Influenza A virus (IAV) is a major cause of seasonal viral respiratory infections and causes ∼36,000 deaths and ∼1.7 million hospitalizations each year in the United States alone. Moreover, IAV has the potential to cause global pandemics, which have significantly greater morbidity and mortality. Morbidity and mortality associated with IAV infections is thought to be the result of significant pulmonary immunopathology from the inflammatory response rather than viral replication. The initial lines of defense against pathogens in the lungs include alveolar epithelial cells, endothelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. Additionally, recruitment of neutrophils and macrophages is required for optimal clearance of IAV. Recent global analysis of lungs from mice infected with highly pathological IAV strains demonstrated enrichment of a mast cell transcriptional response, but the role of mast cells during severe pulmonary viral infections has been under studied. We found that A/WSN/33 causes significant immunopathology in C57Bl/6 mice and viral-induced pathology is mast cell-dependent. A/WSN/33 is able to directly activate bone marrow cultured mast cells (BMCMC) to produce histamine, leukotrienes, inflammatory cytokines, and anti-viral chemokines. Moreover, human H1N1, H3N2, and influenza B virus isolates can activate murine BMCMC in vitro suggesting this pathway could play a role during human infections. BMCMC activation requires infection of mast cells by IAV, which is dependent on the viral hemagglutinin specificity for α2,6-linked sialic acids. Cytokine and chemokine production from BMCMC occurs in a RIG-I-dependent fashion that requires the de novo production of vRNA. Conversely, degranulation occurs through a RIG-I-independent mechanism. Reconstitution of mast cell deficient mice with RIG-I-/- BMCMC generates lung pathology similar to wild-type BMCMC, suggesting that mast cell degranulation, rather than production of cytokines, causes A/WSN/33 induced lung pathology. Using recombinant A/WSN/33 strains, we found an association between binding of the A/WSN/33 hemagglutinin to α2,6-sialic acids and subsequent interactions with neuraminidase is important for degranulation. Thus, we have identified a unique inflammatory cascade that could be therapeutically targeted to limit morbidity following infection with IAV.
|Advisor:||Obar, Joshua J.|
|Commitee:||Harmsen, Allen G., June, Ronald K., Voyich, Jovanka M., Young, Mark J.|
|School:||Montana State University|
|Department:||Veterinary Molecular Biology|
|School Location:||United States -- Montana|
|Source:||DAI-B 76/11(E), Dissertation Abstracts International|
|Subjects:||Microbiology, Virology, Immunology|
|Keywords:||Degranulation, Histamine, Inflammation, Influenza a virus, Lung, Mast cells|
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