Interleukin 18 coexpression during respiratory syncytial virus infection results in enhanced disease mediated by natural killer cells.
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 naïve 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.
Department of Respiratory Medicine, Centre for Respiratory Infection, National Heart and Lung Institute, Imperial College London, St. Mary's Campus, London W2 1PG, United Kingdom.
James A
JA
Harker
Alexandra
A
Godlee
Jennifer L
JL
Wahlsten
Debbie C P
DC
Lee
Lucy G
LG
Thorne
Devika
D
Sawant
John S
JS
Tregoning
Rachel R
RR
Caspi
Alexander
A
Bukreyev
Peter L
PL
Collins
Peter J M
PJ
Openshaw
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D047589:Leukocyte Reduction Procedures; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology*; D022261:Respiratory Syncytial Virus Vaccines / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D012136:Respiratory Syncytial Viruses / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D014766:Viremia; D015431:Weight Loss
D000914:Antibodies, Viral; D020382:Interleukin-18; D022261:Respiratory Syncytial Virus Vaccines; D014614:Vaccines, Synthetic