Perforin and Granzymes Have Distinct Roles in Defensive Immunity and Immunopathology

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. Bo...

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Bibliographic Details
Published in:	Immunity (Cambridge, Mass.) Vol. 25; no. 5; pp. 835 - 848
Main Authors:	van Dommelen, Serani L.H., Sumaria, Nital, Schreiber, Robert D., Scalzo, Anthony A., Smyth, Mark J., Degli-Esposti, Mariapia A.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-11-2006 Elsevier Limited
Subjects:	Animals Apoptosis CELLIMMUNO Cytomegalovirus - immunology Cytomegalovirus Infections - immunology Cytomegalovirus Infections - pathology Cytotoxicity, Immunologic Enzyme-Linked Immunosorbent Assay Granzymes - immunology Immune system Infections Interferon-gamma - immunology Interferon-gamma - metabolism Killer Cells, Natural - immunology Medical research Membrane Glycoproteins - immunology Mice MICROBIO Murine cytomegalovirus Perforin Pore Forming Cytotoxic Proteins - immunology Tumor Necrosis Factor-alpha - immunology Tumor Necrosis Factor-alpha - metabolism Viral infections MICROBIO CELLIMMUNO
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Summary:	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-α (TNF-α) 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1074-7613 1097-4180
DOI:	10.1016/j.immuni.2006.09.010