title: Perforin and granzymes have distinct roles in defensive immunity and immunopathology.
abstract: Successful control of viral infection requires the host to eliminate the infecting pathogen without causing overt immunopathology. Here we showed that perforin (Prf1) and granzymes (Gzms) have distinct roles in defensive immunity and immunopathology in a well-established model of viral infection. Both Prf1 and Gzms drastically affected the outcome of murine cytomegalovirus (MCMV) infection. Viral titres increased markedly in both Prf1(-/-) and Gzma(-/-)Gzmb(-/-) mice, but Gzma(-/-)Gzmb(-/-) mice recovered and survived infection, whereas Prf1(-/-) mice did not. Indeed, infected Prf1-deficient hosts developed a fatal hemophagocytic lymphohistiocytosis (HLH)-like syndrome. This distinction in outcome depended on accumulation of mononuclear cells and T cells in infected Prf1(-/-) mice. Importantly, blocking experiments that clearly identified tumor necrosis factor-alpha (TNF-alpha) as the principal contributor to the lethality observed in infected Prf1(-/-) mice provided support for the clinical potential of such an approach in HLH patients whose disease is triggered by viral infection.
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Western Australia, Australia.
authors.forename: Serani L H
authors.initials: SL
authors.lastname: van Dommelen
authors.forename: Nital
authors.initials: N
authors.lastname: Sumaria
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Scalzo
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
mesh_terms: D000818:Animals; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology*; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D053804:Granzymes / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes