title: Genetic and pharmacologic alteration of cathepsin expression influences reovirus pathogenesis.
abstract: 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), Ctsb(-/-), Ctsl(-/-), and Ctss(-/-) mice with the virulent reovirus strain T3SA+. The survival rate of Ctsb(-/-) mice was enhanced in comparison to that of wt mice, whereas the survival rates of Ctsl(-/-) and Ctss(-/-) 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 Ctsl(-/-) and Ctss(-/-) mice in comparison to the levels for wt and Ctsb(-/-) 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.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Johnson
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Doyle
authors.forename: J Denise
authors.initials: JD
authors.lastname: Wetzel
authors.forename: R Paul
authors.initials: RP
authors.lastname: McClung
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Katunuma
authors.forename: James D
authors.initials: JD
authors.lastname: Chappell
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Terence S
authors.initials: TS
authors.lastname: Dermody
mesh_terms: D000818:Animals; D001921:Brain / Q000821:virology; D002401:Cathepsin B / Q000235:genetics* / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D012087:Reoviridae / Q000378:metabolism*; D012088:Reoviridae Infections / Q000235:genetics*; D013997:Time Factors
chemical_list: D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C028217:cathepsin S