Chalmers, I. W. | Search bioRxiv

bioRxiv2022

Protective human IgE responses are promoted by comparable life-cycle dependent Tegument Allergen-Like protein expression in Schistosoma haematobium and Schistosoma mansoni infection

Schistosoma haematobium is the most prevalent of the human-infecting schistosome species, causing significant morbidity in endemically exposed populations. Despite this, it has been relatively understudied compared to its fellow species, S. mansoni. Here we provide the first comprehensive characterization of the S. haematobium Tegument Allergen-Like protein family, a key protein family directly linked to protective immunity in S. mansoni infection. Comparable with observations for S. mansoni, parasite phylogenetic analysis and relative gene expression combined with host serological analysis support a cross-reactive relationship between S. haematobium TAL proteins, exposed to the host immune system as adult worms die, and closely related proteins, exposed during penetration by the infecting cercarial and early schistosomulae stages. Specifically, our results strengthen the evidence for host immunity driven by cross-reactivity between family members TAL3 and TAL5, establishing it for the first time for S. haematobium infection. Furthermore, we build upon this relationship to include the involvement of an additional member of the TAL protein family, TAL11 for both schistosome species. Finally, we show a close association between experience of infection and intensity of transmission and the development of protective IgE responses to these antigens, thus improving our knowledge of the mechanisms by which protective host immune responses develop. This knowledge will be critical in understanding how control efforts such as mass drug administration campaigns influence the development of host immunity and subsequent patterns of infection and disease within endemic populations. Author SummaryS. haematobium is the most prevalent of the human infecting schistosomes. Along with S. mansoni, it is responsible for the majority of schistosomiasis cases that are borne by the populations of sub-Saharan Africa, where the global burden of this infection is centered. Here, we provide insight into the IgE antibody response that protects against these infections. Through utilization of in silico analysis and transcriptional studies of parasite life stages, in combination with immuno-epidemiological studies, we explore the relationship between host immune protection and a parasite protein family named the Tegument Allergen-Like (TAL) proteins. Our results show that several members of the TAL protein family are important in host protection to both these major schistosome species. For the first time we demonstrate that a progressive cross-reactive TAL-IgE response occurs against S. haematobium, similar to that previous observed in S. mansoni infection. We additionally expand upon previous knowledge for S. mansoni, identifying further complexity in the cross-reactive relationship between TAL family members, providing evidence of a key role for family member TAL11 in induction of the protective host immune response.

immunology↗

bioRxiv2020

Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) is a druggable target involved in parasite survival, oviposition and stem cell proliferation.

Schistosomiasis is a chronically-debilitating neglected tropical disease (NTD) that predominantly affects people living in resource-poor communities of tropical and subtropical countries. Schistosoma mansoni, one of three species responsible for most human infections, undergoes strict developmental regulation of gene expression that is carefully controlled by both genetic- and epigenetic- processes. As inhibition of S. mansoni epigenetic machinery components has been shown to impair key transitions throughout the parasites digenetic lifecycle, this knowledge is currently fuelling the search for new epi-drug - based anthelmintics. In this study, the anti-schistosomal activity of 39 re-purposed Homo sapiens Lysine Specific Demethylase 1 (HsLSD1) inhibitors was investigated on key life cycle stages associated with both definitive (schistosomula, juvenile worms, sexually-mature adults) and intermediate host (miracidia) infection. The most active compound (compound 33; e.g. schistosomula phenotype EC50 = 4.370 {micro}M; adult worm motility EC50 = 2.137 {micro}M) was subsequently used to provide further insight into the critical role of S. mansoni lysine specific demethylase 1 (SmLSD1) in adult worm oviposition and stem cell proliferation. Here, compound 33 treatment of adult schistosomes led to significant defects in egg production, intra-egg vitellocyte/ovum packaging and gonadal/neoblast stem cell proliferation. A greater abundance of H3K4me2 marks accompanied these phenotypes and supported specific inhibition of SmLSD1 in adult schistosomes by compound 33. In silico screening indicated that compound 33 likely inhibits SmLSD1 activity by covalently reacting with the FAD cofactor. This work suggests that evaluation of HsLSD1 - targeting epi-drugs could have utility in the search for next-generation anti-schistosomals. The ability of compound 33 to inhibit parasite survival, oviposition, H3K4me2 demethylation and stem cell proliferation warrants further investigations of this compound and its epigenetic target. This data further highlights the importance of histone methylation in S. mansoni lifecycle transitions. Author summaryAffecting over 200 million people, schistosomiasis is a chronic disease caused by the parasitic worm Schistosoma mansoni. The frontline drug for schistosomiasis treatment is praziquantel. Owing to the concern surrounding praziquantel insensitivity or resistance developing, current research is directed towards the identification of novel drugs. We have focused our search for compounds that affect essential aspects of schistosome biology including parasite movement, fertility, cell proliferation and survival. Since all of these functions are potentially influenced by epigenetic regulation of gene expression, we investigated the activity of compounds that alter histone methylation status. In this report, we show that S. mansoni Lysine Specific Demethylase 1 (SmLSD1), a histone demethylase, is critical to miracidia-to-sporocyst transitioning, adult worm motility, egg production and parasite survival. Inhibition of SmLSD1 with compounds developed to inhibit the human paralog show promising potential as novel anti-schistosomal agents.

microbiology↗