RNA Sequencing of H3N2 Influenza Virus-Infected Human Nasal Epithelial Cells from Multiple Subjects Reveals Molecular Pathways Associated with Tissue Injury and Complications.

Kai Sen Tan,Hyung Won Choi,Olaf Rotzschke,Bernett Lee,Vincent T Chow,Ting Ting He,Mark Thong,Yan Yan,Josephine Lum,Anand Kumar Andiappan,Hui Fang Lim,See Aik Tang,Jing Liu,De Yun Wang,Yew Kwang Ong

doi:10.3390/cells8090986

Abstract

The human nasal epithelium is the primary site of exposure to influenza virus, the initiator of host responses to influenza and the resultant pathologies. Influenza virus may cause serious respiratory infection resulting in major complications, as well as severe impairment of the airways. Here, we elucidated the global transcriptomic changes during H3N2 infection of human nasal epithelial cells from multiple individuals. Using RNA sequencing, we characterized the differentially-expressed genes and pathways associated with changes occurring at the nasal epithelium following infection. We used in vitro differentiated human nasal epithelial cell culture model derived from seven different donors who had no concurrent history of viral infections. Statistical analysis highlighted strong transcriptomic signatures significantly associated with 24 and 48 h after infection, but not at the earlier 8-h time point. In particular, we found that the influenza infection induced in the nasal epithelium early and altered responses in interferon gamma signaling, B-cell signaling, apoptosis, necrosis, smooth muscle proliferation, and metabolic alterations. These molecular events initiated at the infected nasal epithelium may potentially adversely impact the airway, and thus the genes we identified could serve as potential diagnostic biomarkers or therapeutic targets for influenza infection and associated disease management.

Highlights

The global burden of inter-pandemic influenza is high
The responsesofofall allseven seven human nasal epithelial cells (hNECs) hNECs donors infection were plotted on a principal component analysis (PCA)
Besides the interferon and antiviral pathways, we identified several functions of interest initiated by the nasal epithelium that may contribute to the pathology and pathogenesis of influenza

Summary

Introduction

The global burden of inter-pandemic influenza is high. It is estimated to affect 1 billion people annually, with 3–5 million severe cases requiring hospitalization or intensive care treatment, resulting in approximately 0.5 million deaths [1]. When the influenza virus breaches the defense of the human airway epithelium, it causes a myriad of innate responses by the infected host in response to viral invasion [5,6] Among these changes are critical factors that can determine disease severity, and which may lead to the development of diagnostic, prognostic prediction markers, or anti-influenza therapies [7,8,9,10]. We need greater clarity on the different immune responses in view of the rising prevalence of chronic diseases such as diabetes mellitus and asthma Patients with these disorders are especially susceptible to severe influenza complications compared to healthy subjects [12]. The establishment of a baseline response against influenza infection of “healthy” tissue is beneficial to facilitate future comparative studies to better manage influenza in patients with co-morbidities

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