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. 2012 Feb;86(4):2251-8.
doi: 10.1128/JVI.06209-11. Epub 2011 Dec 14.

Natural killer cells are involved in acute lung immune injury caused by respiratory syncytial virus infection

Fengqi Li  1 , Hanqing Zhu, Rui Sun, Haiming Wei, Zhigang Tian
Affiliations

Natural killer cells are involved in acute lung immune injury caused by respiratory syncytial virus infection

Fengqi Li et al. J Virol. 2012 Feb.

Abstract

It is known that respiratory syncytial virus (RSV) is the main cause of bronchiolitis and pneumonia in young children. RSV infection often leads to severe acute lung immunopathology, but the underlying immune mechanisms are not yet fully elucidated. Here, we found that RSV infection induced severe acute lung immune injury and promoted the accumulation and activation of lung natural killer (NK) cells at the early stage of infection in BALB/c mice. Activated lung NK cells highly expressed activating receptors NKG2D and CD27 and became functional NK cells by producing a large amount of gamma interferon (IFN-γ), which was responsible for acute lung immune injury. NK cell depletion significantly attenuated lung immune injury and reduced infiltration of total inflammatory cells and production of IFN-γ in bronchoalveolar lavage fluid (BALF). These data show that NK cells are involved in exacerbating the lung immune injury at the early stage of RSV infection via IFN-γ secretion.

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Figures

Fig 1
Fig 1
RSV infection induces acute lung immune injury in mice. Female BALB/c mice were infected i.n. with 1 × 106 PFU of RSV. (A and B) Clinical characteristics (A) and body weight changes (B) of mice were measured after RSV infection. (C) Lung histology were determined by hematoxylin and eosin (H&E) staining (original magnification, ×200) at the indicated times after RSV infection. (D) RSV loads in the lungs were detected by real-time quantitative PCR at the indicated times after RSV infection. *, P < 0.05; **, P < 0.01.
Fig 2
Fig 2
RSV infection induces lung immune responses in mice. Female BALB/c mice were infected i.n. with 1 × 106 PFU of RSV. (A) Cell numbers in BALF were calculated. (B) Lung mononuclear cells were labeled with anti-mouse CD3 and DX5, and percentages were determined by flow cytometry assay at the indicated times after RSV infection. x axis, FL-1 height; y axis, FL-3 height. (C) Percentages of NK cells (CD3−, DX5+) and T cells (CD3+ DX5−). (D and E) At day 2 after RSV infection, lung mononuclear cells were labeled with anti-mouse CD3, DX5, and NKp46 and determined by flow cytometry assay. (D) Expression of NKp46 on CD3− DX5+ cells. (E) Expression of DX5 on CD3− NKp46+ cells. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Fig 3
Fig 3
Lung NK cells and T cells are activated after RSV infection. Female BALB/c mice were infected i.n. with 1 × 106 PFU of RSV. (A) At days 0, 1, 2, 3, 5, 7, 9, and 11 after RSV infection, the expression of CD69 on NK cells (CD3− DX5+) and T cells (CD3+ DX5−) was detected by flow cytometry assay. (B) Numbers inside the histogram represent mean fluorescence intensity (MFI) levels of CD69 on NK cells and T cells. **, P < 0.01; ***, P < 0.001.
Fig 4
Fig 4
RSV infection upregulates the expression of NKG2D and CD27 on lung NK cells. Female BALB/c mice were infected i.n. with 1 × 106 PFU of RSV. (A) After RSV infection, expression of NKG2D and CD27 on lung NK cells (CD3− DX5+) was detected by flow cytometry assay at the indicated times. (B) Percentages of NKG2D+ and CD27+ NK cells. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Fig 5
Fig 5
NK cell-derived IFN-γ is involved in acute lung immune injury during RSV infection. Female BALB/c mice were infected i.n. with 1 × 106 PFU of RSV. (A) IFN-γ levels in BALF were detected by ELISA at the indicated times after RSV infection. (B) Expression of IFN-γ in lung NK cells (CD3−DX5+) was detected by intracellular cytokine staining at the indicated times. (C) Percentages of IFN-γ+ NK cells. (D to F) Female BALB/c mice were treated i.v. with 100 μg of rat anti-mouse IFN-γ MAb for IFN-γ neutralization in vivo (rat IgG1, κ as control) 24 h before and 48 h after infection with RSV at 1 × 106 PFU. (E and F) At day 3 after infection, lung histology was determined by H&E staining (original magnification, ×200) (E) and RSV loads in the lungs were detected by real-time quantitative PCR (F). *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Fig 6
Fig 6
Depletion of NK cells attenuates acute lung immune injury caused by RSV infection. (A) Mice were treated i.v. with 50 μg of rabbit anti-mouse AsGM-1 for NK cell depletion (normal rabbit serum as control) 24 h before and 48 h after infection with RSV at 1 × 106 PFU. (B) At 24 h after primary anti-AsGM-1 treatment, the effects of the NK cell depletion in lung, spleen, and liver tissue from BALB/c mice were detected by flow cytometry assay; percentages of NK cells (CD3− DX5+) are shown. (C to G) Body weight changes in NK cell-depleted BALB/c mice were measured at the indicated times (C), and at day 3 after infection, lung histology was determined by H&E staining (original magnification, ×200) (D), RSV loads in the lungs were detected by real-time quantitative PCR (E), cell numbers in BALF were calculated (F), and IFN-γ levels in BALF were detected by ELISA (G). (H and I) Using samples from NK cell-depleted SCID mice, lung histology were determined by H&E staining (original magnification, ×200) (H) and RSV loads in the lungs were detected by real-time quantitative PCR at day 3 after infection (I). *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Fig 7
Fig 7
Working model of NK cell-mediated acute lung immune injury during RSV infection. RSV infection promotes activation of lung NK cells, which highly express CD27 and become functional NK cells. At the same time, expression of activating NK cell receptor NKG2D upregulates and may recognize its ligand, which is expressed on RSV-infected cells. Furthermore, NK cell-derived IFN-γ induces RSV-infected cell damage, which may lead to acute lung immune injury at the early stage of RSV infection.
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