NOX1 and NOX2 as Therapeutic Targets in Influenza


Principal Investigator: JOHN DAVID LAMBETH
Abstract: Description (as provided by the applicant): Influenza virus shows high rates of mutation and recombination that soon renders immunization ineffective and requires yearly production of vaccines. In addition, up to 85% of isolates are resistant to available antiviral molecules targete against the virus itself. These factors demonstrate an unmet medical need for drugs that target host-encoded functions and that are therefore not subject to viral selection. Furthermore, highly lethal strains of influenza (e.g. 1918 flu, bird flu) occasionally arise, causing morbidity/mortaliy through the propensity of these viruses to induce a "cytokine storm" that mediates lung cell dysfunction and damage (acute respiratory distress syndrome or ARDS). Such pathogenic changes include disruptions in alveolar fluid transport, apoptosis of alveolar epithelial cells, an infiltration/destruction of lung tissue by neutrophils and monocytes. Currently, effective treatments to prevent lung damage do not exist. Similar changes occur with other pathogens including SARS-Coronavirus and anthrax, where host-directed therapies developed for influenza are also expected to be effective. Nox enzymes are NADPH-oxidases that generate superoxide and secondary reactive oxygen species (ROS) that act as signaling molecules, and in high concentrations directly damage biomolecules. We propose a signaling cascade involving both epithelial NOX1- and monocyte/PMN Nox2-generated ROS as key steps that: a) facilitate viral replication and/or spread and b) mediate lung damage. The generation of epithelial ROS by Nox1 is among the earliest events that trigger the cytokine storm and cellular functional changes. Using Nox knockout mice and inhibitors, preliminary evidence suggests that inhibition of Nox1 and Nox2 will be therapeutically beneficial in influenza infection. This application represents a collaborative effort between Emory and the Centers for Disease Control (CDC), where studies using highly virulent strains of influenza (PR8, H5N1 bird flu) can be carried out. The Lambeth Laboratory, known for its expertise in Nox discovery, enzymology and cell biology, has discovered (using high- and low-throughput screens) four chemical series of small molecule Nox inhibitors. In collaboration with the Emory Institute for Drug Discovery, our group will furthe develop these inhibitors, improving their potency, isoform selectivity, metabolic stability, and pharmacological properties and will coordinate preclinical development as candidate drugs. The Gangappa Laboratory, part of the Influenza group at the CDC will: 1) infect live virus into genetically deleted mice to demonstrate proof-of-concept for Nox1 and/or Nox2 as therapeutic targets, and 2) test drug candidates in infected and non-infected WT mice. The overall goal is to develop novel pre-clinical drug candidates that target Nox-generated ROS, thereby blocking host signaling pathways that lead to lung tissue damage and viral replication/spread. Such compounds will be generally useful in the treatment of all strains of influenza and likely other pathogens (SARS-CoV, anthrax) that result in severe lung dysfunction/pathology. Public Health Relevance: Highly lethal types of flu and other viruses (e.g. SARS-coronavirus) arise occasionally (bird flu, 1918 flu), and the lack of effective vaccines can result in pandemics that cause large numbers of fatalities. These viruses are lethal because of their tendency to cause a "cytokine storm" resulting in damage to the lung as well as changes in the way the lungs keep fluids from accumulating. The goal of this grant application is to develop and test in animal models compounds that target enzymes in lung cells called NADPH-oxidases (Nox enzymes) and that can be further developed into drugs that inhibit viral replication and treat or prevent the lung damage that occurs in pandemic influenza.
Funding Period: 2012-07-01 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc Ebselen and congeners inhibit NADPH oxidase 2-dependent superoxide generation by interrupting the binding of regulatory subunits
    Susan M E Smith
    Department of Pathology, Emory School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA
    Chem Biol 19:752-63. 2012

Detail Information


  1. pmc Ebselen and congeners inhibit NADPH oxidase 2-dependent superoxide generation by interrupting the binding of regulatory subunits
    Susan M E Smith
    Department of Pathology, Emory School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA
    Chem Biol 19:752-63. 2012
    ..Ebselen also blocked translocation of p47phox to neutrophil membranes. Thus, ebselen and its analogs represent a class of compounds that inhibit ROS generation by interrupting the assembly of Nox2-activating regulatory subunits...

Research Grants30

  1. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  2. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  3. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
  4. Cell Adhesion Mechanisms in Vascular Disease &Thrombosis
    MARK HOWARD GINSBERG; Fiscal Year: 2013
    ..abstract_text> ..
  5. Oklahoma Center for Respiratory and Infectious Diseases
    Lin Liu; Fiscal Year: 2013
    ..The completion of the goals of the present COBRE will have a major impact on research programs on respiratory infectious diseases in the State of Oklahoma. ..
  6. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  7. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  8. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  9. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  10. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  11. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  12. Acute Renal Failure Mediated Lung Injury
    Sarah Faubel; Fiscal Year: 2013
    ..The experiments in this grant will provide useful leads into the development of interventions to affect the systemic consequences of AKI and improve the mortality of patients with AKI. ..
  13. Immune Regulation of Virus Clearance and Tissue Injury at Sites of Infection
    Thomas J Braciale; Fiscal Year: 2013
    ..To determine the impact of viral infection on the production of Te-derived IL- 10. The proposed studies are designed to complement ongoing related studies in Projects 2, 3 and 4. ..