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.
Highlights
The normal response to influenza A infection ranges from mild to asymptomatic; a serosurveillance study of volunteers who tested positive for antibodies against H1N1 revealed that the majority did not experience any symptoms [1]
High dose influenza infected pregnant mice, lost 20% of their initial body weight following pre-term delivery, reaching moribund endpoints; this loss was comparable to the high dose infected non-pregnant controls, which were at 73.3% initial body weight by 6 days post-infection (DPI)
The enhanced morbidity and mortality seen in pregnant women infected with the swine origin 2009 pandemic influenza virus triggered investigations into the underlying mechanisms of increased risk
Summary
The normal response to influenza A infection ranges from mild to asymptomatic; a serosurveillance study of volunteers who tested positive for antibodies against H1N1 revealed that the majority did not experience any symptoms [1]. Studies dating back to the 1918 pandemic suggest that pregnancy increases influenza-associated morbidity and mortality, with pregnant women at risk for developing severe influenza complications [2]. This pattern holds for all the major recent pandemics including 1918 (Spanish flu), 1957 (Asian flu), and 2009 (H1N1/2009) and to a lesser degree, for seasonal flu [2, 3]. Mouse models of pregnancy and influenza have shown that infection during gestation has a detrimental effect on neonatal growth and development [12, 13] These findings are similar to the higher maternal mortality seen in human pregnancies during previous pandemics [14]
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