Date Published: September 15, 2016
Publisher: Public Library of Science
Author(s): Olivia J. Hall, Nathachit Limjunyawong, Meghan S. Vermillion, Dionne P. Robinson, Nicholas Wohlgemuth, Andrew Pekosz, Wayne Mitzner, Sabra L. Klein, Stacey Schultz-Cherry.
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.
Hormonal contraceptives are listed as an essential medication by the World Health Organization (WHO) because of the profound benefits these compounds can have on women’s health outcomes, including decreased rates of maternal mortality and improved perinatal outcomes and child survival, by widening the intervals between pregnancies . Hormonal contraceptive formulations vary, but all contain some form of progesterone (P4) either alone or in combination with estrogen. There are currently over 100 million young adult women on P4-based contraceptives worldwide , with the WHO projecting that over 800 million women will be using contraceptives, including P4-based contraceptives, by 2030 . Despite the staggering numbers of women taking these compounds, very few studies evaluate the impact of contraceptives on responses to infection or vaccination, especially in non-sexually transmitted diseases.
Hosts have evolved several mechanisms for overcoming viral infections, such as the induction of antiviral defenses that increase resistance to infection, or the activation of regulatory and repair responses that increase tolerance to the negative consequences of infection. In the present study, P4 significantly protected females during IAV infection by altering inflammation, improving pulmonary function, and promoting a pulmonary repair environment, which resulted in an earlier recovery. The protective effects of P4 were primarily mediated by the induction of AREG during both lethal and sublethal infections. Progesterone did not increase resistance to infection in females as demonstrated by the lack of an effect of P4 treatment on virus titers, clearance of infectious virus, numbers of Th1 cells, and CD8+ T cell activity in lungs. Instead, P4 reduced the detrimental consequences of IAV infection in females by increasing their tolerance to infection. Several host immunological factors, including TGF-β, Tregs, and regulatory populations of CD39+ Th17 cells, are associated with maintaining the balance between protective and pathological immune responses during IAV infection. Although P4 treatment had no effect on the numbers of Tregs in the lungs during IAV infection, concentrations of TGF-β and IL-6, the expression of Il23 and Il22, the number of Th17 cells, as well as the proportion of Th17 cells expressing CD39, were increased. Regulatory Th17 cells express the ectonucleotidase CD39 and are associated with repair following inflammation and infection [40, 41]. Th17 cells also promote epithelial cell proliferation and repair in the gut, primarily through the induction of IL-22 . Consequently, treatment of females with P4 increased IL-22, a cytokine that has been shown to mediate regeneration of lung epithelial cells following IAV infection . Whether the P4-induced increase in regulatory Th17 cells and IL-22 promotes cellular proliferation and repair of the lung epithelium during IAV infection by increasing AREG production requires consideration. Because P4 directly induced AREG production in respiratory epithelial cells in vitro, P4-induced AREG production may occur independent of the reparative effects of regulatory Th17 cells in the lungs during IAV infection.