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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 VV-HA-TNF in TNFR mutant  mice. Groups of five female mice  of the strains indicated were infected intravenously with 107  PFU of VV-HA-TNF. The virus was recovered from the ovaries of mice 3 d after infection.  Data represent the mean titer ±  SEM for the total ovarian tissue  of five individual mice and are  representative of four separate  experiments. 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 <0.01, compared to wild-type mice, Student's t  test. *** P <0.001, compared to wild-type mice.
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Figure 1: Replication of VV-HA-TNF in TNFR mutant mice. Groups of five female mice of the strains indicated were infected intravenously with 107 PFU of VV-HA-TNF. The virus was recovered from the ovaries of mice 3 d after infection. Data represent the mean titer ± SEM for the total ovarian tissue of five individual mice and are representative of four separate experiments. 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 <0.01, compared to wild-type mice, Student's t test. *** P <0.001, compared to wild-type mice.

Mentions: To determine the relative roles of p55 and p75 in the attenuation of VV-HA-TNF, mice bearing mutations in either or both TNFRs were infected with VV-HA-TNF. The yields of virus recovered from TNFR-deficient mice indicated that TNF bound both p55 and p75 to initiate antiviral mechanisms (Fig. 1). Although the levels of virus were undetectable in the ovaries of wild-type mice 3 d after infection with VV-HA-TNF, elevated replication occurred in either p55- or p75-mutant mice (P <0.001). The contribution of both receptors to the attenuation of VV-HA-TNF was confirmed by the increase in virus replication in mice deficient for both TNFRs compared to wild-type mice (P <0.01). Indeed, the attenuation of VV-HA-TNF was completely abrogated in the double TNFR−/− mice, as the rVV replicated to the same extent as the control virus, VV-HA-TK (Table 1 and Fig. 1). There is no evidence from these experiments to suggest that the antiviral activity of TNF was mediated by mechanisms other than via p55 or p75. These data indicate that both p55 and p75 are necessary and sufficient to limit the replication of VV-HA-TNF. In addition, the replication of VV-HA-TNF was significantly greater in p75−/− and p55−/−p75−/− mice compared to p55−/− mice (P <0.05; Fig. 1).


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 VV-HA-TNF in TNFR mutant  mice. Groups of five female mice  of the strains indicated were infected intravenously with 107  PFU of VV-HA-TNF. The virus was recovered from the ovaries of mice 3 d after infection.  Data represent the mean titer ±  SEM for the total ovarian tissue  of five individual mice and are  representative of four separate  experiments. 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 <0.01, compared to wild-type mice, Student's t  test. *** P <0.001, compared to wild-type mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2199110&req=5

Figure 1: Replication of VV-HA-TNF in TNFR mutant mice. Groups of five female mice of the strains indicated were infected intravenously with 107 PFU of VV-HA-TNF. The virus was recovered from the ovaries of mice 3 d after infection. Data represent the mean titer ± SEM for the total ovarian tissue of five individual mice and are representative of four separate experiments. 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 <0.01, compared to wild-type mice, Student's t test. *** P <0.001, compared to wild-type mice.
Mentions: To determine the relative roles of p55 and p75 in the attenuation of VV-HA-TNF, mice bearing mutations in either or both TNFRs were infected with VV-HA-TNF. The yields of virus recovered from TNFR-deficient mice indicated that TNF bound both p55 and p75 to initiate antiviral mechanisms (Fig. 1). Although the levels of virus were undetectable in the ovaries of wild-type mice 3 d after infection with VV-HA-TNF, elevated replication occurred in either p55- or p75-mutant mice (P <0.001). The contribution of both receptors to the attenuation of VV-HA-TNF was confirmed by the increase in virus replication in mice deficient for both TNFRs compared to wild-type mice (P <0.01). Indeed, the attenuation of VV-HA-TNF was completely abrogated in the double TNFR−/− mice, as the rVV replicated to the same extent as the control virus, VV-HA-TK (Table 1 and Fig. 1). There is no evidence from these experiments to suggest that the antiviral activity of TNF was mediated by mechanisms other than via p55 or p75. These data indicate that both p55 and p75 are necessary and sufficient to limit the replication of VV-HA-TNF. In addition, the replication of VV-HA-TNF was significantly greater in p75−/− and p55−/−p75−/− mice compared to p55−/− mice (P <0.05; Fig. 1).

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