Progesterone-Based Therapy Protects Against Influenza by Promoting Lung Repair and Recovery in Females

• Published in: PLoS pathogens Vol. 12; no. 9; p. e1005840
• Main Authors: Hall, Olivia J., Limjunyawong, Nathachit, Vermillion, Meghan S., Robinson, Dionne P., Wohlgemuth, Nicholas, Pekosz, Andrew, Mitzner, Wayne, Klein, Sabra L.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2016; Public Library of Science (PLoS)
• Subjects: Amphiregulin - genetics; Amphiregulin - immunology; Animals; Antigens, CD - genetics; Antigens, CD - immunology; Apyrase - genetics; Apyrase - immunology; Biology and life sciences; Birth control; Care and treatment; Cytokines - genetics; Cytokines - immunology; Dosage and administration; Drug therapy; Environmental health; Epidermal growth factor; Female; Females; Funding; Health sciences; Immunology; Infections; Influenza; Influenza A virus; Influenza A virus - immunology; Lung; Lung - immunology; Lung - pathology; Lungs; Management; Maternal mortality; Medicine and health sciences; Mice; Mice, Knockout; Multivariate analysis; Orthomyxoviridae; Orthomyxoviridae Infections - genetics; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Progesterone; Public health; Respiratory function; Rodents; Th17 Cells - immunology; Th17 Cells - pathology; Variance analysis; Viral diseases; Women's health; Womens health; United States > US; Maryland; Baltimore Maryland
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005840

Over 100 million women use progesterone therapies worldwide. Despite having immunomodulatory and repair properties, their effects on the outcome of viral diseases outside of the reproductive tract have not been evaluated. Administration of exogenous progesterone (at concentrations that mimic the luteal phase) to progesterone-depleted adult female mice conferred protection from both lethal and sublethal influenza A virus (IAV) infection. Progesterone treatment altered the inflammatory environment of the lungs, but had no effects on viral load. Progesterone treatment promoted faster recovery by increasing TGF-β, IL-6, IL-22, numbers of regulatory Th17 cells expressing CD39, and cellular proliferation, reducing protein leakage into the airway, improving pulmonary function, and upregulating the epidermal growth factor amphiregulin (AREG) in the lungs. Administration of rAREG to progesterone-depleted females promoted pulmonary repair and improved the outcome of IAV infection. Progesterone-treatment of AREG-deficient females could not restore protection, indicating that progesterone-mediated induction of AREG caused repair in the lungs and accelerated recovery from IAV infection. Repair and production of AREG by damaged respiratory epithelial cell cultures in vitro was increased by progesterone. Our results illustrate that progesterone is a critical host factor mediating production of AREG by epithelial cells and pulmonary tissue repair following infection, which has important implications for women's health.