Pregnancy Downregulates Plasmablast Metabolic Gene Expression Following Influenza Without Altering Long-Term Antibody Function

Abstract

While the majority of influenza-infected individuals show no or mild symptomatology, pregnant women are at higher risk of complications and infection-associated mortality. Although enhanced lung pathology and dysregulated hormones are thought to underlie adverse pregnancy outcomes following influenza infection, how pregnancy confounds long-term maternal anti-influenza immunity remains to be elucidated. Previously, we linked seasonal influenza infection to clinical observations of adverse pregnancy outcomes, enhanced lung and placental histopathology, and reduced control of viral replication in lungs of infected pregnant mothers. Here, we expand on this work and demonstrate that lower infectious doses of the pandemic A/California/07/2009 influenza virus generated adverse gestational outcomes similar to higher doses of seasonal viruses. Mice infected during pregnancy demonstrated lower hemagglutination inhibition and neutralizing antibody titers than non-pregnant animals until 63 days post infection. These differences in humoral immunity suggest that pregnancy impacts antibody maturation mechanisms without alterations to B cell frequency or antibody secretion. This is further supported by transcriptional analysis of plasmablasts, which demonstrate downregulated B cell metabolism and post-translational modification systems only among pregnant animals. In sum, these findings corroborate a link between adverse pregnancy outcomes and severe pathology observed during pandemic influenza infection. Furthermore, our data propose that pregnancy directly confounds humoral responses following influenza infection which resolves post-partem. Additional studies are required to specify the involvement of plasmablast metabolism with early humoral immunity abnormalities to best guide vaccination strategies and improve our understanding of the immunological consequences of pregnancy.

Suppression of progesterone by influenza A virus mediates adverse maternal and fetal outcomes in mice

“…While many models of IAV infection during pregnancy have focused on uncovering mechanisms of maternal disease (Engels et al, 2017; Marcelin et al, 2011; Pazos et al, 2012; Swieboda et al, 2020; Vermillion et al, 2018), the mechanisms of adverse fetal outcomes remain less clear. Placental tissue damage, in the absence of direct viral infection, has been reported in mice (Chan et al, 2010; Littauer et al, 2017; Swieboda et al, 2020) and in limited observational human studies (Kanmaz et al, 2011; Meijer et al, 2014). Despite no infectious virus in the placenta (data not shown), at 3 dpi, there was significant placental damage, including mixing of maternal and fetal red blood cells ( Fig.…”

“…Pregnancy impacts pulmonary innate immune activity and tissue repair following IAV infection, as pregnant dams have greater proinflammatory cytokine concentrations and numbers of neutrophils and macrophages in lungs than nonpregnant females (Chan et al, 2010; Engels et al, 2017; Lauzon-Joset et al, 2019; Marcelin et al, 2011; Pazos et al, 2012). Moreover, IAV infection during pregnancy is associated with pulmonary tissue damage, impaired epithelial regeneration, reduced progesterone (P4) concentrations, and a shift of alveolar macrophages from a classical to an alternative activation state (Lauzon-Joset et al, 2019; Marcelin et al, 2011; Swieboda et al, 2020; Vermillion et al, 2018). Pregnant dams infected with IAV have reduced adaptive immune responses including reduced IAV-specific antibody titers, numbers of circulating CD4 + and CD8 + T cells, and IAV-specific cytotoxic T cell activity, with these effects associated with changes in circulating P4 and estrogens (Chan et al, 2010; Engels et al, 2017; Peluso et al, 1980; Swieboda et al, 2020).…”

“…Moreover, IAV infection during pregnancy is associated with pulmonary tissue damage, impaired epithelial regeneration, reduced progesterone (P4) concentrations, and a shift of alveolar macrophages from a classical to an alternative activation state (Lauzon-Joset et al, 2019; Marcelin et al, 2011; Swieboda et al, 2020; Vermillion et al, 2018). Pregnant dams infected with IAV have reduced adaptive immune responses including reduced IAV-specific antibody titers, numbers of circulating CD4 + and CD8 + T cells, and IAV-specific cytotoxic T cell activity, with these effects associated with changes in circulating P4 and estrogens (Chan et al, 2010; Engels et al, 2017; Peluso et al, 1980; Swieboda et al, 2020). Whether IAV-induced changes in circulating concentrations of sex steroids are a cause or consequence of maternal disease during infection has not been determined.…”

Role of hormones in the pregnancy and sex‐specific outcomes to infections with respiratory viruses*

“…In pregnancy, the maternal adaptive immune response is attenuated through the decreased production of specific cytokines (IFNα and IFNγ) as well as the impaired maturation of antibodies critical to neutralizing pathogenic respiratory viruses, like IAV. 269 Whether increased morbidity is due to prolonged viral insult or damage from dysregulated maternal immune activation is often uncertain. The inflammatory state that follows IAV infection, however, has been closely linked with the development of neurocognitive disorders in children.…”

“…The immunomodulation of B cell production and differentiation by sex hormones is best exemplified in pregnancy where sex hormones directly affect B cell differentiation and proliferation (Figure 5). 269 …”