Lamanna, O. K. | Search bioRxiv

bioRxiv2024

RNA-seq gene expression profiling of the bladder in a mouse model of urogenital schistosomiasis

Background: Parasitic flatworms of the Schistosoma genus cause schistosomiasis, which affects over 230 million people. Schistosoma haematobium causes the urogenital form of schistosomiasis (UGS), which can lead to hematuria, fibrosis, and increased risk of secondary infections by bacteria or viruses. UGS is also linked to bladder cancer. To understand the bladder pathology during S. haematobium infection, our group previously developed a mouse model that involves the injection of S. haematobium eggs into the bladder wall. Using this model, we studied changes in epigenetics profile, as well as changes in gene and protein expression in the host bladder tissues. In the current study, we expand upon this work by examining the expression level of both host and parasite genes using RNA sequencing (RNA-seq) in the mouse bladder wall injection model of S. haematobium infection. Methods: We used a mouse model of S. haematobium infection in which parasite eggs or vehicle control were injected into the bladder walls of female BALB/c mice. RNA-seq was performed on the RNA isolated from the bladders four days after bladder wall injection. Results/Conclusions: RNA-seq analysis of egg- and vehicle control-injected bladders revealed the differential expression of 1025 mouse genes in the egg-injected bladders, including genes associated with cellular infiltration, immune cell chemotaxis, cytokine signaling, and inflammation We also observed the upregulation of immune checkpoint-related genes, which suggests that while the infection causes an inflammatory response, it also dampens the response to avoid excessive inflammation-related damage to the host. Identifying these changes in host signaling and immune responses improves our understanding of the infection and how it may contribute to the development of bladder cancer. Analysis of the differential gene expression of the parasite eggs between bladder-injected versus uninjected eggs revealed 119 S. haematobium genes associated with transcription, intracellular signaling, and metabolism. The analysis of the parasite genes also revealed fewer transcript reads compared to that found in the analysis of mouse genes, highlighting the challenges of studying parasite egg biology in the mouse model of S. haematobium infection. Author summaryMore than 230 million people worldwide are estimated to carry infection with parasites belonging to the Schistosoma genus, which cause morbidity associated with parasite egg deposition. Praziquantel, the drug of choice to treat the infection, does not prevent reinfection, and its decades-long history as the main treatment raises concerns for drug resistance. Of the schistosome species, Schistosoma haematobium causes urogenital disease and has a strong association with bladder cancer. The possibility for drug resistance and the gap in knowledge with respect to the mechanisms driving S. haematobium-related bladder cancer highlight the need to better understand the biology of the infection to aid in the development of new therapeutic strategies. In this study, we used a mouse model of S. haematobium infection that delivers parasite eggs directly to the host mouse bladder wall, and we examined the changes in the gene expression profile of the host and the parasite by RNA-sequencing. The results corroborated previous findings with respect to the hosts inflammatory responses against the parasite eggs, as well as revealed alterations in other immune response genes that deepen our understanding of the mechanisms involved in urogenital schistosomiasis pathogenesis.

molecular biology↗

bioRxiv2021

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

BackgroundUrogenital schistosomiasis remains a major public health concern worldwide. In response to egg deposition, the host bladder undergoes gross and molecular morphological changes relevant for disease manifestation. However, limited mechanistic studies to date imply that the molecular mechanisms underlying pathology have not been well-defined. We leveraged a mouse model of urogenital schistosomiasis to perform for the first time, proteome profiling of the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to elucidate the protein pathways involved in urogenital schistosomiasis-induced pathology. MethodsPurified S. haematobium eggs or control vehicle were microinjected into the bladder walls of mice. Mice were sacrificed seven days post-injection and bladder proteins isolated and processed for proteome profiling using mass spectrometry. ResultsWe demonstrate that biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism were significantly enriched in S. haematobium infection. ConclusionS. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Our findings highlight the potential bladder protein indicators for host-parasite interplay and provide new insights into the complex dynamics of pathology and characteristic bladder tissue changes in urogenital schistosomiasis. The findings will be relevant for development of improved interventions for disease control. Author summaryThe molecular mechanisms underlying the urinary and genital pathology from urogenital schistosomiasis have not been well-defined. This has mainly been due to limited mechanistic studies and the lack of a suitable animal model for S. haematobium infection. We leveraged a mouse model of urogenital schistosomiasis, along with proteomics analysis, to determine the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to define protein pathways that may be involved in morbidity from urogenital schistosomiasis infection. Our results show that S. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism are significantly enriched in S. haematobium infection. Our findings highlight important protein indicators of host-parasite interactions in the bladder and their association with tissue changes in urogenital schistosomiasis. The findings presented here will be relevant for development of improved interventions for disease control, and contribute to realizing the 2021-2030 NTD goals by demonstrating evidence on the early events that occur during schistosome infection.

molecular biology↗