Airway epithelial cell regulation of T cell responses during viral infection

Abstract

The majority of acute respiratory tract infections are caused by viruses, with Influenza A viruses (IAV), Respiratory Syncytial virus (RSV) and Coronaviruses (CoV) three important causes of disease. The symptoms of infection can be very similar despite different aetiology and mechanisms of infection. Each virus can also result in a wide range of patient outcomes from asymptomatic infections to life threatening lower respiratory infections such as pneumonia. The ongoing COVID-19 pandemic is an important example of the considerable variation in patient outcome that can occur in response to a single viral agent, SARS-CoV2. Differences in how the host immune system responds to infection can contribute to this variation with the most severe cases frequently associated with excessive cytokine production and T cell dysregulation.
Given that T cells are a key factor in both viral clearance and immune mediated tissue damage, it is important to understand how different respiratory viruses impact T cell driven immunity. Epithelial cells that line the airways are often the primary target of respiratory viruses. These cells are increasingly understood to play a direct role in antiviral immunity, regulating and directing aspects of both the innate and adaptive responses at the site of infection. Signals released from epithelial cells can influence all stages of the T cell life cycle; both indirectly by influencing Dendritic cell polarisation and directly through T cell co-receptor expression as well as cytokine and chemokine production.
The primary aim of this work was to use transcriptomics data to compare T cell modulatory signals produced by respiratory epithelial cells in response to infection with different viruses. Published microarray data from experiments using well differentiated primary bronchial epithelial cells as models of RSV, IAV and SARS-CoV1 infection were re-analysed using differential expression analysis and gene expression was compared across viruses with a focus on T cell recruitment, activation and inhibition.
In addition, this project worked to develop an Air liquid interface model of RSV infection using the BCI-NS1.1 cell line with a view to validating the transcriptomics analysis. The validity of the model was explored using RT-PCR to monitor RSV amplification over time as well as CXCL10 expression as a marker of antiviral gene expression.
Considerable differences were observed in the transcriptomic responses between viruses. RSV and SARS-CoV1 upregulated far fewer genes than two strains of IAV. Focused exploration of T cell related genes identified differences in expression of chemokine genes as well as the cytokines IL6, IL1B and IL23a. The BCi-NS1.1 cell line showed promise as a candidate for an RSV ALI infection model, however consistent and reliable infection was not demonstrated despite more productive infection occurring in primary bronchial epithelial cells. While this suggests that differentiated BCi-NS1.1 cells are not permissive to infection, further work discussed in this report is needed to improve the model before this conclusion can be made.

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Identifiers

ORCID for Karl Staples: orcid.org/0000-0003-3844-6457

ORCID for Ashley Heinson: orcid.org/0000-0001-8695-6203

ORCID for Cosma Mirella Spalluto: orcid.org/0000-0001-7273-0844

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