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 co-infection in a mouse model

“…4). Our previous studies have shown that RV induces a robust type I IFN response in the LA-4 cell line (30), thus the lack of PR8 inhibition we saw is 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 (31).…”

“…Next, we used a murine lung epithelial cell line (LA-4) that is susceptible to infection by both viruses (30) to determine if co-infection by RV would interfere with PR8 replication in vitro . LA-4 cells were inoculated with RV 6 or 12 hours before or simultaneously with PR8.…”

The transcriptional and translational landscape of equine torovirus

“…Similarly, although differential translational analyses or proteomic studies have not been conducted upon toroviruses, some of the identified proteins have been recognised as being incorporated into nidovirid virions (for example, TCP-1 and multiple heat shock proteins within arterivirus particles) (39). Others have been identified as being upregulated upon infection with coronaviruses, such as the solute carrier family 25 members (40). 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 non-structural protein 1β and contribute to viral RNA replication (41).…”

Chronic exposure to arsenite enhances influenza virus infection in cultured cells

“…Respiratory epithelial cells act as a physical barrier against infections (Vareille, Kieninger, Edwards, & Regamey, ) and as immune system cells, secreting antiviral factors to influence both the innate and adaptive immune response to infections (Ibricevic et al, ; Maelfait et al, ; Seo & Webster, ; Stegemann‐Koniszewski et al, ; Swamy, Jamora, Havran, & Hayday, ; Vanleuven, Ridenhour, Gonzalez, Miller, & Miura, ). Several studies have demonstrated that damage to the lung epithelial barrier can lead to increased viral and bacterial infection (Golovkine et al, , Henderson et al, ; 2016; Short et al, ; Sufiawati & Tugizov, ).…”