Abstract
Tumor necrosis factor (TNF)-related cytokines regulate cell death and survival and provide strong selective pressures for viruses, such as cytomegalovirus (CMV), to evolve counterstrategies in order to persist in immune-competent hosts. Signaling by the lymphotoxin (LT)-beta receptor or TNF receptor-1, but not Fas or TRAIL receptors, inhibits the cytopathicity and replication of human CMV by a nonapoptotic, reversible process that requires nuclear factor kappa B (NF-kappa B)-dependent induction of interferon-beta (IFN-beta). Efficient induction of IFN-beta requires virus infection and LT signaling, demonstrating the need for both host and viral factors in the curtailment of viral replication without cellular elimination. LT alpha-deficient mice and LT beta R-Fc transgenic mice were profoundly susceptible to murine CMV infection. Together, these results reveal an essential and conserved role for LTs in establishing host defense to CMV.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Carrier Proteins / physiology
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Cells, Cultured
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Cytomegalovirus / growth & development
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Cytomegalovirus / pathogenicity
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Cytomegalovirus / physiology*
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Fas-Associated Death Domain Protein
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Herpesviridae Infections / etiology
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Host-Parasite Interactions*
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Humans
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Interferon-beta / biosynthesis*
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Interferon-beta / genetics
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Interferon-beta / physiology
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Lymphotoxin beta Receptor
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Lymphotoxin-alpha / genetics
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Lymphotoxin-alpha / pharmacology*
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Membrane Proteins / pharmacology*
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Mice
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Mice, Transgenic
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Muromegalovirus
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NF-kappa B / physiology
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Proteins / physiology
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RNA, Messenger / biosynthesis
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Receptors, Tumor Necrosis Factor / genetics
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Survival Rate
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TNF Receptor-Associated Factor 3
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Transcriptional Activation*
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Tumor Necrosis Factor Ligand Superfamily Member 14
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Tumor Necrosis Factor-alpha / pharmacology*
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Virus Replication / drug effects
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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FADD protein, human
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Fadd protein, mouse
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Fas-Associated Death Domain Protein
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LTBR protein, human
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Ltbr protein, mouse
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Lymphotoxin beta Receptor
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Lymphotoxin-alpha
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Membrane Proteins
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NF-kappa B
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Proteins
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RNA, Messenger
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Receptors, Tumor Necrosis Factor
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TNF Receptor-Associated Factor 3
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TNFSF14 protein, human
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Tnfsf14 protein, mouse
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Tumor Necrosis Factor Ligand Superfamily Member 14
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Tumor Necrosis Factor-alpha
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Interferon-beta