Primary structure of the major pepsin inhibitor from the intestinal parasitic nematode Ascaris suum

Martzen, Mark R.; McMullen, Brad A.; Smith, Nancy E.; Fujikawa, Kazuo; Peanasky, Robert J.

doi:10.1021/bi00484a003

Cited by 45 publications

(31 citation statements)

References 30 publications

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“…An additional orthologue from A. suum was identified by a BLASTp search. The amino acid sequence of this aspartyl protease inhibitor (GenBank P19400 [26]) showed 19% identity to P. tenuis. This ORF was different from both of the A. suum ORFs deduced from ESTs.…”

Section: Resultsmentioning

confidence: 99%

An Aspartyl Protease Inhibitor Orthologue Expressed byParelaphostrongylus tenuisIs Immunogenic in an Atypical Host

Duffy

MacAfee

Burt

et al. 2002

Clin Vaccine Immunol

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Parelaphostrongylus tenuis is a neurotropic nematode common in white-tailed deer (Odocoileus virginianus) of eastern North America. This parasite is the causative agent of a debilitating neurologic disease in atypical hosts, including domestic livestock. In order to identify proteins of potential significance in the host-parasite relationship, a cDNA library was produced from adult P. tenuis mRNA. Screening the library with antisera from infected red deer (Cervus elaphus elaphus) and immunized AO strain rats, we identified clones with sequence similarities to aspartyl protease inhibitors from several parasitic nematodes. Antibody that was generated against this recombinant protein of P. tenuis (Pt-API-1) detected the native protein in E/S products, in muscle and gonad, and on the surface of the cuticle of adult male and female P. tenuis. The native protein was detected in internal structures of first-stage (L1) and third-stage (L3) larvae. Reverse transcription-PCR confirmed expression of Pt-api-1 in L1, L3, and adult male and female worms. Expression of Pt-API-1 throughout the life cycle of P. tenuis suggests an essential function. Antibodies specific for recombinant Pt-API-1 were detected by enzyme-linked immunosorbent assay in sera from 12 red deer experimentally infected with P. tenuis. Antibodies were detected within 28 to 56 days postinfection. Responses were sustained or biphasic in animals with patent infections, consistent with expression of Pt-API-1 by L1. Our results are compatible with findings in other parasitic nematodes showing that aspartyl protease inhibitors are highly immunogenic.

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Section: Resultsmentioning

confidence: 99%

An Aspartyl Protease Inhibitor Orthologue Expressed byParelaphostrongylus tenuisIs Immunogenic in an Atypical Host

Duffy

MacAfee

Burt

et al. 2002

Clin Vaccine Immunol

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“…(77). Ov-spi-1 and Ov-api-1 genes code for part of a family of proteinase inhibitors originally characterized from Ascaris and which has not been seen outside of the phylum Nematoda (3,51). These inhibitors could support the identification of synthetic molecules to specifically inhibit the endogenous or exogenous corresponding enzymes, and thus interfere with the function of these molecules during development in the host.…”

Section: Resultsmentioning

confidence: 99%

Identification of Potential Vaccine and Drug Target Candidates by Expressed Sequence Tag Analysis and Immunoscreening ofOnchocerca volvulusLarval cDNA Libraries

et al. 2000

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The search for appropriate vaccine candidates and drug targets against onchocerciasis has so far been confronted with several limitations due to the unavailability of biological material, appropriate molecular resources, and knowledge of the parasite biology. To identify targets for vaccine or chemotherapy development we have undertaken two approaches. First, cDNA expression libraries were constructed from life cycle stages that are critical for establishment of Onchocerca volvulus infection, the third-stage larvae (L3) and the molting L3. A gene discovery effort was then initiated by random expressed sequence tag analysis of 5,506 cDNA clones. Cluster analyses showed that many of the transcripts were up-regulated and/or stage specific in either one or both of the cDNA libraries when compared to the microfilariae, L2, and both adult stages of the parasite. Homology searches against the GenBank database facilitated the identification of several genes of interest, such as proteinases, proteinase inhibitors, antioxidant or detoxification enzymes, and neurotransmitter receptors, as well as structural and housekeeping genes. Other O. volvulus genes showed homology only to predicted genes from the free-living nematode Caenorhabditis elegans or were entirely novel. Some of the novel proteins contain potential secretory leaders. Secondly, by immunoscreening the molting L3 cDNA library with a pool of human sera from putatively immune individuals, we identified six novel immunogenic proteins that otherwise would not have been identified as potential vaccinogens using the gene discovery effort. This study lays a solid foundation for a better understanding of the biology of O. volvulus as well as for the identification of novel targets for filaricidal agents and/or vaccines against onchocerciasis based on immunological and rational hypothesis-driven research.

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“…The question of selectivity has previously been approached using a peptide inhibitor derived from the round worm Ascaris (27), which was reported to have little or no activity against cathepsin D compared with cathepsin E. However, studies with the naturally occurring inhibitor have been limited by difficulties of purification, and recent analysis has suggested that the recombinant inhibitor may have a slightly different inhibitory profile (28). Follow-up of the initial studies of cathepsin E's role in Ag processing has therefore been limited (29).…”

Section: Discussionmentioning

confidence: 99%

The Expression and Function of Cathepsin E in Dendritic Cells

Chain¹,

Free

Medd³

et al. 2005

The Journal of Immunology

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Cathepsin E is an aspartic proteinase that has been implicated in Ag processing within the class II MHC pathway. In this study, we document the presence of cathepsin E message and protein in human myeloid dendritic cells, the preeminent APCs of the immune system. Cathepsin E is found in a perinuclear compartment, which is likely to form part of the endoplasmic reticulum, and also a peripheral compartment just beneath the cell membrane, with a similar distribution to that of Texas Red-dextran within 2 min of endocytosis. To investigate the function of cathepsin E in processing, a new soluble targeted inhibitor was synthesized by linking the microbial aspartic proteinase inhibitor pepstatin to mannosylated BSA via a cleavable disulfide linker. This inhibitor was shown to block cathepsin D/E activity in cell-free assays and within dendritic cells. The inhibitor blocked the ability of dendritic cells from wild-type as well as cathepsin D-deficient mice to present intact OVA, but not an OVA-derived peptide, to cognate T cells. The data therefore support the hypothesis that cathepsin E has an important nonredundant role in the class II MHC Ag processing pathway within dendritic cells.

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Primary structure of the major pepsin inhibitor from the intestinal parasitic nematode Ascaris suum

Cited by 45 publications

References 30 publications

An Aspartyl Protease Inhibitor Orthologue Expressed byParelaphostrongylus tenuisIs Immunogenic in an Atypical Host

An Aspartyl Protease Inhibitor Orthologue Expressed byParelaphostrongylus tenuisIs Immunogenic in an Atypical Host

Identification of Potential Vaccine and Drug Target Candidates by Expressed Sequence Tag Analysis and Immunoscreening ofOnchocerca volvulusLarval cDNA Libraries

The Expression and Function of Cathepsin E in Dendritic Cells

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