Influenza A Virus Pathogenesis in a Non-Human Primate Model of Pregnancy

Abstract

Influenza A viruses (IAVs) have caused pandemics throughout the last 100+ years and remain a danger to global health due to their evolutionary mechanisms and persistence in worldwide avian populations. Pregnant women infected with pandemic IAVs have greater risk of respiratory disease severity and pregnancy complications. We hypothesized that aberrations in the pregnant primate's innate immune response to pandemic IAV predisposes them to severe IAV lung disease and atypical placental function. We infected pregnant and non-pregnant non-human primates (NHPs) with 2009 H1N1 and euthanized them at 5 days post-infection. Pulmonary physiology tests showed that severe IAV respiratory disease emerged at a similar frequency in both pregnant and non-pregnant macaque females. We observed that upregulation of antiviral gene expression in the lungs was similar in both infected pregnant and non-pregnant females relative to uninfected females. However, frequencies of IAV-infected alveolar macrophages are significantly higher in pregnant macaques relative to non-pregnant females. A multivariate linear regression model suggests that pulmonary TLR9 expression combined with baseline oxygenation values predict endpoint disease severity, regardless of pregnancy status. We did not find evidence of viral infection in most placentas or any fetuses. We encountered no significant differences in frequency of injury between placentas from infected and uninfected NHPs. In spite of this, we found evidence of elevated antiviral gene expression and pro-inflammatory cytokine circulation in placentas from infected versus uninfected NHPs. We calculated that maternal lung viral load correlated significantly and positively with antiviral gene expression, suggesting that the extent of maternal infection is triggering placental innate immunity. We believe that our translational NHP model reveals interesting insights into the maternal innate immune response to IAV infection and crosstalk with placental immune activation. Future studies should use longer experimental timelines to quantify enhanced mortality and pregnancy complication risks from maternal IAV infection.