Transcriptional analysis of immune-related gene expression in p53-deficient mice with increased susceptibility to influenza A virus infection.
BACKGROUND
p53 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.


METHODS
p53KO 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.


RESULTS
p53KO 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.


CONCLUSIONS
Lack 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.
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No. 518, Ziyue Road, Shanghai,, 200241, PR China. yanwenjun01@163.com.
Wenjun
W
Yan
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No. 518, Ziyue Road, Shanghai,, 200241, PR China. jianchaowei@shvri.ac.cn.
Jianchao
J
Wei
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No. 518, Ziyue Road, Shanghai,, 200241, PR China. dengxf2008@gmail.com.
Xufang
X
Deng
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No. 518, Ziyue Road, Shanghai,, 200241, PR China. shizixue858@126.com.
Zixue
Z
Shi
Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730046, China. zhuzixiang@caas.cn.
Zixiang
Z
Zhu
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No. 518, Ziyue Road, Shanghai,, 200241, PR China. shaodonghua@shvri.ac.cn.
Donghua
D
Shao
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No. 518, Ziyue Road, Shanghai,, 200241, PR China. lbb@shvri.ac.cn.
Beibei
B
Li
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No. 518, Ziyue Road, Shanghai,, 200241, PR China. shwang@shvri.ac.cn.
Shaohui
S
Wang
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No. 518, Ziyue Road, Shanghai,, 200241, PR China. gztong@shvri.ac.cn.
Guangzhi
G
Tong
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No. 518, Ziyue Road, Shanghai,, 200241, PR China. zhiyongma@shvri.ac.cn.
Zhiyong
Z
Ma
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004198:Disease Susceptibility; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000276:immunology
D016207:Cytokines; D016159:Tumor Suppressor Protein p53