Lymphotoxins and cytomegalovirus cooperatively induce interferon-beta, establishing host-virus détente.
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.
Benedict
C A
CA
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Banks
T A
TA
Senderowicz
L
L
Ko
M
M
Britt
W J
WJ
Angulo
A
A
Ghazal
P
P
Ware
C F
CF
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000254:growth & development / Q000472:pathogenicity / Q000502:physiology*; D053200:Fas-Associated Death Domain Protein; D006566:Herpesviridae Infections / Q000209:etiology; D006790:Host-Parasite Interactions; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000494:pharmacology*; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D018146:Muromegalovirus; D016328:NF-kappa B / Q000502:physiology; D011506:Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D015996:Survival Rate; D048008:TNF Receptor-Associated Factor 3; D015533:Transcriptional Activation; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D008565:Membrane Proteins; D016328:NF-kappa B; D011506:Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D048008:TNF Receptor-Associated Factor 3; C505914:TNFSF14 protein, human; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta