Influenza virus infection is one of the most common acute respiratory diseases and remains one of the largest disease burdens on humans, with severe primary viral pneumonia often resulting in death. The pathogenicity of influenza includes a host response that can include a severe systemic inflammatory reaction (cytokine storm) and ensuing vascular leak. Vascular leak is a fundamental element in the pathogenesis of circulatory shock and multiple organ failure, which can lead to death in influenza patients. The laboratories of Dr. Dean Li, co-Âfounder and former Chief Scientific Officer of Navigen, and Dr. Shannon Odelberg, along with Navigen, have demonstrated that vascular leak associated with inflammation is mediated by activation of the small GTPase, ARF6, a common nodal point in the signaling pathways of several inflammatory cytokines and growth factors. Navigenâs objective is to reduce morbidity and mortality associated with influenza infections by modifying this host response. Specifically, we propose to evaluate the efficacy of our small-Âmolecule ARF6 inhibitors with the hypothesis that inhibition of ARF6 will reduce vascular leak elicited by the infection while having no adverse effect on immunity-Âbased clearance of the virus.
Public Health Relevance Statement: NARRATIVE Influenza infection remains one of the largest disease burdens on humans, with severe primary viral pneumonia often resulting in death. The pathogenicity includes a host response that can include a severe systemic inflammatory reaction and ensuing vascular leak. Navigen has demonstrated that vascular leak associated with inflammation is mediated by activation of the small GTPase ARF6 and proposes to evaluate its small-Âmolecule ARF6 inhibitors in a mouse model of H1N1 infection.
NIH Spending Category: Acute Respiratory Distress Syndrome; Biodefense; Emerging Infectious Diseases; Infectious Diseases; Influenza; Lung; Pneumonia; Pneumonia & Influenza; Rare Diseases
Project Terms: Acute; Acute Lung Injury; Adherens Junction; Adult Respiratory Distress Syndrome; Adverse effects; Alveolar; Alveolitis; Animals; Antiviral Agents; Award; base; Birds; Blood; Blood capillaries; Blood Vessels; Bronchoalveolar Lavage Fluid; burden of illness; cadherin 5; CCL2 gene; Cell Count; Cell surface; Cells; Cellular Infiltration; Cellular Structures; Cessation of life; chemokine; Clinical; CXCL10 gene; cytokine; cytokine release syndrome; Data; Dose; Drug Kinetics; Dyes; Edema; Elements; Endothelium; Evans blue stain; Family suidae; Ferrets; Funding; Goals; Growth Factor; Histology; Hour; Human; Immune response; Immunity; improved; In Vitro; in vivo; Infection; Inflammation; Inflammatory; Inflammatory Infiltrate; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; influenzavirus; inhibitor/antagonist; Injections; Intention; Interferon Type II; Interleukin-6; Laboratories; Lead; Left; Lesion; Ligands; Lung; Lung diseases; Measures; Mediating; meetings; Modeling; Monitor; Monomeric GTP-Binding Proteins; Morbidity - disease rate; mortality; mouse model; Multiple Organ Failure; Mus; National Heart, Lung, and Blood Institute; Nodal; Oseltamivir; Outcome; Oxygen; pandemic disease; Pathogenesis; Pathogenicity; Patients; Pharmacology; Phase; Pneumococcal Infections; Prevention; programs; Proteins; Publishing; Pulmonary Edema; Pulmonary Pathology; pulmonary vascular permeability; RANTES; Reaction; receptor; Recombinants; response; Secondary to; Shock; Signal Pathway; Small Business Innovation Research Grant; small molecule; Testing; Time; TNF gene; Toxic effect; Toxicology; Viral; Viral Load result; Viral Physiology; Viral Pneumonia; Virus; Virus Dis
