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The human immune response to RSV includes a loop between the tumor suppressor p53 and expression of APOBEC3 genes
Author(s) -
Gladwell Wesley,
Menendez Daniel,
Li Heather,
Yost Oriana,
Resnick Michael A.,
Kleeberger Steve
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.755.3
Subject(s) - immune system , biology , innate immune system , immunology , viral replication , bronchiolitis , virology , virus , gene , cancer research , genetics
Background Respiratory syncytial virus (RSV) infects nearly all children by theirsecond year of life with re‐infections occurring throughout adolescence andadulthood. RSV infection typicallyresults in mild host symptoms. However, susceptible individuals can develop severe lower respiratory tract infectionsand bronchiolitis, sometimes leading to hospitalization or death. Recently we established that in addition toits protective role against cancer development, the tumor suppressor p53 alsocontributes to host immune responses regulating the expression of several genesincluding the APOBEC3 family of DNA cytidine deaminases (A3), consideredsentinels in innate immune response against viral infections. Objective Usinghuman lung cancer cells, we tested the role of p53 in response to RSV infectionand its replication through the regulation of the A3 gene family as well asother components of the immune response.Methods A549 and H1299 cells were infected with RSV (Strain A2). Cells were thenharvested 72–120 hours post‐infection and qPCR and Nanostring arrays? were usedto evaluate mRNA expression of RSV‐g, P53, A3s and other immune targets. Expression of RSV was assessed? by ConfocalMicroscopy and cytofluorometry while Annexin V/PI assay was used to evaluateapoptosis. Results In response to acute and chronic RSV infection in human lung cancer cells, p53 was activated and had an impact on RSV replication, which involves theexpression in a p53 dependent manner of several members of the A3 gene familyas well as other innate immune genes. APOBEC3G (A3G) was highly induced in a dose‐ and time‐dependent mannerafter RSV only in lung cancer cells harboring WT p53. Accordingly, overexpression of A3G in lungcancer cells reduced RSV replication. Furthermore, a Nanotstring transcriptome analysis (immune code set) after RSV infectionrevealed a strong p53 dependent regulation of immune response genes, includingseveral components of the innate immune antiviral response. In addition, RSV infection induced p53phosphorylation at serine 15 and triggered p53‐dependent apoptosis in p53 functional cells while p53 deficiency correlated with increased viralreplication and increased syncytia phenotype. Conclusions Overall, our findings establish that the “guardian of the genome” role ascribed to p53 also extends to a unique component of the immune system – the A3 genes – revealing novel components in the antiviralimmune response against RSV infection. Support or Funding Information Supported by NIEHS Division of Intramural Research Program. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .