Schistosoma mansoni Larval Extracellular Vesicle protein 1 (SmLEV1) is an immunogenic antigen found in EVs released from pre-acetabular glands of invading cercariae

Author summaryFrom the moment they start to penetrate the human skin, juvenile schistosomes secrete bioactive molecules to facilitate invasion, evade the host immune response, and establish a long-lived infection. One component of these secretions are pre-packaged, membrane-bound extracellular vesicles (EVs) capable of modulating the host immune response. Whilst EVs contain a subset of known biologically relevant molecules, many EV proteins remain uncharacterised. Here we investigate the most abundant protein found within EVs released by early skin-stage schistosomes-SmLEV1. We show that the lev1 gene is only found in the schistosomes and closely related species and is most abundantly expressed during the early stages of human infection. Localising the SmLEV1 protein to the pre-acetabular glands of the cercarial head, highlights this gland as a source of larval EVs. Vaccination with SmLEV1 had minimal effects on parasite burden, but significantly reduced the liver granuloma volume, implicating SmLEV1 as a potential anti-pathology target for schistosomiasis. Our collective findings are the first characterisation of SmLEV1 and provide essential data and resources for the ongoing study of schistosome EVs. Extracellular Vesicles (EVs) are an integral component of cellular/organismal communication and have been found in the excreted/secreted (ES) products of both protozoan and metazoan parasites. Within the blood fluke schistosomes, EVs have been isolated from egg, schistosomula, and adult lifecycle stages. However, the role(s) that EVs have in shaping aspects of parasite biology and/or manipulating host interactions is poorly defined. Herein, we characterise the most abundant EV-enriched protein in Schistosoma mansoni tissue-migrating schistosomula (Schistosoma mansoni Larval Extracellular Vesicle protein 1 (SmLEV1)). Comparative sequence analysis demonstrates that lev1 orthologs are found in all published Schistosoma genomes, yet homologs are not found outside of the Schistosomatidae. Lifecycle expression analyses collectively reveal that smlev1 transcription peaks in cercariae, is male biased in adults, and is processed by alternative splicing in intra-mammalian lifecycle stages. Immunohistochemistry of cercariae using a polyclonal anti-recombinant SmLEV1 antiserum localises this protein to the pre-acetabular gland, with some disperse localisation to the surface of the parasite. S. mansoni-infected Ugandan fishermen exhibit a strong IgG(1) response against SmLEV1 (dropping significantly after praziquantel treatment), with 11% of the cohort exhibiting an IgE response and minimal levels of detectable antigen-specific IgG(4). Furthermore, mice vaccinated with rSmLEV1 show a slightly reduced parasite burden upon challenge infection and significantly reduced granuloma volumes, compared with control animals. Collectively, these results describe SmLEV1 as a Schistosomatidae-specific, EV-enriched immunogen. Further investigations are now necessary to uncover the full extent of SmLEV1's role in shaping schistosome EV function and definitive host relationships.

Automated summary

The study identified a protein, SmLEV1, abundantly present in extracellular vesicles (EVs) released by early skin-stage schistosomes. SmLEV1 was found to be localized to the pre-acetabular glands of the cercarial head and showed potential anti-pathology effects in reducing liver granuloma volume. Vaccination with SmLEV1 resulted in slightly reduced parasite burden and significantly decreased granuloma volumes, suggesting SmLEV1 as a Schistosomatidae-specific, EV-enriched immunogen with implications for schistosome EV function and host relationships.