{"doi":"10.1128/jvi.01095-09","title":"Genetic and Pharmacologic Alteration of Cathepsin Expression Influences Reovirus Pathogenesis","abstract":"<jats:title>ABSTRACT</jats:title><jats:p>The cathepsin family of endosomal proteases is required for proteolytic processing of several viruses during entry into host cells. Mammalian reoviruses utilize cathepsins B (Ctsb), L (Ctsl), and S (Ctss) for disassembly of the virus outer capsid and activation of the membrane penetration machinery. To determine whether cathepsins contribute to reovirus tropism, spread, and disease outcome, we infected 3-day-old wild-type (wt),<jats:italic>Ctsb</jats:italic><jats:sup>−/−</jats:sup>,<jats:italic>Ctsl</jats:italic><jats:sup>−/−</jats:sup>, and<jats:italic>Ctss</jats:italic><jats:sup>−/−</jats:sup>mice with the virulent reovirus strain T3SA+. The survival rate of<jats:italic>Ctsb</jats:italic><jats:sup>−/−</jats:sup>mice was enhanced in comparison to that of wt mice, whereas the survival rates of<jats:italic>Ctsl</jats:italic><jats:sup>−/−</jats:sup>and<jats:italic>Ctss</jats:italic><jats:sup>−/−</jats:sup>mice were diminished. Peak titers at sites of secondary replication in all strains of cathepsin-deficient mice were lower than those in wt mice. Clearance of the virus was delayed in<jats:italic>Ctsl</jats:italic><jats:sup>−/−</jats:sup>and<jats:italic>Ctss</jats:italic><jats:sup>−/−</jats:sup>mice in comparison to the levels for wt and<jats:italic>Ctsb</jats:italic><jats:sup>−/−</jats:sup>mice, consistent with a defect in cell-mediated immunity in mice lacking cathepsin L or S. Cathepsin expression was dispensable for establishment of viremia, but cathepsin L was required for maximal reovirus growth in the brain. Treatment of wt mice with an inhibitor of cathepsin L led to amelioration of reovirus infection. Collectively, these data indicate that cathepsins B, L, and S influence reovirus pathogenesis and suggest that pharmacologic modulation of cathepsin activity diminishes reovirus disease severity.</jats:p>","journal":"Journal of Virology","year":2009,"id":599157,"datarank":0.519860385419959,"base_score":3.4657359027997265,"endowment":3.4657359027997265,"self_citation_contribution":0.519860385419959,"citation_network_contribution":0.0,"self_endowment_contribution":0.519860385419959,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":31,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1535586,"name":"Joshua D. 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Johnson","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Genetic and Pharmacologic Alteration of Cathepsin Expression Influences Reovirus Pathogenesis","abstract":"<jats:title>ABSTRACT</jats:title><jats:p>The cathepsin family of endosomal proteases is required for proteolytic processing of several viruses during entry into host cells. Mammalian reoviruses utilize cathepsins B (Ctsb), L (Ctsl), and S (Ctss) for disassembly of the virus outer capsid and activation of the membrane penetration machinery. To determine whether cathepsins contribute to reovirus tropism, spread, and disease outcome, we infected 3-day-old wild-type (wt),<jats:italic>Ctsb</jats:italic><jats:sup>−/−</jats:sup>,<jats:italic>Ctsl</jats:italic><jats:sup>−/−</jats:sup>, and<jats:italic>Ctss</jats:italic><jats:sup>−/−</jats:sup>mice with the virulent reovirus strain T3SA+. The survival rate of<jats:italic>Ctsb</jats:italic><jats:sup>−/−</jats:sup>mice was enhanced in comparison to that of wt mice, whereas the survival rates of<jats:italic>Ctsl</jats:italic><jats:sup>−/−</jats:sup>and<jats:italic>Ctss</jats:italic><jats:sup>−/−</jats:sup>mice were diminished. Peak titers at sites of secondary replication in all strains of cathepsin-deficient mice were lower than those in wt mice. Clearance of the virus was delayed in<jats:italic>Ctsl</jats:italic><jats:sup>−/−</jats:sup>and<jats:italic>Ctss</jats:italic><jats:sup>−/−</jats:sup>mice in comparison to the levels for wt and<jats:italic>Ctsb</jats:italic><jats:sup>−/−</jats:sup>mice, consistent with a defect in cell-mediated immunity in mice lacking cathepsin L or S. Cathepsin expression was dispensable for establishment of viremia, but cathepsin L was required for maximal reovirus growth in the brain. Treatment of wt mice with an inhibitor of cathepsin L led to amelioration of reovirus infection. Collectively, these data indicate that cathepsins B, L, and S influence reovirus pathogenesis and suggest that pharmacologic modulation of cathepsin activity diminishes reovirus disease severity.</jats:p>","is_dataset_classified":null,"base_score":3.4657359027997265,"endowment":3.4657359027997265,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19640986","pmcid":"PMC2748054","openalex_id":"https://openalex.org/W2113007991","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"P30 CA68485","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI32539","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA068485","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"P60 DK020593","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"T32 AI007611","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"P60 DK20593","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM008554","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"T32 AI07611","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM08554","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI032539","title":null}],"total_grants":10,"fwci":1.4819,"citation_percentile":0.80902365,"influential_citations":0,"citation_trend":[{"year":2012,"count":6},{"year":2013,"count":4},{"year":2014,"count":2},{"year":2015,"count":1},{"year":2016,"count":1},{"year":2017,"count":1},{"year":2018,"count":1},{"year":2019,"count":2},{"year":2020,"count":2},{"year":2021,"count":2},{"year":2022,"count":2},{"year":2023,"count":2},{"year":2025,"count":2}],"oa_status":"green","license":"https://journals.asm.org/non-commercial-tdm-license","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2748054","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2748054","host_type":"repository"},{"url":"https://journals.asm.org/doi/pdf/10.1128/JVI.01095-09","host_type":"publisher"},{"url":"https://doi.org/10.1128/jvi.01095-09","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/19640986","host_type":"repository"}],"fields_of_study":["Viral gastroenteritis research and epidemiology","Virus-based gene therapy research","interferon and immune responses","Animals","Brain","Cathepsin B","Cathepsin L","Cathepsins","Cell Line","Cysteine Endopeptidases","Gene Expression Regulation","Inflammation","Mice","Mice, Inbred C57BL","Mice, Transgenic","Models, Biological","Reoviridae","Reoviridae Infections","Time Factors"],"mesh_terms":["Animals","Brain","Cathepsin B","Cathepsins","Cell Line","Cysteine Endopeptidases","Gene Expression Regulation","Inflammation","Mice, Inbred C57BL","Mice, Transgenic","Models, Biological","Reoviridae","Reoviridae Infections","Time Factors","Mice","Cathepsin L"],"keywords":["Cathepsin L","Biology","Cathepsin","Cathepsin B","Cathepsin L1","Virology","Cathepsin S","Proteases","Cathepsin D","Virus","Pathogenesis","Molecular biology","Immunology","Enzyme"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-28T19:06:53.296853Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}