title: Granzymes are the essential downstream effector molecules for the control of primary virus infections by cytolytic leukocytes.
abstract: Analysis of perforin-deficient mice has identified the cytolytic pathway and perforin as the preeminent effector molecule in T cell-mediated control of virus infections. In this paper, we show that mice lacking both granzyme A (gzmA) and granzyme B (gzmB), which are, beside perforin, key constituents of cytolytic vesicles, are as incapable as are perforin-deficient mice of controlling primary infections by the natural mouse pathogen ectromelia, a poxvirus. Death of gzmAxgzmB double knockout mice occurred in a dose-dependent manner, despite the expression of functionally active perforin and the absence of an intrinsic defect to generate splenic cytolytic T cells. These results establish that both gzmA and gzmB are indispensable effector molecules acting in concert with perforin in granule exocytosis-mediated host defense against natural viral pathogens.
authors.affiliation: Division of Immunology, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia. arno.mullbacher@anu.edu.au
authors.forename: A
authors.initials: A
authors.lastname: Müllbacher
authors.forename: P
authors.initials: P
authors.lastname: Waring
authors.forename: R
authors.initials: R
authors.lastname: Tha Hla
authors.forename: T
authors.initials: T
authors.lastname: Tran
authors.forename: S
authors.initials: S
authors.lastname: Chin
authors.forename: T
authors.initials: T
authors.lastname: Stehle
authors.forename: C
authors.initials: C
authors.lastname: Museteanu
authors.forename: M M
authors.initials: MM
authors.lastname: Simon
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002859:Chromium Isotopes; D003602:Cytotoxicity, Immunologic; D004481:Ectromelia virus / Q000276:immunology*; D004482:Ectromelia, Infectious / Q000276:immunology*; D005260:Female; D053804:Granzymes; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000276:immunology; D008099:Liver / Q000473:pathology / Q000821:virology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000473:pathology / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*
chemical_list: D002859:Chromium Isotopes; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; C509212:GZMA protein, human