Progesterone-Based Contraceptives Reduce Adaptive Immune Responses and Protection against Sequential Influenza A Virus Infections

Abstract

In addition to their intended use, progesterone (P4)-based contraceptives promote anti-inflammatory immune responses, yet their effects on the outcome of infectious diseases, including influenza A virus (IAV) infection, are rarely evaluated. To evaluate their impact on immune responses to sequential IAV infections, adult female mice were treated with placebo or one of two progestins, P4 or levonorgestrel (LNG), and infected with a mouse-adapted H1N1 (maH1N1) virus. Treatment with P4 or LNG reduced morbidity but had no effect on pulmonary virus titers during primary H1N1 infection compared to placebo treatment. In serum and bronchoalveolar lavage fluid, total anti-IAV IgG and IgA titers and virus-neutralizing antibody titers but not hemagglutinin stalk antibody titers were lower in progestin-treated mice than placebo-treated mice. Females were challenged 6 weeks later with either an maH1N1 drift variant (maH1N1dv) or maH3N2 IAV. The level of protection following infection with the maH1N1dv was similar among all groups. In contrast, following challenge with maH3N2, progestin treatment reduced survival as well as the numbers and activity of H1N1- and H3N2-specific memory CD8 T cells, including tissue-resident cells, compared with placebo treatment. In contrast to primary IAV infection, progestin treatment increased the titers of neutralizing and IgG antibodies against both challenge viruses compared with those achieved with placebo treatment. While the immunomodulatory properties of progestins protected immunologically naive female mice from the severe outcomes from IAV infection, it made them more susceptible to secondary challenge with a heterologous IAV, despite improving their antibody responses against a secondary IAV infection. Taken together, the immunomodulatory effects of progestins differentially regulate the outcome of infection depending on exposure history. The impact of hormone-based contraceptives on the outcome of infectious diseases outside the reproductive tract is rarely considered. Using a mouse model, we have made the novel observation that treatment with either progesterone or a synthetic analog found in hormonal contraceptives, levonorgestrel, impacts sequential influenza A virus infection by modulating antibody responses and decreasing the numbers and activity of memory CD8 T cells. Progestins reduced the antibody responses during primary H1N1 virus infection but increased antibody titers following a sequential infection with either an H1N1 drift variant or an H3N2 virus. Following challenge with an H3N2 virus, female mice treated with progestins experienced greater mortality with increased pulmonary inflammation and reduced numbers and activity of CD8 T cells. This study suggests that progestins significantly affect adaptive immune responses to influenza A virus infection, with their effect on the outcome of infection depending on exposure history.

Progesterone-based compounds affect immune responses and susceptibility to infections at diverse mucosal sites

“…58 During pulmonary infection, females treated with time-release capsules of either P4 and LNG exhibit lower antibody production systemically in serum and locally in brochoalveolar lavage fluid, than do nonhormone treated female mice. 59 Taken together, these data illustrate that P4 and related compounds alter the functioning of immune cells, which could have profound effects on the pathogenesis of diseases at mucosal sites.…”

“…For example, during influenza A virus infection of the respiratory tract, excessive inflammation and tissue damage lead to severe symptoms, whereas the presence of P4 or LNG dampens inflammation and leads to faster recovery. 15,59 Conversely, during HSV-1 infection of the reproductive tract, dampened inflammation, including reduced numbers CD8 þ T cells and lower secretion of pro-inflammatory cytokines, caused by DMPA leads to increased virus reactivation. 62,89 Similarly, following infection of the reproductive tract with Neisseria gonorrhoeae, treatment with progestins decreases the number of Th17 cells and prevents proper control of the bacterial infection.…”

“…104 In mice infected with influenza A virus, treatment with either P4 or LNG prevents severe outcome by decreasing pulmonary inflammation and promoting faster recovery during a primary infection. 15,59 P4-based treatments promote pulmonary repair following clearance of influenza A viruses by elevating levels of TGF-b, IL-6, IL-22, and increasing numbers of regulatory CD39 þ Th17 cells in the lungs. Production of the epidermal growth factor amphiregulin is also increased following P4 treatment, which promotes proliferation and repair of respiratory epithelial cells during influenza A virus infection 15 ( Figure 3).…”

“…Treatment with either P4 or LNG also reduces virus-specific antibody titers as well as virus-specific memory CD8 þ T cells numbers, which results in worse outcome following secondary influenza A virus challenge in female mice. 59 Although the anti-inflammatory effects of P4-based compounds protect against a primary virus infection, the reduction in memory T-cell responses increase susceptibility to secondary influenza A virus challenge. Because P4-based compounds reduce inflammation and expedite repair of lung tissue following primary influenza A virus infection, females may be less susceptible to secondary bacterial infections, which are the primary cause of mortality following influenza A virus infection in humans.…”

Influenza in High-Risk Hosts—Lessons Learned from Animal Models

“…In contrast, ovariectomized female mice exogenously treated with P4 have increased morbidity following influenza virus infection, which is also noted in pregnant mice during peak P4 levels (Davis et al 2017). Hormonal contraceptives containing P4 reduce memory responses to heterotypic influenza challenges through decreasing the activity of memory CD8 + T cells (Hall et al 2017).…”