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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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Survival of TNFR−/− mice infected with EV. Groups of five  male mice of various strains were infected with 5 × 103 PFU EV in a volume of 20 μl via the footpad. The strains of mice infected were C57BL/6  × 129 (wild-type control, ⋄; p55−/−, □; p75−/−, ○; and p55−/−p75−/−,  ▵). Similar observations were made in a duplicate experiment. Morbidity  is discussed in the text.
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Figure 3: Survival of TNFR−/− mice infected with EV. Groups of five male mice of various strains were infected with 5 × 103 PFU EV in a volume of 20 μl via the footpad. The strains of mice infected were C57BL/6 × 129 (wild-type control, ⋄; p55−/−, □; p75−/−, ○; and p55−/−p75−/−, ▵). Similar observations were made in a duplicate experiment. Morbidity is discussed in the text.

Mentions: To further test the antiviral role of the two TNFRs, survival of TNFR mutant mice infected with EV was monitored. Wild-type mice recovered from infection with high doses (5 × 103 PFU) of the virulent Moscow strain of EV. Prominent swelling of the inoculated footpad was observed in the wild-type mice. However, the footpad resumed a normal appearance ∼14 d after infection. There were no other visible signs of morbidity in these mice. In contrast, clinical signs of susceptibility to EV, ranging from atrophy of the infected foot to skin lesions and even mortality, were seen in the TNFR mutant mice. Like the wild-type mice, all p55−/− mice survived infection with EV (Fig. 3). However, the reduced resistance of these mice was indicated by the symptoms of mousepox observed. Within 10 d of infection, the inoculated foot of all p55−/− mice was severely atrophied. Tail lesions were apparent in some (20%) mice after 17 d, but these were resolved at the termination of the experiment (42 d after infection). Mice lacking p75 were significantly more susceptible to EV, with most (80%) mice succumbing to lethal infection in the period from 10 to 21 d after infection (Fig. 3). Morbidity and mortality of p55−/− p75−/− mice was consistent with the increased susceptibility of p75−/− mice. EV infection was lethal for the majority (60%) of p55−/−p75−/− mice, which died between 10 and 17 d after infection (Fig. 3). Atrophy of the inoculated hind foot was evident in all mice within 8 d of infection. At the termination of the experiment, the surviving mice showed generalized skin lesions.


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)

Survival of TNFR−/− mice infected with EV. Groups of five  male mice of various strains were infected with 5 × 103 PFU EV in a volume of 20 μl via the footpad. The strains of mice infected were C57BL/6  × 129 (wild-type control, ⋄; p55−/−, □; p75−/−, ○; and p55−/−p75−/−,  ▵). Similar observations were made in a duplicate experiment. Morbidity  is discussed in the text.
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Related In: Results  -  Collection

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Figure 3: Survival of TNFR−/− mice infected with EV. Groups of five male mice of various strains were infected with 5 × 103 PFU EV in a volume of 20 μl via the footpad. The strains of mice infected were C57BL/6 × 129 (wild-type control, ⋄; p55−/−, □; p75−/−, ○; and p55−/−p75−/−, ▵). Similar observations were made in a duplicate experiment. Morbidity is discussed in the text.
Mentions: To further test the antiviral role of the two TNFRs, survival of TNFR mutant mice infected with EV was monitored. Wild-type mice recovered from infection with high doses (5 × 103 PFU) of the virulent Moscow strain of EV. Prominent swelling of the inoculated footpad was observed in the wild-type mice. However, the footpad resumed a normal appearance ∼14 d after infection. There were no other visible signs of morbidity in these mice. In contrast, clinical signs of susceptibility to EV, ranging from atrophy of the infected foot to skin lesions and even mortality, were seen in the TNFR mutant mice. Like the wild-type mice, all p55−/− mice survived infection with EV (Fig. 3). However, the reduced resistance of these mice was indicated by the symptoms of mousepox observed. Within 10 d of infection, the inoculated foot of all p55−/− mice was severely atrophied. Tail lesions were apparent in some (20%) mice after 17 d, but these were resolved at the termination of the experiment (42 d after infection). Mice lacking p75 were significantly more susceptible to EV, with most (80%) mice succumbing to lethal infection in the period from 10 to 21 d after infection (Fig. 3). Morbidity and mortality of p55−/− p75−/− mice was consistent with the increased susceptibility of p75−/− mice. EV infection was lethal for the majority (60%) of p55−/−p75−/− mice, which died between 10 and 17 d after infection (Fig. 3). Atrophy of the inoculated hind foot was evident in all mice within 8 d of infection. At the termination of the experiment, the surviving mice showed generalized skin lesions.

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