Antiviral host factors constitutively expressed to high levels can confer intrinsic immunity. Unlike, induced antiviral responses, these pre-existing intrinsic defences can protect cells against the initial stages of virus infection. However, there has been little investigation into the existence of such defences at mucosal surfaces, major portals of virus entry. Accordingly, a role for intrinsic immunity to influenza A virus (IAV) infection of the lung and respiratory tract is yet to be established. We therefore set out to investigate the hypothesis that constitutive expression of key antiviral host factors in cells of the lung and respiratory tract may confer intrinsic immunity to IAV infection. We focused on the TRIpartite Motif (TRIM) proteins, a family known to play a role in multiple aspects of host immunity to virus infection. By analysing a cell line of lung origin restrictive to IAV plaque formation, we identified constitutive expression of TRIM22, an antiviral effector and interferon stimulated gene (ISG) product reported to restrict a number of viruses as part of an innate immune response, including IAV. Analysis of open source data, respiratory tissues, and cultured cell lines, demonstrated that TRIM22 was constitutively expressed to high levels in cells of the respiratory epithelium, independently of IAV infection. By depleting TRIM22 in a cell culture model of constitutive expression, we investigated whether constitutive TRIM22 expression confers an intrinsic defence against IAV infection. We found that TRIM22 supresses IAV gene expression, inhibiting the initiating cycle of IAV replication. Reconstitution of TRIM22 expression in a cell line deficient in TRIM22 supressed the expression of foreign reporter genes in a SPRY domain-dependent manner, suggesting a potential mechanism by which TRIM22 may restrict the infection of multiple viruses. Together, our data demonstrate that TRIM22 confers intrinsic immunity to IAV infection in the respiratory tract, thereby establishing an important role for intrinsic immunity in the regulation of IAV infection.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:724017 |
| Date | January 2017 |
| Creators | Charman, Matthew |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/8384/ |
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