title: Multiplicity-dependent activation of a serine protease-dependent cytomegalovirus-associated programmed cell death pathway.
abstract: At a low MOI (≤0.01), cytomegalovirus-associated programmed cell death terminates productive infection via a pathway triggered by the mitochondrial serine protease HtrA2/Omi. This infected cell death is associated with late phase replication events naturally suppressed by the viral mitochondrial inhibitor of apoptosis (vMIA). Here, higher MOI (ranging from 0.1-3.0) triggers cell death earlier during infection independent of viral DNA synthesis. Thus, MOI-dependent activating signals early, at high MOI, or late, at low MOI, during replication promote serine protease-dependent death that is suppressed by vMIA. Treatment with an antioxidant targeting reactive oxygen species (ROS) or the serine protease inhibitor N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) delays cell death, and the combination has an additive impact. These studies identify serine proteases and ROS as important factors triggering programmed cell death induced by vMIA-deficient virus, and show that this death pathway occurs earlier and reduces viral yields as the MOI is increased.
authors.affiliation: Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, 1462 Clifton Rd NE, Atlanta, GA 30322, USA. alouisemccormick@gmail.com
authors.forename: A Louise
authors.initials: AL
authors.lastname: McCormick
authors.forename: Linda
authors.initials: L
authors.lastname: Roback
authors.forename: Grace
authors.initials: G
authors.lastname: Wynn
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
mesh_terms: D017209:Apoptosis; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000472:pathogenicity* / Q000502:physiology; D003588:Cytopathogenic Effect, Viral; D005347:Fibroblasts / Q000821:virology*; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
chemical_list: D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D015842:Serine Proteinase Inhibitors; D014764:Viral Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2