Regulation of Early Host Immune Responses Shapes the Pathogenicity of Avian Influenza A Virus.

Jiya Sun,Xiangwei Wu,Xuye Yuan,Genhong Cheng,Jingfeng Wang,Tianqi Sui,Aiping Wu,Taijiao Jiang

doi:10.3389/fmicb.2019.02007

Abstract

Avian influenza A viruses (IAV) can cross the species barrier and cause disease in humans. Understanding the pathogenesis of avian IAV remains a challenge. Interferon-mediated antiviral responses and multiple cytokines production are important host cellular antiviral immunity against IAV infection. To elucidate the pathogenicity of avian IAV, a system approach was adopted to investigate dysregulation of the two host cellular antiviral immune responses in contrast with human IAV. As a result, we revealed that avian IAV not only disrupted normal early host cellular interferon-mediated antiviral responses, but also caused abnormal cytokines production through different pathways. For avian IAV infection, dysregulation of STAT2 was mainly responsible for abnormal cellular interferon-mediated antiviral responses, and IRF5 and NFKB1 played crucial roles in unusual cytokines production. In contrast, for human IAV infection, IRF1, IRF7, and STAT1 contributed to cellular cytokines production. Furthermore, differential activation of pattern recognition receptors (PRRs) likely led to avian IAV-related abnormal early host cellular antiviral immunity, where TLR7 and RIG-I were activated by avian and human IAV, respectively. Finally, a pathogenesis model was proposed that combined of early host cellular interferon-mediated antiviral responses with cytokines production could partly explain the pathogenicity of avian IAV. In conclusion, our study provides a new perspective of the pathogenesis of avian IAV, which will be helpful in preventing their infections in the future.

Highlights

Influenza virus is a long-term threat to global public health
Through focusing on a set of host cellular antiviral state genes (ASGs) and multiple cytokines, we proposed a novel unified model to explain the pathogenicity of highly pathogenic avian influenza A viruses (IAV), which resulted from dysregulation of early host cellular interferon-mediated antiviral responses and cytokines production
We focused on regulation of host cellular type I interferon-mediated antiviral responses and multiple cytokines production to understand the pathogenicity of highly pathogenic avian IAV (Figure 1)

Summary

Introduction

Influenza virus is a long-term threat to global public health. In contrast to human influenza A viruses (IAV) such as H1N1 (Du et al, 2017) that usually causes seasonal epidemic every year, avian IAV such as H5N1 (Creanga et al, 2017; Peng et al, 2017) and H7N9 (Wu et al, 2013) suddenly jump from their avian hosts to human and cause a high mortality rate, about 60% for H5N1 and 38% for H7N9 (Yu et al, 2008; Gao et al, 2013), which has brought serious social panic (Su et al, 2015).Early Host Responses for FluIn order to improve the ability to control avian IAV, there is an urgent need for a deep understanding of their pathogenicities.Computationally, the pathogenicity of avian IAV is often explored in two ways: identification of viral genome mutations and characterizing host cellular responses by using in vitro cell lines (Li et al, 2011; Josset et al, 2014; Simon et al, 2015) or in vivo mammalian models (Belser and Tumpey, 2013; Morrison et al, 2014; Su et al, 2017). Many studies have taken a systematic approach to investigate virus-induced host cellular transcriptomes (Li et al, 2011; Josset et al, 2014; Simon et al, 2015; Chasman et al, 2016) for elucidation of avian IAV pathogenesis. Chasman et al (2016) inferred pathogenicity-related gene modules by integrating cellular transcriptomes involving highly and low pathogenic IAV. These findings provide some clues to the pathogenicity of avian IAV in the context of the complicated virus–host interaction, dysregulation of early host cellular antiviral immune responses has not been systematically investigated

Methods

Results

Conclusion