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. 2017 Apr 4:8:587.
doi: 10.3389/fmicb.2017.00587. eCollection 2017.

C-C Motif Chemokine Ligand 2 (CCL2) Mediates Acute Lung Injury Induced by Lethal Influenza H7N9 Virus

Chengcai Lai  1 , Keyu Wang  1 , Zhongpeng Zhao  1 , Liangyan Zhang  1 , Hongjing Gu  1 , Penghui Yang  1   2 , Xiliang Wang  1
Affiliations

C-C Motif Chemokine Ligand 2 (CCL2) Mediates Acute Lung Injury Induced by Lethal Influenza H7N9 Virus

Chengcai Lai et al. Front Microbiol. .

Abstract

An avian-origin influenza A (H7N9) virus was a cause for concern in China in the spring of 2013. Most H7N9 infections resulted in acute respiratory distress syndrome (ARDS), which is a severe form of acute lung injury (ALI) that contributes to morbidity and mortality. In this study, we induced viral ALI by infecting wild-type and CCL2-deficient mice with influenza H7N9 virus. The results suggested a close association between C-C motif chemokine ligand 2 (CCL2) expressions and ALI induced by a lethal H7N9 virus strain (A/Hebei/01/2013). Elevated CCL2 levels were also detected in confirmed human cases of H7N9 and the bronchoalveolar lavage fluid (BALF) of H7N9-infected mice. Moreover, CCL2 was overexpressed in the lung tissue of infected mice. More importantly, CCL2 deficiency ameliorated H7N9-induced ALI in mice as determined by weight loss, survival rate, the wet:dry ratio of the lung, and pathology. Taken together, our findings demonstrate that CCL2 is essential for H7N9 virus infection and thus that it is a potential therapeutic target for influenza.

Keywords: CCL2; acute lung injury (ALI); experimental mouse model; influenza H7N9 Hb01 virus; lethal influenza H7N9 virus.

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Figures

Figure 1
Figure 1
Influenza H7N9 Hb01-induced ALI in mice. Four-week-old B6 mice were anesthetized and inoculated with 103 TCID50 Hb01 virus in 20 μL allantoic fluid (AF) or an identical volume of control AF. Survival rates (A) and body weight changes (B) of B6 mice (n = 10) inoculated with AF and Hb01. Wet:dry ratios (C) of mouse lung tissues (n = 6) at 5 DPI. H&E-stained images (D) and infiltrating cell counts (n = 100 fields) of the lung tissues of infected mice at 5 DPI (magnification = 200×). ***p < 0.001.
Figure 2
Figure 2
Cytokine and chemokine levels in BALF of Hb01-infected mice. Cytokine and chemokine concentrations in mouse BALF (n = 6) at 5 days after inoculation with 103 TCID50 Hb01 or an identical volume of allantoic fluid were determined using a Mouse Cytokine 23-Plex Array (Bio-Rad Laboratories). *p < 0.05, **p < 0.01, and ***p < 0.001.
Figure 3
Figure 3
CCL2 levels were significantly increased in the serum of H7N9-infected patients and the BALF and lung tissues of Hb01-infected mice. The serum concentration of CCL2 of H7N9-infected patients (n = 29) was determined using a Bio-Plex Human Cytokine 25-Plex array (Bio-Rad Laboratories) (A). Four-week-old B6 mice were anesthetized and inoculated with 103 TCID50 Hb01 virus. The level of CCL2 in BALF (B) was assayed using a Mouse Cytokine 23-Plex Array (Bio-Rad Laboratories) at the indicated time points. (C) The CCL2 level in mouse lung tissue at 5 days after Hb01 infection was evaluated by fluorescence microscopy. CCL2 was stained with Alexa Flour 488 (green) and nuclei were strained with DAPI (blue). *p < 0.05.
Figure 4
Figure 4
CCL2−/− mice exhibited reduced severity of lung injury. Four-week-old CCL2−/− and wild-type B6 mice were inoculated with 103 TCID50 Hb01 virus. Survival rates (A) and body weight changes (B) of wild-type and CCL2−/− mice (n = 10) were monitored for 2 weeks after Hb01 challenge. Wet:dry ratios (C) of lung tissues (n = 6) at 5 DPI. HE-stained images (D) and infiltrating cell counts (n = 100 fields) of lung tissues at 5 DPI (magnification = 200×). *p < 0.05, **p < 0.01, and ***p < 0.001.
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References

    1. Belser J. A., Gustin K. M., Pearce M. B., Maines T. R., Zeng H., Pappas C., et al. . (2013). Pathogenesis and transmission of avian influenza A (H7N9) virus in ferrets and mice. Nature 501, 556–559. 10.1038/nature12391 - DOI - PMC - PubMed
    1. Chen Y., Liang W., Yang S., Wu N., Gao H., Sheng J., et al. . (2013). Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet 381, 1916–1925. 10.1016/S0140-6736(13)60903-4 - DOI - PMC - PubMed
    1. Chi Y., Zhu Y., Wen T., Cui L., Ge Y., Jiao Y., et al. . (2013). Cytokine and chemokine levels in patients infected with the novel avian influenza A (H7N9) virus in China. J. Infect. Dis. 208, 1962–1967. 10.1093/infdis/jit440 - DOI - PubMed
    1. Dawson T. C., Beck M. A., Kuziel W. A., Henderson F., Maeda N. (2000). Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am. J. Pathol. 156, 1951–1959. 10.1016/S0002-9440(10)65068-7 - DOI - PMC - PubMed
    1. Dessing M. C., van der Sluijs K. F., Florquin S., van der Poll T. (2007). Monocyte chemoattractant protein 1 contributes to an adequate immune response in influenza pneumonia. Clin. Immunol. 125, 328–336. 10.1016/j.clim.2007.08.001 - DOI - PubMed

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