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Influenza virus facilitates its infectivity by activating p53 to inhibit the expression of interferon-induced transmembrane proteins (IFITMs)

ABSTRACT: Transcriptome analysis of mock or H1N1 IAV PR8 infected p53WT A549 and p53null A549-KO3 cells by Affymetrix GeneChip Human Transcriptome 2.0 Arrays to achieve a set of genes those are regulated by p53 and responsive to IAV infection. Influenza A virus infection activates cellular p53, however it has not been clear whether this process has pro- or anti- viral effects. In this study, using human isogenic p53 wildtype A549 cells and p53null A549-KO3 cells generated from the CRISPR/Cas9 technology, we report that p53null cells exhibit significantly reduced viral propagation property when infected with influenza A virus (H1N1/A/Puerto Rico/8/34). Here, using genome-wide microarray analysis we revealed that p53 regulates the expression of a large set of interferon-inducible genes, some of which are directly associated with viral infectivity and later experimentally validated to be responsible for p53-regulated IAV infectivity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106279 | GEO | 2018/05/31

REPOSITORIES: GEO

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Project description:Multiple respiratory viruses including Influenza A virus (IAV) can be transmitted via expiratory aerosol particles, and many studies have established that environmental conditions can affect viral infectivity during airborne transmission. Low aerosol pH was recently identified as a major factor influencing the infectivity of aerosol-borne IAV and SARS-CoV-2, however, there is a fundamental lack of understanding as to the mechanisms leading to viral inactivation within the acidic aerosol micro-environment. Here, we identified that the early stages of the IAV infection cycle were impacted by transient exposure to acidic aerosol conditions (pH below 5.5), which was primarily attributed to loss of binding function of the viral protein haemagglutinin. Viral capsid integrity was also somewhat affected by transient acidic exposure. We then characterised the structural changes associated with loss of viral infectivity using whole-virus hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), and observed discrete regions of unfolding in the external viral protein haemagglutinin and in the internal matrix protein 1. Viral nucleoprotein structure appeared to be unaffected by exposure to acidic aerosol conditions, and no changes to viral genome integrity or to lipids within the viral envelope were detected using our whole-virus methods. Collectively, these data indicate that viral inactivation observed under indoor aerosol conditions is mediated by specific protein conformational changes, particularly to haemagglutinin. This study additionally provides a proof-of-concept that HDX-MS is a highly effective method for characterisation of internal and external proteins of whole enveloped viruses such as IAV. Overall, improved understanding of the fate of respiratory viruses within exhaled aerosols will aid the development of novel strategies and therapeutics to control the severity of seasonal and/or pandemic influenza, and constitutes a global public health priority.

Project description:Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response. In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination. A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation. Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication.

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Influenza virus facilitates its infectivity by activating p53 to inhibit the expression of interferon-induced transmembrane proteins (IFITMs)

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