Ocular Tropism of Influenza A Viruses: Identification of H7 Subtype-Specific Host Responses in Human Respiratory and Ocular Cells

Abstract

Highly pathogenic avian influenza (HPAI) H7 virus infection in humans frequently

A(H7N9) Virus Results in Early Induction of Proinflammatory Cytokine Responses in both Human Lung Epithelial and Endothelial Cells and Shows Increased Human Adaptation Compared with Avian H5N1 Virus

“…H7 influenza viruses associated with human ocular disease have been previously shown to downregulate numerous genes related to NF-B signaling in lung epithelial cells compared with virus subtypes typically associated with respiratory disease (18,28). As A(H7N9) viruses have been associated with respiratory instead of ocular disease, we examined the induction of NF-B signaling related genes in Calu-3 cells following Anhui/1 virus infection and compared our findings to previously published data (Fig.…”

“…It was previously shown that the transcriptomic response in human bronchial epithelial cells to A(H7N9) virus was more similar to the response to human H3N2 virus than to the response to either avian H5 or H7 subtype virus (45). We and others have shown previously that H7 subtype viruses associated with ocular disease in humans are generally highly infectious in human bronchial epithelial cells but elicit delayed and weakened induction of host inflammatory responses and NF-B signaling compared with H5N1 viruses (17,18,20,28). In contrast, while A(H7N9) viruses maintained the high infectivity and replicative ability in human bronchial epithelial cells observed with other H7 viruses ( Fig.…”

“…A(H7N9) virus elicits a cytokine transcription profile different from that of other H7 subtype viruses in human bronchial epithelial cells (17,18,20,28). Moreover, A(H7N9) viruses do not display an ocular tropism typically associated with subtype H7 influenza viruses (6).…”

“…Infection of Calu-3 cells with all viruses induced expression of several common genes (red), including those for IFN-␤, IL-6, and TNF. However, Anhui/1 virus infection resulted in the significant induction of a broader panel of NF-B-responsive genes than obtained with the HPAI H7 subtype viruses A/Netherlands/219/03 (H7N7; NL/219) and A/Mexico/7218/12 (H7N3; Mx/7218) (18,28). While numerous genes associated with NF-B signaling were downregulated (green) following Anhui/1 virus infection, the breadth of gene downregulation was muted compared with that with the HPAI H7 viruses and more closely resembled that of Thai/16, an HPAI H5N1 virus, and the seasonal Brisbane/59 (H1N1) virus.…”

“…While the association of acute lung injury following human infection with A(H7N9) virus necessitates a greater understanding of the ability of this virus to cause severe disease, there are only limited studies examining the tropism of H7 subtype viruses for human lung tissues and the induction of host responses in these cells following virus infection (9,12,(17)(18)(19)(20)(21). In this study, we characterized the infectivity, replication, and elicitation of cytokines and inflammatory mediators following A(H7N9) virus infection of human bronchial epithelial cells and pulmonary microvascular endothelial cells.…”