guanosine-triphosphate and Influenza--Human

Antiviral compounds have been developed for use in chemoprophylaxis and chemotherapy of a variety of infections in humans, including those caused by influenza viruses, respiratory syncytial virus, and herpesviruses. The efficacy of several of these compounds has been demonstrated in rigorously controlled trials. Advances in molecular virology have led to the identification of biochemically defined, virus-specific functions that serve as appropriate targets for the future development of antiviral compounds. Clinical investigators and practicing physicians are now confronting questions previously raised with the use of antibacterial antibiotics. These questions concern appropriate routes of administration for antiviral compounds, optimal dosage regimens, risks of long-term prophylaxis, and the emergence of resistant organisms.

Topics: Acyclovir; Adult; Aged; Amantadine; Antiviral Agents; Chickenpox; Clinical Trials as Topic; Cytomegalovirus; Encephalitis; Foscarnet; Guanosine Triphosphate; Herpes Simplex; Herpes Zoster; Herpesviridae Infections; Humans; Infant, Newborn; Infant, Newborn, Diseases; Influenza A virus; Influenza, Human; Phosphonoacetic Acid; Respiratory Tract Infections; Ribavirin; Rimantadine; Vidarabine; Virus Diseases

Influenza A virus (IAV)-induced polymorphonuclear leukocyte (pMNL) dysfunction is important in causing secondary bacterial infections that lead to most influenza-related deaths. We previously showed that PMNLs exposed to IAV followed by a variety of stimuli (e.g., FMLP, PMA) demonstrate inhibition of various activation steps and endstage functions, suggesting IAV alters an early step in cell signalling. The present study examined IAV's effect on trimeric and monomeric G-proteins, since alterations of these proteins could explain IAV-induced PMNL dysfunction to various stimuli. PMNLs exposed to IAV for 30 min had decreased membrane-associated basal and high affinity guanosine triphosphatase (GTPase) activity compared with control cells. immunoblotting studies, using trimeric G-protein alpha and beta subunit-specific Abs, showed IAV decreased plasma membrane association of the trimeric G-proteins alpha subunits Gi2 and Gq by 33% +/- 5 and 46% +/- 8, respectively; binding of Gi3 and Gs was not altered. Similar studies involving monomeric G-proteins demonstrated that IAV decreased the membrane binding of rap1A (35% +/- 4), but not rac G-proteins. Corresponding increases in these IAV-altered G-proteins were detected in intracellular compartments. These data suggest the mechanism of IAV-induced PMNL dysfunction involves alterations in the binding of trimeric and monomeric G-proteins to plasma membranes.

Topics: Adult; Cell Membrane; GTP Phosphohydrolases; GTP-Binding Proteins; Guanosine Triphosphate; Humans; Immunoblotting; Influenza A virus; Influenza, Human; Neutrophils; Protein Binding