The addition of tumor necrosis factor plus beta interferon induces a novel synergistic antiviral state against poxviruses in primary human fibroblasts.
Tumor necrosis factor (TNF) and members of the interferon (IFN) family have been shown to independently inhibit the replication of a variety of viruses. In addition, previous reports have shown that treatment with various combinations of these antiviral cytokines induces a synergistic antiviral state that can be significantly more potent than addition of any of these cytokines alone. The mechanism of this cytokine synergy and its effects on global gene expression, however, are not well characterized. Here, we use DNA microarray analysis to demonstrate that treatment of uninfected primary human fibroblasts with TNF plus IFN-beta induces a distinct synergistic state characterized by significant perturbations of several hundred genes which are coinduced by the individual cytokines alone, as well as the induction of more than 850 novel host cell genes. This synergy is mediated directly by the two ligands, not by intermediate secreted factors, and is necessary and sufficient to completely block the productive replication and spread of myxoma virus in human fibroblasts. In contrast, the replication of two other poxviruses, vaccinia virus and tanapox virus, are only partially inhibited in these cells by the synergistic antiviral state, whereas the spread of both of these viruses to neighboring cells was efficiently blocked. Taken together, our data indicate that the combination of TNF and IFN-beta induces a novel synergistic antiviral state that is highly distinct from that induced by either cytokine alone.
Bartee
Eric
E
Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida 32610, USA.
Mohamed
Mohamed R
MR
Lopez
M Cecilia
MC
Baker
Henry V
HV
McFadden
Grant
G
D002478:Cells, Cultured; D004357:Drug Synergism; D005347:Fibroblasts / Q000276:immunology* / Q000821:virology*; D020869:Gene Expression Profiling; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology* / Q000494:pharmacology; D016899:Interferon-beta / Q000276:immunology* / Q000494:pharmacology; D009233:Myxoma virus / Q000276:immunology* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology; D014616:Vaccinia virus / Q000276:immunology; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000276:immunology; D018158:Yatapoxvirus / Q000276:immunology
D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta