Lung epithelial cells have virus-specific and shared gene expression responses to infection by diverse respiratory viruses

Abstract

The severity of respiratory viral infections is partially determined by the cellular response mounted by infected lung epithelial cells. Disease prevention and treatment is dependent on our understanding of the shared and unique responses elicited by diverse viruses, yet few studies compare host responses to viruses from different families while controlling other experimental parameters. Murine models are commonly used to study the pathogenesis of respiratory viral infections, and in vitro studies using murine cells provide mechanistic insight into the pathogenesis observed in vivo. We used microarray analysis to compare changes in gene expression of murine lung epithelial cells infected individually by three respiratory viruses causing mild (rhinovirus, RV1B), moderate (coronavirus, MHV-1), and severe (influenza A virus, PR8) disease in mice. RV1B infection caused numerous gene expression changes, but the differential effect peaked at 12 hours post-infection. PR8 altered an intermediate number of genes whose expression continued to change through 24 hours. MHV-1 had comparatively few effects on host gene expression. The viruses elicited highly overlapping responses in antiviral genes, though MHV-1 induced a lower type I interferon response than the other two viruses. Signature genes were identified for each virus and included host defense genes for PR8, tissue remodeling genes for RV1B, and transcription factors for MHV-1. Our comparative approach identified universal and specific transcriptional signatures of virus infection that can be used to distinguish shared and virus-specific mechanisms of pathogenesis in the respiratory tract.

Attenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse Model

“…In contrast, in vitro coinfection by parainfluenza virus (parainfluenza virus type 2 [PIV2]) has been shown to enhance IAV infection, which is dependent on the cell-cell fusion activity of PIV2 (38). Our previous studies have shown that RV induces a robust type I IFN response in the LA-4 cell line (33); thus, the lack of PR8 inhibition in vitro is likely not due to the absence of an IFN response. This is not surprising, as the NS1 protein of PR8 is known to antagonize type I IFN responses (39).…”

Transcriptional and Translational Landscape of Equine Torovirus

“…Similarly, although differential translational analyses or proteomic studies have not been conducted on toroviruses, some of the identified proteins have been recognized as being incorporated into nidovirid virions (for example, TCP-1 and multiple heat shock proteins within arterivirus particles) ( 45 ). Others have been identified as being upregulated upon infection with coronaviruses, such as the solute carrier family 25 members ( 46 ). Notably, both poly(C) and poly(A) binding proteins were preferentially translated in infected cells; these have been previously identified as interaction partners of arteriviral nonstructural protein 1β and contribute to viral RNA replication ( 47 ).…”

Innate Immune Responses to Highly Pathogenic Coronaviruses and Other Significant Respiratory Viral Infections

“…Not only can airway epithelial cells produce a large array of cytokines/chemokines in response to an acute viral infection, but, depending on the magnitude of PRR engagement and the combination of PAMPs and DAMPs triggered, these epithelial cells can modulate the type of chemokines/cytokines produced and influence the influx of innate and adaptive immune cells (158,160). The response to different viral infections is generally similar, however, the response can be tailored in timing, magnitude and the induced gene signatures in response to each virus (179). Unlike RSV and MERS-CoV, which both productively infect alveolar (24) Ciliated epithelial cells of the upper and lower respiratory tract (25) The ciliated cells of the human airway epithelium are the main target, it also infects basal cells (26) and immune cells, such as Macrophages, B cells CD4 + and CD8 + T cells (27) Upper and lower airways epithelial cell ( macrophages (73,180), seasonal influenza and SARS-CoV usually lead to non-productive infections in these cells (181).…”