Abstract
Backgroundp53 is a tumor suppressor that contributes to the host immune response against viral infections in addition to its well-established protective role against cancer development. In response to influenza A virus (IAV) infection, p53 is activated and plays an essential role in inhibiting IAV replication. As a transcription factor, p53 regulates the expression of a range of downstream responsive genes either directly or indirectly in response to viral infection. We compared the expression profiles of immune-related genes between IAV-infected wild-type p53 (p53WT) and p53-deficient (p53KO) mice to gain an insight into the basis of p53-mediated antiviral response.Methodsp53KO and p53WT mice were infected with influenza A/Puerto Rico/8/1934 (PR8) strain. Clinical symptoms and body weight changes were monitored daily. Lung specimens of IAV-infected mice were collected for analysis of virus titers and gene expression profiles. The difference in immune-related gene expression levels between IAV-infected p53KO and p53WT mice was comparatively determined using microarray analysis and confirmed by quantitative real-time reverse transcription polymerase chain reaction.Resultsp53KO mice showed an increased susceptibility to IAV infection compared to p53WT mice. Microarray analysis of gene expression profiles in the lungs of IAV-infected mice indicated that the increased susceptibility was associated with significantly changed expression levels in a range of immune-related genes in IAV-infected p53KO mice. A significantly attenuated expression of Ifng (encoding interferon (IFN)-gamma), Irf7 (encoding IFN regulator factor 7), and antiviral genes, such as Mx2 and Eif2ak2 (encoding PKR), were observed in IAV-infected p53KO mice, suggesting an impaired IFN-mediated immune response against IAV infection in the absence of p53. In addition, dysregulated expression levels of proinflammatory cytokines and chemokines, such as Ccl2 (encoding MCP-1), Cxcl9, Cxcl10 (encoding IP-10), and Tnf, were detected in IAV-infected p53KO mice during early IAV infection, reflecting an aberrant inflammatory response.ConclusionLack of p53 resulted in the impaired expression of genes involved in IFN signaling and the dysregulated expression of cytokine and chemokine genes in IAV-infected mice, suggesting an essential role of p53 in the regulation of antiviral and inflammatory responses during IAV infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0127-8) contains supplementary material, which is available to authorized users.
Highlights
Influenza A virus (IAV) is a member of the Orthomyxoviridae family of RNA viruses and a primary cause of respiratory tract infections that result in approximately 500,000 deaths per year worldwide [1]
We observed that p53-deficient mice infected with Puerto Rico/8/1934 (PR8) virus showed increased mortality, severe weight loss, and higher viral loads in the infected lungs compared to PR8-infected p53WT mice (Fig. 1), suggesting that p53 was involved in host defense mechanisms against IAV infection
These observations were in good agreement with a previous description that p53 serves as a host antiviral factor against IAV infection [15]
Summary
Influenza A virus (IAV) is a member of the Orthomyxoviridae family of RNA viruses and a primary cause of respiratory tract infections that result in approximately 500,000 deaths per year worldwide [1]. IAV evokes the host immune response to inhibit viral replication and clear viral infections. An aberrant host immune response during IAV infection has been hypothesized to be the main cause of IAV-related pneumonia. The host immune response to IAV infection has been extensively studied for more than 70 years; many uncertainties still exist [2]. The p53 protein primarily functions as a transcription factor that positively and negatively regulates the expression of a large and disparate group of responsive genes [6]. The IFN-stimulated response elements have been identified in p53 gene [7]. P53 upregulates the expression of several IFNinducible proteins, including IFN regulatory factor (IRF) 9, IRF5, IFN-stimulated gene 15, and toll-like receptor 3, suggesting a crosstalk between the p53 and IFN pathways [10]
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