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

Abstract

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.

Overactive Epidermal Growth Factor Receptor Signaling Leads to Increased Fibrosis after Severe Acute Respiratory Syndrome Coronavirus Infection

“…Taken together, these studies indicate that activation of EGFR contributes to fibrosis and that inhibition of EGFR signaling can protect against fibrosis. Studies on influenza A virus show that amphiregulin protects against virus-induced lung pathology in female mice, further complicating the picture (59). Other studies have also shown that tyrosine kinase inhibitors exacerbate PF (60) and that conditional loss of the EGFR ligand HB-EGF contributes to liver fibrosis (61), demonstrating the complex nature of EGFR signaling pathway integration.…”

New fronts emerge in the influenza cytokine storm

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Influenza virus matrix protein M1 interacts with SLD5 to block host cell cycle

“…Tissue sections (8 um) were cut, mounted on glass slides, and stained as described previously (Hall et al, 2016). Tissue sections (8 um) were cut, mounted on glass slides, and stained as described previously (Hall et al, 2016).…”