Item Details

Alveolar Macrophages Protect Against Lethal Influenza a Virus Pneumonia

Cardani, Amber
Format
Thesis/Dissertation; Online
Author
Cardani, Amber
Advisor
Braciale, Thomas
Abstract
The Influenza A Virus is a prominent human pathogen with the potential to cause pandemics outbreaks and high mortality rates. A primary feature of lethal influenza infection is viral pneumonia. Viral pneumonia results from the direct infection of alveolar epithelial cells by the Influenza A Virus subsequently causing extensive alveolar inflammation and injury. During clinical influenza infection alveolar epithelial cell infection manifests as diffuse alveolar damage leading to acute respiratory distress syndrome. Alveolar macrophages, the lung-resident macrophage, reside in the alveolar airspaces. This location strategically positions them on the frontline of defense against pathogens that are invading the alveoli and causing pneumonia. However, their pathophysiological role during influenza infection remains to be elucidated. To explore the contribution of alveolar macrophages to the outcome of influenza infection, we generated a novel mouse model with a selective deficiency in alveolar macrophages. While their wild type counterparts survived experimental influenza infection, the alveolar macrophage deficient mice developed severe diffuse alveolar damage and lethal respiratory compromise. Their lethal injury was a result of increased infection of their type 1 alveolar epithelial cells, and the subsequent elimination of these infected cells by the adaptive immune T cell response. Further analysis revealed that in order to render type 1 alveolar epithelial cells resistant to IAV infection, alveolar macrophages suppress leukotriene D4 production and autocrine signaling in type 1 alveolar epithelial cells. These results suggest that alveolar macrophages play a previously unappreciated role in protecting type 1 alveolar epithelial cells against IAV infection, and thereby regulating the severity of infection, through suppression of cysteinyl leukotriene metabolite production in type 1 alveolar epithelial cells.
Date Received
20160421
Published
University of Virginia, Department of Microbiology, Immunology, and Cancer Biology, PHD (Doctor of Philosophy), 2016
Published Date
2016-04-15
Degree
PHD (Doctor of Philosophy)
Collection
Libra ETD Repository
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