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Defective interfering virus protects elderly mice from influenza.

Scott PD, Meng B, Marriott AC, Easton AJ, Dimmock NJ - Virol. J. (2011)

Bottom Line: We have identified and characterised a defective-interfering (DI) influenza A virus particles containing a highly deleted segment 1 RNA that has broad-spectrum antiviral activity.Homologous protection is mediated by replication competition between the deleted and full-length genomes, and heterologous protection occurs through stimulation of innate immunity, especially interferon type I.The defective interfering virus is effective in preventing severe influenza A in elderly mice and may offer a new approach to protection of the human population.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Life Sciences, University of Warwick, Coventry, UK.

ABSTRACT

Background: We have identified and characterised a defective-interfering (DI) influenza A virus particles containing a highly deleted segment 1 RNA that has broad-spectrum antiviral activity. In young adult mice it exerts protection against several different subtypes of influenza A virus (defined here as homologous or genetically compatible protection) and against a paramyxovirus and an influenza B virus (heterologous or genetically unrelated protection). Homologous protection is mediated by replication competition between the deleted and full-length genomes, and heterologous protection occurs through stimulation of innate immunity, especially interferon type I.

Methods: A single dose of the protective DI virus was administered intranasally to elderly mice at -7, -1 and +1 days relative to intranasal challenge with influenza A virus.

Results: A single dose of the DI virus given 1 or 7 days protected elderly mice, reducing a severe, sometimes fatal disease to a subclinical or mild infection. In contrast, all members of control groups treated with inactivated DI virus before challenge became extremely ill and most died. Despite the subclinical/mild nature of their infection, protected mice developed solid immunity to a second infectious challenge.

Conclusions: The defective interfering virus is effective in preventing severe influenza A in elderly mice and may offer a new approach to protection of the human population.

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Related in: MedlinePlus

A single dose of influenza A virus 244/PR8 given 1 day before infection protects elderly (18-month-old) mice from influenza, and these mice are then immune to further challenge. Mice were anaesthetized and inoculated intranasally on day -1 with 244/PR8 or inactivated 244/PR8 (solid arrow), and were infected on day 0 (open arrow) with influenza A/WSN (panels a, b). Mice that had survived WSN challenge through treatment with protecting virus in a, b were challenged with a second high dose of WSN 3 weeks after the first infection (panels c, d) to establish their immune status. These mice were inoculated intranasally (open arrow) with a 500-fold higher dose of WSN than used in (a, b). (a, c) mean clinical disease assessment; (b, d) percentage weight change. ■, 12 μg 244/PR8 followed by WSN (n = 5); ▲, 12 μg inactivated 244/PR8 followed by WSN (n = 6); ●, 12 μg 244/PR8 followed by diluent (n = 2); ◆, naïve 5-week-old mice given only the high dose WSN challenge (n = 5). Mice were assessed clinically and weighed daily. Weights are not presented after 2 or more mice died. The percentage of mice surviving at the end of the study is in parenthesis. Data are representative of two separate experiments.
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Figure 1: A single dose of influenza A virus 244/PR8 given 1 day before infection protects elderly (18-month-old) mice from influenza, and these mice are then immune to further challenge. Mice were anaesthetized and inoculated intranasally on day -1 with 244/PR8 or inactivated 244/PR8 (solid arrow), and were infected on day 0 (open arrow) with influenza A/WSN (panels a, b). Mice that had survived WSN challenge through treatment with protecting virus in a, b were challenged with a second high dose of WSN 3 weeks after the first infection (panels c, d) to establish their immune status. These mice were inoculated intranasally (open arrow) with a 500-fold higher dose of WSN than used in (a, b). (a, c) mean clinical disease assessment; (b, d) percentage weight change. ■, 12 μg 244/PR8 followed by WSN (n = 5); ▲, 12 μg inactivated 244/PR8 followed by WSN (n = 6); ●, 12 μg 244/PR8 followed by diluent (n = 2); ◆, naïve 5-week-old mice given only the high dose WSN challenge (n = 5). Mice were assessed clinically and weighed daily. Weights are not presented after 2 or more mice died. The percentage of mice surviving at the end of the study is in parenthesis. Data are representative of two separate experiments.

Mentions: Mice were inoculated intranasally with a single dose of DI virus one day before intranasal infection with WSN. Figure 1a shows the clinical picture: mice given protecting virus alone or diluent (mock infected, data not shown) remained completely well. Those given UV-inactivated protecting virus before the infectious challenge became ill on day 5, progressing to serious disease that peaked on days 7-8. Most (67% or 4/6) were dead by day 8. In contrast, mice treated with active 244/PR8 before infection were all protected. Sixty percent (3/5) were protected completely, while 2/5 developed a mild illness, peaking on day 9 and from which they recovered completely. Comparison between the groups treated with active or inactive DI virus showed a highly significant statistical difference in the severity of disease (p = 0.0043) with a one tailed Mann-Whitney U test. Figure 1b shows that body weight in both 244/PR8 alone controls oscillated around the zero mark, as did mock infected controls (not shown). This contrasts with young adults where there is a steady weight gain. Mice given inactivated 244/PR8 before challenge lost weight at least 3 days ahead of clinical disease. Mice treated with 244/PR8 before infection showed only a small and transient weight loss, peaking at a maximum of 7% weight loss on days 9-10. They then regained the weight they had lost.


Defective interfering virus protects elderly mice from influenza.

Scott PD, Meng B, Marriott AC, Easton AJ, Dimmock NJ - Virol. J. (2011)

A single dose of influenza A virus 244/PR8 given 1 day before infection protects elderly (18-month-old) mice from influenza, and these mice are then immune to further challenge. Mice were anaesthetized and inoculated intranasally on day -1 with 244/PR8 or inactivated 244/PR8 (solid arrow), and were infected on day 0 (open arrow) with influenza A/WSN (panels a, b). Mice that had survived WSN challenge through treatment with protecting virus in a, b were challenged with a second high dose of WSN 3 weeks after the first infection (panels c, d) to establish their immune status. These mice were inoculated intranasally (open arrow) with a 500-fold higher dose of WSN than used in (a, b). (a, c) mean clinical disease assessment; (b, d) percentage weight change. ■, 12 μg 244/PR8 followed by WSN (n = 5); ▲, 12 μg inactivated 244/PR8 followed by WSN (n = 6); ●, 12 μg 244/PR8 followed by diluent (n = 2); ◆, naïve 5-week-old mice given only the high dose WSN challenge (n = 5). Mice were assessed clinically and weighed daily. Weights are not presented after 2 or more mice died. The percentage of mice surviving at the end of the study is in parenthesis. Data are representative of two separate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117841&req=5

Figure 1: A single dose of influenza A virus 244/PR8 given 1 day before infection protects elderly (18-month-old) mice from influenza, and these mice are then immune to further challenge. Mice were anaesthetized and inoculated intranasally on day -1 with 244/PR8 or inactivated 244/PR8 (solid arrow), and were infected on day 0 (open arrow) with influenza A/WSN (panels a, b). Mice that had survived WSN challenge through treatment with protecting virus in a, b were challenged with a second high dose of WSN 3 weeks after the first infection (panels c, d) to establish their immune status. These mice were inoculated intranasally (open arrow) with a 500-fold higher dose of WSN than used in (a, b). (a, c) mean clinical disease assessment; (b, d) percentage weight change. ■, 12 μg 244/PR8 followed by WSN (n = 5); ▲, 12 μg inactivated 244/PR8 followed by WSN (n = 6); ●, 12 μg 244/PR8 followed by diluent (n = 2); ◆, naïve 5-week-old mice given only the high dose WSN challenge (n = 5). Mice were assessed clinically and weighed daily. Weights are not presented after 2 or more mice died. The percentage of mice surviving at the end of the study is in parenthesis. Data are representative of two separate experiments.
Mentions: Mice were inoculated intranasally with a single dose of DI virus one day before intranasal infection with WSN. Figure 1a shows the clinical picture: mice given protecting virus alone or diluent (mock infected, data not shown) remained completely well. Those given UV-inactivated protecting virus before the infectious challenge became ill on day 5, progressing to serious disease that peaked on days 7-8. Most (67% or 4/6) were dead by day 8. In contrast, mice treated with active 244/PR8 before infection were all protected. Sixty percent (3/5) were protected completely, while 2/5 developed a mild illness, peaking on day 9 and from which they recovered completely. Comparison between the groups treated with active or inactive DI virus showed a highly significant statistical difference in the severity of disease (p = 0.0043) with a one tailed Mann-Whitney U test. Figure 1b shows that body weight in both 244/PR8 alone controls oscillated around the zero mark, as did mock infected controls (not shown). This contrasts with young adults where there is a steady weight gain. Mice given inactivated 244/PR8 before challenge lost weight at least 3 days ahead of clinical disease. Mice treated with 244/PR8 before infection showed only a small and transient weight loss, peaking at a maximum of 7% weight loss on days 9-10. They then regained the weight they had lost.

Bottom Line: We have identified and characterised a defective-interfering (DI) influenza A virus particles containing a highly deleted segment 1 RNA that has broad-spectrum antiviral activity.Homologous protection is mediated by replication competition between the deleted and full-length genomes, and heterologous protection occurs through stimulation of innate immunity, especially interferon type I.The defective interfering virus is effective in preventing severe influenza A in elderly mice and may offer a new approach to protection of the human population.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Life Sciences, University of Warwick, Coventry, UK.

ABSTRACT

Background: We have identified and characterised a defective-interfering (DI) influenza A virus particles containing a highly deleted segment 1 RNA that has broad-spectrum antiviral activity. In young adult mice it exerts protection against several different subtypes of influenza A virus (defined here as homologous or genetically compatible protection) and against a paramyxovirus and an influenza B virus (heterologous or genetically unrelated protection). Homologous protection is mediated by replication competition between the deleted and full-length genomes, and heterologous protection occurs through stimulation of innate immunity, especially interferon type I.

Methods: A single dose of the protective DI virus was administered intranasally to elderly mice at -7, -1 and +1 days relative to intranasal challenge with influenza A virus.

Results: A single dose of the DI virus given 1 or 7 days protected elderly mice, reducing a severe, sometimes fatal disease to a subclinical or mild infection. In contrast, all members of control groups treated with inactivated DI virus before challenge became extremely ill and most died. Despite the subclinical/mild nature of their infection, protected mice developed solid immunity to a second infectious challenge.

Conclusions: The defective interfering virus is effective in preventing severe influenza A in elderly mice and may offer a new approach to protection of the human population.

Show MeSH
Related in: MedlinePlus