Interleukin 18 coexpression during respiratory syncytial virus infection results in enhanced disease mediated by natural killer cells

James A. Harker, Alexandra Godlee, Jennifer L. Wahlsten, Debbie C P Lee, Lucy G. Thorne, Devika Sawant, John S. Tregoning, Rachel R. Caspi, Alexander Bukreyev, Peter L. Collins, Peter J M Openshaw

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Respiratory syncytial virus (RSV) causes bronchiolitis, the main cause of infantile hospitalization. Immunity against reinfection is poor, and there is great interest in boosting vaccine responses using live vectors expressing host cytokines. We therefore constructed a recombinant RSV expressing murine interleukin 18 (RSV/IL-18), a cytokine capable of inducing strong antiviral immune responses. In vitro RSV/IL-18 replicated at wild-type levels and produced soluble IL-18. In naive BALB/c mice, RSV/IL-18 infection significantly increased both IL-18 mRNA and protein and attenuated the peak viral load 3-fold. Despite a reduced viral load, RSV/IL-18 infection caused a biphasic weight loss at days 2 and 6 postinfection that was not seen in wild-type infection. Day 2 disease was associated with enhanced pulmonary natural killer (NK) cell numbers and activity and was prevented by NK cell depletion during infection; day 6 disease was correlated with CD8 T-cell recruitment and was enhanced by NK cell depletion. IL-18 expression during priming also enhanced RSV- specific antibody responses and T-cell responses on secondary RSV infection. Therefore, while IL-18 boosted antiviral immunity and reduced the viral load, its coexpression worsened disease. This is the first recombinant RSV with this property, and these are the first studies to demonstrate that NK cells can induce pathology during pulmonary viral infections.

Original languageEnglish (US)
Pages (from-to)4073-4082
Number of pages10
JournalJournal of Virology
Volume84
Issue number8
DOIs
StatePublished - Apr 2010
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Harker, J. A., Godlee, A., Wahlsten, J. L., Lee, D. C. P., Thorne, L. G., Sawant, D., Tregoning, J. S., Caspi, R. R., Bukreyev, A., Collins, P. L., & Openshaw, P. J. M. (2010). Interleukin 18 coexpression during respiratory syncytial virus infection results in enhanced disease mediated by natural killer cells. Journal of Virology, 84(8), 4073-4082. https://doi.org/10.1128/JVI.02014-09