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A secreted schistosome cathepsin B1 cysteine protease and acute schistosome infection induce a transient T helper 17 response.

ABSTRACT: The natural history of schistosome infection in the mammalian host is determined by CD4+ T helper responses mounted against different parasite life cycle stages. A T helper 2 (TH2) response to schistosome eggs is required for host survival and establishment of chronic infection. However, a TH2 cell-derived cytokine also contributes to an immune milieu that is conducive to schistosome growth and development. Thus, the same responses that allow for host survival have been co-opted by schistosomes to facilitate parasite development and transmission, underscoring the significance of CD4+ T cell responses to both worms and eggs in the natural history of schistosome infection. Here we show that a cathepsin B1 cysteine protease secreted by schistosome worms not only induces TH2 responses, but also TH1 and TH17 responses, by a mechanism that is dependent on the proteolytic activity of the enzyme. Further investigation revealed that, in addition to the expected TH1 and TH2 responses, acute schistosome infection also induces a transient TH17 response that is rapidly down-regulated at the onset of oviposition. TH17 responses are implicated in the development of severe egg-induced pathology. The regulation of worm-induced TH17 responses during acute infection could therefore influence the expression of high and low pathology states as infection progresses.

SUBMITTER: Soloviova K

PROVIDER: S-EPMC6353221 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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A secreted schistosome cathepsin B1 cysteine protease and acute schistosome infection induce a transient T helper 17 response.

Soloviova Kateryna K Fox Ellen C EC Dalton John P JP Caffrey Conor R CR Davies Stephen J SJ

PLoS neglected tropical diseases 20190117 1

The natural history of schistosome infection in the mammalian host is determined by CD4+ T helper responses mounted against different parasite life cycle stages. A T helper 2 (TH2) response to schistosome eggs is required for host survival and establishment of chronic infection. However, a TH2 cell-derived cytokine also contributes to an immune milieu that is conducive to schistosome growth and development. Thus, the same responses that allow for host survival have been co-opted by schistosomes ...[more]

PMID: 30653492

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Project description:The liver fluke Opisthorchis viverrini is classified as a class I carcinogen due to the association between cholangiocarcinoma and chronic O. viverrini infection. During its feeding activity within the bile duct, the parasite secretes several cathepsin F cysteine proteases that may induce or contribute to the pathologies associated with hepatobiliary abnormalities.Here, we describe the cDNA, gene organization, phylogenetic relationships, immunolocalization, and functional characterization of the cathepsin F cysteine protease gene, here termed Ov-cf-1, from O. viverrini. The full length mRNA of 1020 nucleotides (nt) encoded a 326 amino acid zymogen consisting of a predicted signal peptide (18 amino acids, aa), prosegment (95 aa), and mature protease (213 aa). BLAST analysis using the Ov-CF-1 protein as the query revealed that the protease shared identity with cathepsin F-like cysteine proteases of other trematodes, including Clonorchis sinensis (81%), Paragonimus westermani (58%), Schistosoma mansoni and S. japonicum (52%), and with vertebrate cathepsin F (51%). Transcripts encoding the protease were detected in all developmental stages that parasitize the mammalian host. The Ov-cf-1 gene, of approximately 3 kb in length, included seven exons interrupted by six introns; the exons ranged from 69 to 267 bp in length, the introns from 43 to 1,060 bp. The six intron/exon boundaries of Ov-cf-1 were conserved with intron/exon boundaries in the human cathepsin F gene, although the gene structure of human cathepsin F is more complex. Unlike Ov-CF-1, human cathepsin F zymogen includes a cystatin domain in the prosegment region. Phylogenetic analysis revealed that the fluke, human, and other cathepsin Fs branched together in a clade discrete from the cathepsin L cysteine proteases. A recombinant Ov-CF-1 zymogen that displayed low-level activity was expressed in the yeast Pichia pastoris. Although the recombinant protease did not autocatalytically process and activate to a mature enzyme, trans-processing by Fasciola hepatica cathepsin L cleaved the prosegment of Ov-CF-1, releasing a mature cathepsin F with activity against the peptide Z-Phe-Arg-NHMec >50 times that of the zymogen. Immunocytochemistry using antibodies raised against the recombinant enzyme showed that Ov-CF-1 is expressed in the gut of the mature hermaphroditic fluke and also in the reproductive structures, including vitelline glands, egg, and testis. Ov-CF-1 was detected in bile duct epithelial cells surrounding the flukes several weeks after infection of hamsters with O. viverrini and, in addition, had accumulated in the secondary (small) bile ducts where flukes cannot reach due to their large size.A cathepsin F cysteine protease of the human liver fluke O. viverrini has been characterized at the gene and protein level. Secretion of this protease may contribute to the hepatobiliary abnormalities, including cholangiocarcinogenesis, observed in individuals infected with this parasite.

Dataset Information

A secreted schistosome cathepsin B1 cysteine protease and acute schistosome infection induce a transient T helper 17 response.

Publications

A secreted schistosome cathepsin B1 cysteine protease and acute schistosome infection induce a transient T helper 17 response.

Similar Datasets

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