Influenza-Induced Oxidative Stress Sensitizes Lung Cells to Bacterial-Toxin-Mediated Necroptosis
Norberto Gonzalez-Juarbe,
Ashleigh N. Riegler,
Alexander S. Jureka,
Ryan P. Gilley,
Jeffrey D. Brand,
John E. Trombley,
Ninecia R. Scott,
Maryann P. Platt,
Peter H. Dube,
Chad M. Petit,
Kevin S. Harrod,
Carlos J. Orihuela
Affiliations
Norberto Gonzalez-Juarbe
Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA; Infectious Diseases and Genomic Medicine Group, J Craig Venter Institute, 9605 Medical Center Drive, Suite 150, Rockville, MD 20850, USA; Corresponding author
Ashleigh N. Riegler
Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA
Alexander S. Jureka
Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA
Ryan P. Gilley
Department of Microbiology, Immunology and Molecular Genetics, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Jeffrey D. Brand
Department of Anesthesiology and Perioperative Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA
John E. Trombley
Department of Anesthesiology and Perioperative Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA
Ninecia R. Scott
Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA
Maryann P. Platt
Infectious Diseases and Genomic Medicine Group, J Craig Venter Institute, 9605 Medical Center Drive, Suite 150, Rockville, MD 20850, USA
Peter H. Dube
Department of Microbiology, Immunology and Molecular Genetics, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Chad M. Petit
Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA
Kevin S. Harrod
Department of Anesthesiology and Perioperative Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA
Carlos J. Orihuela
Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA
Summary: Pneumonias caused by influenza A virus (IAV) co- and secondary bacterial infections are characterized by their severity and high mortality rate. Previously, we have shown that bacterial pore-forming toxin (PFT)-mediated necroptosis is a key driver of acute lung injury during bacterial pneumonia. Here, we evaluate the impact of IAV on PFT-induced acute lung injury during co- and secondary Streptococcus pneumoniae (Spn) infection. We observe that IAV synergistically sensitizes lung epithelial cells for PFT-mediated necroptosis in vitro and in murine models of Spn co-infection and secondary infection. Pharmacoelogical induction of oxidative stress without virus sensitizes cells for PFT-mediated necroptosis. Antioxidant treatment or inhibition of necroptosis reduces disease severity during secondary bacterial infection. Our results advance our understanding on the molecular basis of co- and secondary bacterial infection to influenza and identify necroptosis inhibition and antioxidant therapy as potential intervention strategies.
