium eggs were analyzed via microscopy for angiogenesis and urothelial hyperplasia. Endothelial and urothelial cell lines were incubated with recombinant IPSE protein or an IPSE mutant protein that lacks the native nuclear localization sequence (NLS-) and proliferation measured using CFSE staining and real-time monitoring of cell growth. IPSE’s effects on urothelial cell cycle status was assayed through propidium iodide staining. Endothelial and urothelial cell uptake of fluorophore-labeled IPSE was measured. Findings: Injection of S. haematobium eggs into the bladder triggers angiogenesis, enhances leakiness of bladder blood vessels, and drives urothelial hyperplasia. Wild type IPSE, but not NLS-, increases proliferation of endothelial and urothelial cells and skews urothelial cells towards S phase. Finally, IPSE is internalized by both endothelial and urothelial cells. Interpretation: IPSE drives endothelial and urothelial proliferation, which may depend on internalization of the molecule. The urothelial effects of IPSE depend upon its NLS. Thus, IPSE is a candidate pro-carcinogenic molecule of S. haematobium.

scholarly journals Cytological and Wet Mount Microscopic Observations Made in Urine of Schistosoma haematobium-Infected Children: Hint of the Implication in Bladder Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Patience B. Tetteh-Quarcoo ◽  
Benjamin K. Akuetteh ◽  
Irene A. Owusu ◽  
Solomon E. Quayson ◽  
Simon K. Attah ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Schistosoma Haematobium ◽  
Inflammatory Cells ◽  
Sub Saharan Africa ◽  
Urine Samples ◽  
Urogenital Schistosomiasis ◽  
Cytological Abnormalities ◽  
Sub Saharan ◽  
Carcinoma Of The Bladder ◽  
Infected Urine

Background. Schistosomiasis is the second major human parasitic disease next to malaria, in terms of socioeconomic and public health consequences, especially in sub-Saharan Africa. Schistosoma haematobium (S. haematobium) is a trematode and one of the species of Schistosoma that cause urogenital schistosomiasis (urinary schistosomiasis). Although the knowledge of this disease has improved over the years, there are still endemic areas, with most of the reported cases in Africa, including Ghana. Not much has been done in Ghana to investigate cytological abnormalities in individuals within endemic communities, although there are epidemiologic evidences linking S. haematobium infection with carcinoma of the bladder. Aim. The aim of this study was to identify microscopic and cytological abnormalities in the urine deposits of S. haematobium-infected children. Methodology. Three hundred and sixty-seven (367) urine samples were collected from school children in Zenu and Weija communities. All the samples were examined microscopically for the presence of S. haematobium eggs, after which the infected samples and controls were processed for cytological investigation. Results. S. haematobium ova were present in 66 (18.0%) out of the 367 urine samples. Inflammatory cells (82%, 54/66), hyperkeratosis (47%, 31/66), and squamous cell metaplasia (24%, 16/66) were the main observations made during the cytological examination of the S. haematobium-infected urine samples. Conclusion. Cytological abnormalities in S. haematobium-infected children may play an important role in the severity of the disease, leading to the possible development of bladder cancer in later years, if early attention is not given. Therefore, routine cytological screening for urogenital schistosomiasis patients (especially children) at hospitals in S. haematobium-endemic locations is recommended.

scholarly journals IPSE, a urogenital parasite-derived immunomodulatory molecule, suppresses bladder pathogenesis and anti-microbial peptide gene expression in bacterial urinary tract infection

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Evaristus C. Mbanefo ◽  
Loc Le ◽  
Luke F. Pennington ◽  
Yi- Ju Hsieh ◽  
Justin I. Odegaard ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Receptor Expression ◽  
Interleukin 4 ◽  
Nuclear Localization Sequence ◽  
Parasitic Infections ◽  
Urogenital Schistosomiasis ◽  
Localization Sequence ◽  
Inducing Factors ◽  
Underlying Mechanisms ◽  
Peptide Gene

Abstract Background Parasitic infections can increase susceptibility to bacterial co-infections. This may be true for urogenital schistosomiasis and bacterial urinary tract co-infections (UTI). We previously reported that this co-infection is facilitated by S. haematobium eggs triggering interleukin-4 (IL-4) production and sought to dissect the underlying mechanisms. The interleukin-4-inducing principle from Schistosoma mansoni eggs (IPSE) is one of the most abundant schistosome egg-secreted proteins and binds to IgE on the surface of basophils and mast cells to trigger IL-4 release. IPSE can also translocate into host nuclei using a nuclear localization sequence (NLS) to modulate host transcription. We hypothesized that IPSE is the factor responsible for the ability of S. haematobium eggs to worsen UTI pathogenesis. Methods Mice were intravenously administered a single 25 μg dose of recombinant S. haematobium-derived IPSE, an NLS mutant of IPSE or PBS. Following IPSE exposure, mice were serially weighed and organs analyzed by histology to assess for toxicity. Twenty-four hours after IPSE administration, mice were challenged with the uropathogenic E. coli strain UTI89 by urethral catheterization. Bacterial CFU were measured using urine. Bladders were examined histologically for UTI-triggered pathogenesis and by PCR for antimicrobial peptide and pattern recognition receptor expression. Results Unexpectedly, IPSE administration did not result in significant differences in urine bacterial CFU. However, IPSE administration did lead to a significant reduction in UTI-induced bladder pathogenesis and the expression of anti-microbial peptides in the bladder. Despite the profound effect of IPSE on UTI-triggered bladder pathogenesis and anti-microbial peptide production, mice did not demonstrate systemic ill effects from IPSE exposure. Conclusions Our data show that IPSE may play a major role in S. haematobium-associated urinary tract co-infection, albeit in an unexpected fashion. These findings also indicate that IPSE either works in concert with other IL-4-inducing factors to increase susceptibility of S. haematobium-infected hosts to bacterial co-infection or does not contribute to enhancing vulnerability to this co-infection.

scholarly journals The role of estradiol metabolism in urogenital schistosomiasis-induced bladder cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769224 ◽  
Author(s):  
Nuno Vale ◽  
Maria J Gouveia ◽  
Gabriel Rinaldi ◽  
Júlio Santos ◽  
Lúcio Lara Santos ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Schistosoma Haematobium ◽  
Infectious Agent ◽  
Suppressor Gene ◽  
Urogenital Schistosomiasis ◽  
P53 Expression ◽  
Estradiol Metabolism ◽  
Shed Light ◽  
Tumor Suppressor Gene P53

Urogenital schistosomiasis is a neglected tropical disease that can lead to bladder cancer. How urogenital schistosomiasis induces carcinogenesis remains unclear, although there is evidence that the human blood fluke Schistosoma haematobium, the infectious agent of urogenital schistosomiasis, releases estradiol-like metabolites. These kind of compounds have been implicated in other cancers. Aiming for enhanced understanding of the pathogenesis of the urogenital schistosomiasis-induced bladder cancer, here we review, interpret, and discuss findings of estradiol-like metabolites detected in both the parasite and in the human urine during urogenital schistosomiasis. Moreover, we predict pathways and enzymes that are involved in the production of these metabolites emphasizing their potential effects on the dysregulation of the tumor suppressor gene p53 expression during urogenital schistosomiasis. Enhanced understanding of these potential carcinogens may not only shed light on urogenital schistosomiasis-induced neoplasia of the bladder, but would also facilitate development of interventions and biomarkers for this and other infection-associated cancers at large.

scholarly journals IPSE, a Urogenital Parasite-Derived Immunomodulatory Molecule, Suppresses Bladder Pathogenesis and Anti-Microbial Peptide Gene Expression in Bacterial Urinary Tract Infection

2020 ◽  
Author(s):  
Evaristus C. Mbanefo ◽  
Loc Le ◽  
Luke F. Pennington ◽  
Yi-Ju Hsieh ◽  
Justin I. Odegaard ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Interleukin 4 ◽  
Nuclear Localization Sequence ◽  
Parasitic Infections ◽  
Urogenital Schistosomiasis ◽  
Peptide Expression ◽  
Localization Sequence ◽  
Inducing Factors ◽  
Underlying Mechanisms ◽  
Peptide Gene

Abstract Background: Parasitic infections can increase susceptibility to bacterial co-infections. This may be true for urogenital schistosomiasis and bacterial urinary tract co-infections (UTI). We previously reported that this co-infection is facilitated by S. haematobium eggs triggering interleukin-4 (IL-4) production and sought to dissect the underlying mechanisms. The interleukin-4 inducing principle from Schistosoma mansoni eggs (IPSE) is one of the most abundant schistosome egg-secreted proteins and binds to IgE on the surface of basophils and mast cells to trigger IL-4 release. IPSE can also translocate into host nuclei using a nuclear localization sequence (NLS) to modulate host transcription. We hypothesized that IPSE is the factor responsible for the ability of S. haematobium eggs to worsen UTI pathogenesis. Methods: Mice were intravenously administered a single 25 mg dose of recombinant S. haematobium-derived IPSE, an NLS mutant of IPSE or PBS. Following IPSE exposure, mice were serially weighed, and organs analyzed by histology to assess for toxicity. Twenty-four hours after IPSE administration, mice were challenged with the uropathogenic E. coli strain UTI89 by urethral catheterization. Bacterial cfu were measured using urine. Bladders were examined histologically for UTI-triggered pathogenesis and by PCR for antimicrobial peptide expression.Results: Unexpectedly, IPSE administration did not result in significant differences in urine bacterial CFU. However, IPSE administration did lead to a significant reduction in UTI-induced bladder pathogenesis and the expression of anti-microbial peptides in the bladder. Despite the profound effect of IPSE on UTI-triggered bladder pathogenesis and anti-microbial peptide production, mice did not demonstrate systemic ill effects from IPSE exposure.Conclusions: Our data show that IPSE may play a major role in S. haematobium-associated urinary tract co-infection, albeit in an unexpected fashion. These findings also indicate that IPSE either works in concert with other IL-4-inducing factors to increase susceptibility of S. haematobium-infected hosts to bacterial co-infection, or does not contribute to enhancing vulnerability to this co-infection.

scholarly journals Combination of novel intravesical xenogeneic urothelial cell immunotherapy and chemotherapy enhances anti-tumor efficacy in preclinical murine bladder tumor models

2020 ◽  
Author(s):  
Chi-Ping Huang ◽  
Chun-Chie Wu ◽  
Chih-Rong Shyr
Keyword(s):  
Bladder Cancer ◽  
Tumor Immunity ◽  
Bladder Tumor ◽  
Checkpoint Inhibitors ◽  
Tumor Model ◽  
Vehicle Control ◽  
Urothelial Cell ◽  
Urothelial Cells ◽  
Cell Immunotherapy ◽  
Advanced Bladder Cancer

Abstract Background Immune checkpoint inhibitors induce robust and durable responses in advanced bladder cancer (BC), but only for a subset of patients. Xenovaccination has been proposed as an effective immunotherapeutic approach to induce anti-tumor immunity. Thus, we proposed a novel intravesical xenogeneic urothelial cell immunotherapy strategy to treat advanced BC based on the hypothesis that implanted xenogeneic urothelial cells not only provoke xeno-rejection immune responses but also elicit bystander anti-tumor immunity. Methods Mouse advanced bladder cancer models were treated with vehicle control, intravesical xenogeneic urothelial cells, cisplatin + gemcitabine, or the combination and assessed for tumor responses to treatments. Tumors and spleens samples were collected for immunohistological staining, cellular and molecular analysis assessed by antibody staining, ELISA, cytotoxicity, and flow cytometry, respectively. Results The combination treatment of xenogeneic urothelial cell immunotherapy with chemotherapy was more efficacious than either single therapy to extend survival time in MBT-2 graft bladder tumor model and to suppress tumor progression in murine carcinogen BBN-induced bladder tumor model. The single-cell immunotherapy and combined therapy increased more tumor-infiltrating immune cells in MBT-2 graft tumors compared to vehicle control and chemotherapy treatment groups. The activated T-cell proliferation, cytokine production, and cytotoxicity capacities were also higher in mice with xenogeneic urothelial cell immunotherapy and combination treatments. Conclusions Our results suggest the potential for a novel xenogeneic urothelial cell-based immunotherapy alone and synergy with chemotherapy in the combination therapy. Therefore, our study supports developing xenogeneic urothelial cells as an immunotherapeutic agent in combination with chemotherapy for BC treatment.

scholarly journals IPSE, a Urogenital Parasite-Derived Immunomodulatory Molecule, Suppresses Bladder Pathogenesis and Anti-Microbial Peptide Gene Expression in Bacterial Urinary Tract Co-Infection

2020 ◽  
Author(s):  
Evaristus C. Mbanefo ◽  
Loc Le ◽  
Luke F. Pennington ◽  
Yi-Ju Hsieh ◽  
Justin I. Odegaard ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Interleukin 4 ◽  
Nuclear Localization Sequence ◽  
Parasitic Infections ◽  
Urogenital Schistosomiasis ◽  
Peptide Expression ◽  
Localization Sequence ◽  
Inducing Factors ◽  
Underlying Mechanisms ◽  
Peptide Gene

Abstract Background: Parasitic infections can increase susceptibility to bacterial co-infections. This may be true for urogenital schistosomiasis and bacterial urinary tract co-infections (UTI). We previously reported that this co-infection is facilitated by S. haematobium eggs triggering interleukin-4 (IL-4) production and sought to dissect the underlying mechanisms. The interleukin-4 inducing principle from Schistosoma mansoni eggs (IPSE) is one of the most abundant schistosome egg-secreted proteins and binds to IgE on the surface of basophils and mast cells to trigger IL-4 release. IPSE can also translocate into host nuclei using a nuclear localization sequence (NLS) to modulate host transcription. We hypothesized that IPSE is the factor responsible for the ability of S. haematobium eggs to worsen UTI pathogenesis. Methods: Mice were intravenously administered a single 25 μg dose of recombinant S. haematobium-derived IPSE, an NLS mutant of IPSE or PBS. Following IPSE exposure, mice were serially weighed, and organs analyzed by histology to assess for toxicity. Twenty-four hours after IPSE administration, mice were challenged with the uropathogenic E. coli strain UTI89 by urethral catheterization. Bacterial cfu were measured using urine. Bladders were examined histologically for UTI-triggered pathogenesis and by PCR for antimicrobial peptide expression.Results: Unexpectedly, IPSE administration did not result in significant differences in urine bacterial CFU. However, IPSE administration did lead to a significant reduction in UTI-induced bladder pathogenesis and the expression of anti-microbial peptides in the bladder. Despite the profound effect of IPSE on UTI-triggered bladder pathogenesis and anti-microbial peptide production, mice did not demonstrate systemic ill effects from IPSE exposure.Conclusions: Our data show that IPSE may play a major role in S. haematobium-associated urinary tract co-infection, albeit in an unexpected fashion. These findings also indicate that IPSE either works in concert with other IL-4-inducing factors to increase susceptibility of S. haematobium-infected hosts to bacterial co-infection, or does not contribute to enhancing vulnerability to this co-infection.

scholarly journals IPSE, a Urogenital Parasite-Derived Immunomodulatory Molecule, Suppresses Bladder Pathogenesis and Anti-Microbial Peptide Gene Expression in Bacterial Urinary Tract Infection

2020 ◽  
Author(s):  
Evaristus C. Mbanefo ◽  
Loc Le ◽  
Luke F. Pennington ◽  
Yi-Ju Hsieh ◽  
Justin I. Odegaard ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Receptor Expression ◽  
Interleukin 4 ◽  
Nuclear Localization Sequence ◽  
Parasitic Infections ◽  
Urogenital Schistosomiasis ◽  
Localization Sequence ◽  
Inducing Factors ◽  
Underlying Mechanisms ◽  
Peptide Gene

Abstract Background: Parasitic infections can increase susceptibility to bacterial co-infections. This may be true for urogenital schistosomiasis and bacterial urinary tract co-infections (UTI). We previously reported that this co-infection is facilitated by S. haematobium eggs triggering interleukin-4 (IL-4) production and sought to dissect the underlying mechanisms. The interleukin-4 inducing principle from Schistosoma mansoni eggs (IPSE) is one of the most abundant schistosome egg-secreted proteins and binds to IgE on the surface of basophils and mast cells to trigger IL-4 release. IPSE can also translocate into host nuclei using a nuclear localization sequence (NLS) to modulate host transcription. We hypothesized that IPSE is the factor responsible for the ability of S. haematobium eggs to worsen UTI pathogenesis. Methods: Mice were intravenously administered a single 25 mg dose of recombinant S. haematobium-derived IPSE, an NLS mutant of IPSE or PBS. Following IPSE exposure, mice were serially weighed, and organs analyzed by histology to assess for toxicity. Twenty-four hours after IPSE administration, mice were challenged with the uropathogenic E. coli strain UTI89 by urethral catheterization. Bacterial cfu were measured using urine. Bladders were examined histologically for UTI-triggered pathogenesis and by PCR for antimicrobial peptide and pattern recognition receptor expression.Results: Unexpectedly, IPSE administration did not result in significant differences in urine bacterial CFU. However, IPSE administration did lead to a significant reduction in UTI-induced bladder pathogenesis and the expression of anti-microbial peptides in the bladder. Despite the profound effect of IPSE on UTI-triggered bladder pathogenesis and anti-microbial peptide production, mice did not demonstrate systemic ill effects from IPSE exposure.Conclusions: Our data show that IPSE may play a major role in S. haematobium-associated urinary tract co-infection, albeit in an unexpected fashion. These findings also indicate that IPSE either works in concert with other IL-4-inducing factors to increase susceptibility of S. haematobium-infected hosts to bacterial co-infection, or does not contribute to enhancing vulnerability to this co-infection.

scholarly journals IPSE, a Urogenital Parasite-Derived Immunomodulatory Molecule, Suppresses Bladder Pathogenesis and Anti-Microbial Peptide Gene Expression in Bacterial Urinary Tract Infection

2020 ◽  
Author(s):  
Evaristus C. Mbanefo ◽  
Loc Le ◽  
Luke F. Pennington ◽  
Yi-Ju Hsieh ◽  
Justin I. Odegaard ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Interleukin 4 ◽  
Nuclear Localization Sequence ◽  
Parasitic Infections ◽  
Urogenital Schistosomiasis ◽  
Peptide Expression ◽  
Localization Sequence ◽  
Inducing Factors ◽  
Underlying Mechanisms ◽  
Peptide Gene

Abstract Background: Parasitic infections can increase susceptibility to bacterial co-infections. This may be true for urogenital schistosomiasis and bacterial urinary tract co-infections (UTI). We previously reported that this co-infection is facilitated by S. haematobium eggs triggering interleukin-4 (IL-4) production and sought to dissect the underlying mechanisms. The interleukin-4 inducing principle from Schistosoma mansoni eggs (IPSE) is one of the most abundant schistosome egg-secreted proteins and binds to IgE on the surface of basophils and mast cells to trigger IL-4 release. IPSE can also translocate into host nuclei using a nuclear localization sequence (NLS) to modulate host transcription. We hypothesized that IPSE is the factor responsible for the ability of S. haematobium eggs to worsen UTI pathogenesis. Methods: Mice were intravenously administered a single 25 mg dose of recombinant S. haematobium-derived IPSE, an NLS mutant of IPSE or PBS. Following IPSE exposure, mice were serially weighed, and organs analyzed by histology to assess for toxicity. Twenty-four hours after IPSE administration, mice were challenged with the uropathogenic E. coli strain UTI89 by urethral catheterization. Bacterial cfu were measured using urine. Bladders were examined histologically for UTI-triggered pathogenesis and by PCR for antimicrobial peptide expression.Results: Unexpectedly, IPSE administration did not result in significant differences in urine bacterial CFU. However, IPSE administration did lead to a significant reduction in UTI-induced bladder pathogenesis and the expression of anti-microbial peptides in the bladder. Despite the profound effect of IPSE on UTI-triggered bladder pathogenesis and anti-microbial peptide production, mice did not demonstrate systemic ill effects from IPSE exposure.Conclusions: Our data show that IPSE may play a major role in S. haematobium-associated urinary tract co-infection, albeit in an unexpected fashion. These findings also indicate that IPSE either works in concert with other IL-4-inducing factors to increase susceptibility of S. haematobium-infected hosts to bacterial co-infection, or does not contribute to enhancing vulnerability to this co-infection.

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