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Antiviral activity of tumor necrosis factor (TNF) is mediated via p55 and p75 TNF receptors.

Ruby J, Bluethmann H, Peschon JJ - J. Exp. Med. (1997)

Bottom Line: The antiviral nature of tumor necrosis factor (TNF) is generally well accepted.TNF appears to induce multiple antiviral mechanisms, and to synergize with interferon (IFN)-gamma in promoting antiviral activities.Thus, the antiviral activity of TNF is mediated via both TNFRs in vivo.

View Article: PubMed Central - PubMed

Affiliation: Viral Engineering and Cytokines Group, Division of Immunology and Cell Biology, John Curtin School of Medical Research, Canberra 2601 Australia. j.ruby@microbiology.unimelb.edu.au

ABSTRACT
The antiviral nature of tumor necrosis factor (TNF) is generally well accepted. TNF appears to induce multiple antiviral mechanisms, and to synergize with interferon (IFN)-gamma in promoting antiviral activities. We infected TNF receptor (TNFR)-deficient mice with the virulent murine pathogen, ectromelia virus (EV), and observed that otherwise resistant mice were susceptible to lethal infection. To study the molecular basis of the antiviral action of TNF, mice were infected with a recombinant vaccinia virus encoding murine TNF (VV-HA-TNF). In normal mice, the replication of VV-HA-TNF was highly attenuated. In contrast, mice in which the TNFR type 1 (p55) or the TNFR type 2 (p75) were genetically disrupted showed a moderate defect in their capacity to clear the TNF-encoding virus. The contribution of both TNF receptors to the control of VV-HA-TNF was confirmed by the enhanced replication of VV-HA-TNF in mice deficient for both p55 and p75. These observations were corroborated by infecting TNFR-deficient mice with EV. For both infections, the p55 and p75 TNFRs were necessary to maintain normal levels of resistance. Thus, the antiviral activity of TNF is mediated via both TNFRs in vivo. Furthermore, these studies establish that TNF is an important component of the host response to a natural virus infection.

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Replication of EV  in TNFR−/− mice. Groups of  five male mice of the strains indicated were infected with 5 × 103  PFU of EV (Moscow) in the  right hind footpad. The mice  were killed 7 d after infection  and virus was assayed in the liver,  spleen, and inoculated foot. Data  are representative of the mean  virus titer ± SEM of the tissues  shown for five individual mice.  For the liver, titers are expressed  per gram of tissue. Virus was recovered from the entire spleen  and foot. Morbidity of these  mice is discussed in the text.  Similar data were obtained in a  duplicate experiment in which  mice were infected with 104  PFU of EV (data not shown).  The limit of detection of the  plaque-forming assay was 100  PFU and samples below this  level were assigned a value of 50  (1.7 log10) PFU. * P <0.05, in  comparison with wild-type mice,  Student's t test. ** P <0.01, in  comparison with wild-type mice.  *** P <0.001, in comparison with  wild-type mice.
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Figure 2: Replication of EV in TNFR−/− mice. Groups of five male mice of the strains indicated were infected with 5 × 103 PFU of EV (Moscow) in the right hind footpad. The mice were killed 7 d after infection and virus was assayed in the liver, spleen, and inoculated foot. Data are representative of the mean virus titer ± SEM of the tissues shown for five individual mice. For the liver, titers are expressed per gram of tissue. Virus was recovered from the entire spleen and foot. Morbidity of these mice is discussed in the text. Similar data were obtained in a duplicate experiment in which mice were infected with 104 PFU of EV (data not shown). The limit of detection of the plaque-forming assay was 100 PFU and samples below this level were assigned a value of 50 (1.7 log10) PFU. * P <0.05, in comparison with wild-type mice, Student's t test. ** P <0.01, in comparison with wild-type mice. *** P <0.001, in comparison with wild-type mice.

Mentions: As described above, the overexpression of TNF could affect antiviral activity. Therefore, we sought evidence of a role for TNF in the physiological control of virus infection. Various strains of TNFR mutant mice were infected with the natural murine pathogen EV. The mice used in these studies were genetically resistant to EV; both C57BL and 129 backgrounds contribute to resistance to EV and B6 × 129 mice were more resistant than either parent strain (Ruby, J., unpublished data, and Karupiah, G., personal communication). Consistent with the resistant phenotype, no virus was detected in the livers of wild-type mice 7 d after infection (Fig. 2). In contrast, virus was demonstrated in the livers of mice with mutations in either TNFR. The level of EV recovered from the livers of p55−/− mice was consistently higher than that in wild-type mice, although the difference was not statistically significant. However, significantly higher yields of EV were obtained from the livers of p75−/− (P <0.001) and p55−/−p75−/− mice (P <0.01) relative to wild-type mice (Fig. 2). Furthermore, EV replicated to a significantly greater extent in the livers of p75−/− mice compared to p55−/− mice (P <0.01; Fig. 2).


Antiviral activity of tumor necrosis factor (TNF) is mediated via p55 and p75 TNF receptors.

Ruby J, Bluethmann H, Peschon JJ - J. Exp. Med. (1997)

Replication of EV  in TNFR−/− mice. Groups of  five male mice of the strains indicated were infected with 5 × 103  PFU of EV (Moscow) in the  right hind footpad. The mice  were killed 7 d after infection  and virus was assayed in the liver,  spleen, and inoculated foot. Data  are representative of the mean  virus titer ± SEM of the tissues  shown for five individual mice.  For the liver, titers are expressed  per gram of tissue. Virus was recovered from the entire spleen  and foot. Morbidity of these  mice is discussed in the text.  Similar data were obtained in a  duplicate experiment in which  mice were infected with 104  PFU of EV (data not shown).  The limit of detection of the  plaque-forming assay was 100  PFU and samples below this  level were assigned a value of 50  (1.7 log10) PFU. * P <0.05, in  comparison with wild-type mice,  Student's t test. ** P <0.01, in  comparison with wild-type mice.  *** P <0.001, in comparison with  wild-type mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2199110&req=5

Figure 2: Replication of EV in TNFR−/− mice. Groups of five male mice of the strains indicated were infected with 5 × 103 PFU of EV (Moscow) in the right hind footpad. The mice were killed 7 d after infection and virus was assayed in the liver, spleen, and inoculated foot. Data are representative of the mean virus titer ± SEM of the tissues shown for five individual mice. For the liver, titers are expressed per gram of tissue. Virus was recovered from the entire spleen and foot. Morbidity of these mice is discussed in the text. Similar data were obtained in a duplicate experiment in which mice were infected with 104 PFU of EV (data not shown). The limit of detection of the plaque-forming assay was 100 PFU and samples below this level were assigned a value of 50 (1.7 log10) PFU. * P <0.05, in comparison with wild-type mice, Student's t test. ** P <0.01, in comparison with wild-type mice. *** P <0.001, in comparison with wild-type mice.
Mentions: As described above, the overexpression of TNF could affect antiviral activity. Therefore, we sought evidence of a role for TNF in the physiological control of virus infection. Various strains of TNFR mutant mice were infected with the natural murine pathogen EV. The mice used in these studies were genetically resistant to EV; both C57BL and 129 backgrounds contribute to resistance to EV and B6 × 129 mice were more resistant than either parent strain (Ruby, J., unpublished data, and Karupiah, G., personal communication). Consistent with the resistant phenotype, no virus was detected in the livers of wild-type mice 7 d after infection (Fig. 2). In contrast, virus was demonstrated in the livers of mice with mutations in either TNFR. The level of EV recovered from the livers of p55−/− mice was consistently higher than that in wild-type mice, although the difference was not statistically significant. However, significantly higher yields of EV were obtained from the livers of p75−/− (P <0.001) and p55−/−p75−/− mice (P <0.01) relative to wild-type mice (Fig. 2). Furthermore, EV replicated to a significantly greater extent in the livers of p75−/− mice compared to p55−/− mice (P <0.01; Fig. 2).

Bottom Line: The antiviral nature of tumor necrosis factor (TNF) is generally well accepted.TNF appears to induce multiple antiviral mechanisms, and to synergize with interferon (IFN)-gamma in promoting antiviral activities.Thus, the antiviral activity of TNF is mediated via both TNFRs in vivo.

View Article: PubMed Central - PubMed

Affiliation: Viral Engineering and Cytokines Group, Division of Immunology and Cell Biology, John Curtin School of Medical Research, Canberra 2601 Australia. j.ruby@microbiology.unimelb.edu.au

ABSTRACT
The antiviral nature of tumor necrosis factor (TNF) is generally well accepted. TNF appears to induce multiple antiviral mechanisms, and to synergize with interferon (IFN)-gamma in promoting antiviral activities. We infected TNF receptor (TNFR)-deficient mice with the virulent murine pathogen, ectromelia virus (EV), and observed that otherwise resistant mice were susceptible to lethal infection. To study the molecular basis of the antiviral action of TNF, mice were infected with a recombinant vaccinia virus encoding murine TNF (VV-HA-TNF). In normal mice, the replication of VV-HA-TNF was highly attenuated. In contrast, mice in which the TNFR type 1 (p55) or the TNFR type 2 (p75) were genetically disrupted showed a moderate defect in their capacity to clear the TNF-encoding virus. The contribution of both TNF receptors to the control of VV-HA-TNF was confirmed by the enhanced replication of VV-HA-TNF in mice deficient for both p55 and p75. These observations were corroborated by infecting TNFR-deficient mice with EV. For both infections, the p55 and p75 TNFRs were necessary to maintain normal levels of resistance. Thus, the antiviral activity of TNF is mediated via both TNFRs in vivo. Furthermore, these studies establish that TNF is an important component of the host response to a natural virus infection.

Show MeSH
Related in: MedlinePlus