Influenza A virus PB1-F2 is involved in regulation of cellular redox state in alveolar epithelial cells

Nary Shin, Chul Woong Pyo, Kwang I l Jung, Sang-Yun Choi

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Occurrence of oxidative stress is common in influenza, and renders the host more susceptible to pathogenic effects including cell death. We previously reported that down-regulation of superoxide anion dismutase 1 (SOD1) by influenza A virus (IAV) resulted in a significant increase in the levels of reactive oxygen species (ROS) and viral PB1 polymerase gene product in the early stage of infection. However, the precise molecular mechanism of IAV-mediated ROS generation is not yet fully understood. In this study, we investigated the possible involvement of the key virulence factor PB1-F2 in ROS generation and its contribution to the viral propagation and cell death. The key virulence factor PB1-F2 was found to be responsible, at least in part, for the ROS generation through lowering the SOD1 level in alveolar epithelial A549 cells. PB1-F2 overexpression resulted in SOD1 diminishment and ROS enhancement, while another virulent factor, NS1, did not show significant changes. Inversely, we examined the effects of the absence of PB1-F2 using mutant IAV lacking PB1-F2 expression (mutantΔF2). Infection with mutantΔF2 virus did not significantly lower the SOD1 level, and thus generated moderately low levels of ROS. In addition, the oxidative activity of PB1-F2 was directly reflected by cell viability and death. Infection with the mutant virus reduced the percentage of apoptotic cells more than two-fold compared to the wild-type IAV in A549 cells. Furthermore, expression of exogenous SOD1 gene abrogated a large portion of the PB1-F2-induced apoptosis of cells infected with wild-type IAV, but affected much less of the mutantΔF2 virus-infected cells. These results suggest that the PB1-F2 is directly implicated in virus-induced oxidative stress, thereby contributing to the early stages of IAV replication cycle and ultimately to disease severity.

Original languageEnglish
Pages (from-to)699-705
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume459
Issue number4
DOIs
Publication statusPublished - 2015 Apr 17

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Alveolar Epithelial Cells
Influenza A virus
Viruses
Oxidation-Reduction
Reactive Oxygen Species
Superoxides
Superoxide Dismutase
Cell Death
Virulence Factors
Oxidative Stress
Infection
Oxidative stress
Cell death
Virus Replication
Human Influenza
Genes
Cells
Epithelial Cells
Cell Survival
Down-Regulation

Keywords

  • Apoptosis
  • Influenza A virus
  • PB1-F2
  • ROS
  • Superoxide anion dismutase 1

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Influenza A virus PB1-F2 is involved in regulation of cellular redox state in alveolar epithelial cells. / Shin, Nary; Pyo, Chul Woong; Jung, Kwang I l; Choi, Sang-Yun.

In: Biochemical and Biophysical Research Communications, Vol. 459, No. 4, 17.04.2015, p. 699-705.

Research output: Contribution to journalArticle

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abstract = "Occurrence of oxidative stress is common in influenza, and renders the host more susceptible to pathogenic effects including cell death. We previously reported that down-regulation of superoxide anion dismutase 1 (SOD1) by influenza A virus (IAV) resulted in a significant increase in the levels of reactive oxygen species (ROS) and viral PB1 polymerase gene product in the early stage of infection. However, the precise molecular mechanism of IAV-mediated ROS generation is not yet fully understood. In this study, we investigated the possible involvement of the key virulence factor PB1-F2 in ROS generation and its contribution to the viral propagation and cell death. The key virulence factor PB1-F2 was found to be responsible, at least in part, for the ROS generation through lowering the SOD1 level in alveolar epithelial A549 cells. PB1-F2 overexpression resulted in SOD1 diminishment and ROS enhancement, while another virulent factor, NS1, did not show significant changes. Inversely, we examined the effects of the absence of PB1-F2 using mutant IAV lacking PB1-F2 expression (mutantΔF2). Infection with mutantΔF2 virus did not significantly lower the SOD1 level, and thus generated moderately low levels of ROS. In addition, the oxidative activity of PB1-F2 was directly reflected by cell viability and death. Infection with the mutant virus reduced the percentage of apoptotic cells more than two-fold compared to the wild-type IAV in A549 cells. Furthermore, expression of exogenous SOD1 gene abrogated a large portion of the PB1-F2-induced apoptosis of cells infected with wild-type IAV, but affected much less of the mutantΔF2 virus-infected cells. These results suggest that the PB1-F2 is directly implicated in virus-induced oxidative stress, thereby contributing to the early stages of IAV replication cycle and ultimately to disease severity.",
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