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

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

doi:10.3389/fmicb.2017.00587

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.

Highlights

The influenza pandemic caused by avian influenza A (H7N9) was a cause for concern in eastern China beginning in March 2013(Watanabe et al, 2013; Zhu et al, 2013)
H7N9 infection resulted in fever and cough, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS), which frequently required admission to an intensive care unit (ICU); it was associated with considerable morbidity and mortality (Chen et al, 2013)
The mice began to die at 5 days postinfection (DPI), and almost all had died by 10 DPI (Figure 1A)

Summary

Introduction

The influenza pandemic caused by avian influenza A (H7N9) was a cause for concern in eastern China beginning in March 2013(Watanabe et al, 2013; Zhu et al, 2013). H7N9 infection resulted in fever and cough, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS), which frequently required admission to an intensive care unit (ICU); it was associated with considerable morbidity and mortality (Chen et al, 2013). Most infected patients have exhibited excessive cytokine and chemokine production, which could result in hypercytokinemia and is associated with disease severity (Chen et al, 2013; Chi et al, 2013; Huang et al, 2014; Guo et al, 2015). Hypercytokinemia, known as a “cytokine storm,” is an early indicator of H7N9-induced ALI. C-C motif chemokine ligand 2 (CCL2), known as monocyte chemoattractant protein (MCP)-1, binds to the chemokine receptors CCR2 and CCR5, and is an important regulator of monocyte/macrophage trafficking during infection or in the presence of inflammation (Takahashi et al, 2003; Herold et al, 2006; Yadav et al, 2010)

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Conclusion