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Title

Caspase-dependent Inhibition of mousepox replicationby gzmB

AuthorsPardo, Julián; Gálvez Buerba, Eva Mª ; Koskinen, Aulikki; Simon, Markus M.; Lobigs, Mario; Regner, Matthias; Mullbacher, Arno
KeywordsLymphocyte-mediated apoptosis
Perforin-deficient mice
Granzyme-b
Cell-death
Ectromelia virus
Cytolytic leukocytes
Cytokine response
Viral protein
Target-cells
Issue Date19-Oct-2009
PublisherPublic Library of Science
CitationPLoS ONE 4(10): e7512 (2009)
Abstract[Background] Ectromelia virus is a natural mouse pathogen, causing mousepox. The cytotoxic T (Tc) cell granule serine-protease, granzyme B, is important for its control, but the underlying mechanism is unknown. Using ex vivo virus immune Tc cells, we have previously shown that granzyme B is able to activate several independent pro-apoptotic pathways, including those mediated by Bid/Bak/Bax and caspases-3/-7, in target cells pulsed with Tc cell determinants.
[Methods and Findings] Here we analysed the physiological relevance of those pro-apoptotic pathways in ectromelia infection, by incubating ectromelia-immune ex vivo Tc cells from granzyme A deficient (GzmB+ Tc cells) or granzyme A and granzyme B deficient (GzmA×B−/− Tc cell) mice with ectromelia-infected target cells. We found that gzmB-induced apoptosis was totally blocked in ectromelia infected or peptide pulsed cells lacking caspases-3/-7. However ectromelia inhibited only partially apoptosis in cells deficient for Bid/Bak/Bax and not at all when both pathways were operative suggesting that the virus is able to interfere with apoptosis induced by gzmB in case not all pathways are activated. Importantly, inhibition of viral replication in vitro, as seen with wild type cells, was not affected by the lack of Bid/Bak/Bax but was significantly reduced in caspase-3/-7-deficient cells. Both caspase dependent processes were strictly dependent on gzmB, since Tc cells, lacking both gzms, neither induced apoptosis nor reduced viral titers.
[Significance] Out findings present the first evidence on the biological importance of the independent gzmB-inducible pro-apoptotic pathways in a physiological relevant virus infection model.
Description5 figuras.-- Material suplementario
Publisher version (URL)http://dx.doi.org/10.1371/journal.pone.0007512
URIhttp://hdl.handle.net/10261/210811
DOI10.1371/journal.pone.0007512
ISSN1932-6203
Appears in Collections:(ICB) Artículos
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