Block of death-receptor apoptosis protects mouse cytomegalovirus from macrophages and is a determinant of virulence in immunodeficient hosts.

2.50
Hdl Handle:
http://hdl.handle.net/10033/265892
Title:
Block of death-receptor apoptosis protects mouse cytomegalovirus from macrophages and is a determinant of virulence in immunodeficient hosts.
Authors:
Ebermann, Linda; Ruzsics, Zsolt; Guzmán, Carlos A; van Rooijen, Nico; Casalegno-Garduño, Rosaely; Koszinowski, Ulrich; Cičin-Šain, Luka
Abstract:
The inhibition of death-receptor apoptosis is a conserved viral function. The murine cytomegalovirus (MCMV) gene M36 is a sequence and functional homologue of the human cytomegalovirus gene UL36, and it encodes an inhibitor of apoptosis that binds to caspase-8, blocks downstream signaling and thus contributes to viral fitness in macrophages and in vivo. Here we show a direct link between the inability of mutants lacking the M36 gene (ΔM36) to inhibit apoptosis, poor viral growth in macrophage cell cultures and viral in vivo fitness and virulence. ΔM36 grew poorly in RAG1 knockout mice and in RAG/IL-2-receptor common gamma chain double knockout mice (RAGγC(-/-)), but the depletion of macrophages in either mouse strain rescued the growth of ΔM36 to almost wild-type levels. This was consistent with the observation that activated macrophages were sufficient to impair ΔM36 growth in vitro. Namely, spiking fibroblast cell cultures with activated macrophages had a suppressive effect on ΔM36 growth, which could be reverted by z-VAD-fmk, a chemical apoptosis inhibitor. TNFα from activated macrophages synergized with IFNγ in target cells to inhibit ΔM36 growth. Hence, our data show that poor ΔM36 growth in macrophages does not reflect a defect in tropism, but rather a defect in the suppression of antiviral mediators secreted by macrophages. To the best of our knowledge, this shows for the first time an immune evasion mechanism that protects MCMV selectively from the antiviral activity of macrophages, and thus critically contributes to viral pathogenicity in the immunocompromised host devoid of the adaptive immune system.
Affiliation:
Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Citation:
Block of death-receptor apoptosis protects mouse cytomegalovirus from macrophages and is a determinant of virulence in immunodeficient hosts. 2012, 8 (12):e1003062 PLoS Pathog.
Journal:
PLoS pathogens
Issue Date:
Dec-2012
URI:
http://hdl.handle.net/10033/265892
DOI:
10.1371/journal.ppat.1003062
PubMed ID:
23271968
Type:
Article
Language:
en
ISSN:
1553-7374
Appears in Collections:
publications of the research group immune aging and chronic infections (IMCI)

Full metadata record

DC FieldValue Language
dc.contributor.authorEbermann, Lindaen_GB
dc.contributor.authorRuzsics, Zsolten_GB
dc.contributor.authorGuzmán, Carlos Aen_GB
dc.contributor.authorvan Rooijen, Nicoen_GB
dc.contributor.authorCasalegno-Garduño, Rosaelyen_GB
dc.contributor.authorKoszinowski, Ulrichen_GB
dc.contributor.authorCičin-Šain, Lukaen_GB
dc.date.accessioned2013-01-17T13:04:48Z-
dc.date.available2013-01-17T13:04:48Z-
dc.date.issued2012-12-
dc.identifier.citationBlock of death-receptor apoptosis protects mouse cytomegalovirus from macrophages and is a determinant of virulence in immunodeficient hosts. 2012, 8 (12):e1003062 PLoS Pathog.en_GB
dc.identifier.issn1553-7374-
dc.identifier.pmid23271968-
dc.identifier.doi10.1371/journal.ppat.1003062-
dc.identifier.urihttp://hdl.handle.net/10033/265892-
dc.description.abstractThe inhibition of death-receptor apoptosis is a conserved viral function. The murine cytomegalovirus (MCMV) gene M36 is a sequence and functional homologue of the human cytomegalovirus gene UL36, and it encodes an inhibitor of apoptosis that binds to caspase-8, blocks downstream signaling and thus contributes to viral fitness in macrophages and in vivo. Here we show a direct link between the inability of mutants lacking the M36 gene (ΔM36) to inhibit apoptosis, poor viral growth in macrophage cell cultures and viral in vivo fitness and virulence. ΔM36 grew poorly in RAG1 knockout mice and in RAG/IL-2-receptor common gamma chain double knockout mice (RAGγC(-/-)), but the depletion of macrophages in either mouse strain rescued the growth of ΔM36 to almost wild-type levels. This was consistent with the observation that activated macrophages were sufficient to impair ΔM36 growth in vitro. Namely, spiking fibroblast cell cultures with activated macrophages had a suppressive effect on ΔM36 growth, which could be reverted by z-VAD-fmk, a chemical apoptosis inhibitor. TNFα from activated macrophages synergized with IFNγ in target cells to inhibit ΔM36 growth. Hence, our data show that poor ΔM36 growth in macrophages does not reflect a defect in tropism, but rather a defect in the suppression of antiviral mediators secreted by macrophages. To the best of our knowledge, this shows for the first time an immune evasion mechanism that protects MCMV selectively from the antiviral activity of macrophages, and thus critically contributes to viral pathogenicity in the immunocompromised host devoid of the adaptive immune system.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to PLoS pathogensen_GB
dc.titleBlock of death-receptor apoptosis protects mouse cytomegalovirus from macrophages and is a determinant of virulence in immunodeficient hosts.en
dc.typeArticleen
dc.contributor.departmentDepartment of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.en_GB
dc.identifier.journalPLoS pathogensen_GB

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