The H7N9 influenza A virus infection results in lethal inflammation in the mammalian host via the NLRP3-caspase-1 inflammasome

Rongrong Ren; Shuxian Wu; Jialin Cai; Yuqin Yang; Xiaonan Ren; Yanling Feng; Lixiang Chen; Boyin Qin; Chunhua Xu; Hua Yang; Zhigang Song; Di Tian; Yunwen Hu; Xiaohui Zhou; Guangxun Meng

doi:10.1038/s41598-017-07384-5

The H7N9 influenza A virus infection results in lethal inflammation in the mammalian host via the NLRP3-caspase-1 inflammasome

Sci Rep. 2017 Aug 8;7(1):7625. doi: 10.1038/s41598-017-07384-5.

Authors

Rongrong Ren¹, Shuxian Wu², Jialin Cai³, Yuqin Yang⁴, Xiaonan Ren¹, Yanling Feng¹, Lixiang Chen¹, Boyin Qin¹, Chunhua Xu¹, Hua Yang¹, Zhigang Song¹, Di Tian¹, Yunwen Hu^{1

5}, Xiaohui Zhou^{6

7}, Guangxun Meng⁸

Affiliations

¹ Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.
² CAS Key Laboratory of Molecular Virology & Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
³ Translational Medicine Research Center, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, China.
⁴ Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
⁵ Key Laboratory of medical virology, MOH/MOE, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
⁶ Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China. [email protected].
⁷ Key Laboratory of medical virology, MOH/MOE, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
⁸ CAS Key Laboratory of Molecular Virology & Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China. [email protected].

Abstract

The avian origin influenza A virus (IAV) H7N9 has caused a considerable number of human infections associated with high rates of death since its emergence in 2013. As a vital component of the host innate immune system, the nucleotide-binding domain leucine-rich repeat containing receptor, pyrin domain containing 3 (NLRP3) inflammasome plays a critical role against H1N1 viral infection. However, the function of NLRP3 inflammasome in host immunological responses to the lethal H7N9 virus is still obscure. Here, we demonstrated that mice deficient for NLRP3 inflammasome components, including NLRP3, caspase-1, and Apoptosis-associated speck-like protein containing a CARD (ASC), were less susceptible to H7N9 viral challenge than wild type (WT) controls. Inflammasome deficiency in these animals led to significantly milder mortality and less pulmonary inflammation compared with WT mice. Furthermore, IL-1 receptor deficient mice also exhibited a higher survival rate than WT controls. Thus, our study reveals that the NLRP3 inflammasome is deleterious for the host during H7N9 infection in mice, which is due to an overwhelming inflammatory response via caspase-1 activation and associated IL-1 signal. Therefore, fine-tuning the activity of NLRP3 inflammasome or IL-1 signaling may be beneficial for the host to control H7N9 associated lethal pathogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CARD Signaling Adaptor Proteins / deficiency
CARD Signaling Adaptor Proteins / genetics*
CARD Signaling Adaptor Proteins / immunology
Caspase 1 / deficiency
Caspase 1 / genetics*
Caspase 1 / immunology
Caspases / deficiency
Caspases / genetics*
Caspases / immunology
Caspases, Initiator
Dendritic Cells / immunology
Dendritic Cells / pathology
Dendritic Cells / virology
Female
Gene Expression Regulation
Host-Pathogen Interactions*
Immunity, Innate
Inflammasomes / genetics
Inflammasomes / immunology
Inflammation
Influenza A Virus, H7N9 Subtype / immunology
Influenza A Virus, H7N9 Subtype / pathogenicity*
Lung / immunology
Lung / pathology
Lung / virology
Mice
Mice, Inbred C57BL
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein / deficiency
NLR Family, Pyrin Domain-Containing 3 Protein / genetics*
NLR Family, Pyrin Domain-Containing 3 Protein / immunology
Orthomyxoviridae Infections / genetics*
Orthomyxoviridae Infections / immunology
Orthomyxoviridae Infections / mortality
Orthomyxoviridae Infections / virology
Receptors, Interleukin-1 Type I / deficiency
Receptors, Interleukin-1 Type I / genetics*
Receptors, Interleukin-1 Type I / immunology
Signal Transduction
Survival Analysis

Substances

CARD Signaling Adaptor Proteins
IL1R1 protein, mouse
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Pycard protein, mouse
Receptors, Interleukin-1 Type I
Casp4 protein, mouse
Caspases
Caspases, Initiator
Casp1 protein, mouse
Caspase 1