H1N1 influenza virus infection results in adverse pregnancy outcomes by disrupting tissue-specific hormonal regulation.

Elizabeth Q Littauer,E Stein Esser,Richard W Compans,Elena V Vassilieva,Olivia Q Antao,Ioanna Skountzou,Stacey Schultz-Cherry

doi:10.1371/journal.ppat.1006757

Elizabeth Q Littauer, E Stein Esser + Show 5 more

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https://doi.org/10.1371/journal.ppat.1006757

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Journal: PLoS Pathogens	Publication Date: Nov 27, 2017
Citations: 88	License type: CC BY 4.0

Affiliation: Emory University

Abstract

Increased susceptibility to influenza virus infection during pregnancy has been attributed to immunological changes occurring before and during gestation in order to “tolerate” the developing fetus. These systemic changes are most often characterized by a suppression of cell-mediated immunity and elevation of humoral immune responses referred to as the Th1-Th2 shift. However, the underlying mechanisms which increase pregnant mothers’ risk following influenza virus infection have not been fully elucidated. We used pregnant BALB/c mice during mid- to late gestation to determine the impact of a sub-lethal infection with A/Brisbane/59/07 H1N1 seasonal influenza virus on completion of gestation. Maternal and fetal health status was closely monitored and compared to infected non-pregnant mice. Severity of infection during pregnancy was correlated with premature rupture of amniotic membranes (PROM), fetal survival and body weight at birth, lung viral load and degree of systemic and tissue inflammation mediated by innate and adaptive immune responses. Here we report that influenza virus infection resulted in dysregulation of inflammatory responses that led to pre-term labor, impairment of fetal growth, increased fetal mortality and maternal morbidity. We observed significant compartment-specific immune responses correlated with changes in hormonal synthesis and regulation. Dysregulation of progesterone, COX-2, PGE2 and PGF2α expression in infected pregnant mice was accompanied by significant remodeling of placental architecture and upregulation of MMP-9 early after infection. Collectively these findings demonstrate the potential of a seasonal influenza virus to initiate a powerful pro-abortive mechanism with adverse outcomes in fetal health.

Highlights

IntroductionPregnant women are among the high-risk groups who are more susceptible to seasonal and pandemic influenza viral infections, with pronounced lung immunopathology [2] and increased incidence of complications, such as pre-eclampsia, pneumonia or heart failure during all 3 trimesters of gestation resulting in high hospitalization rates and mortality [1, 3,4,5,6,7,8]
Influenza virus has been responsible for four pandemics in the past century, with an additional global health burden of seasonal influenza-related illness estimated at five million cases of severe illness and nearly 500,000 deaths annually [1].Pregnant women are among the high-risk groups who are more susceptible to seasonal and pandemic influenza viral infections, with pronounced lung immunopathology [2] and increased incidence of complications, such as pre-eclampsia, pneumonia or heart failure during all 3 trimesters of gestation resulting in high hospitalization rates and mortality [1, 3,4,5,6,7,8]
Influenza viral infection during pregnancy results in shorter gestation period In order to assess the impact of seasonal influenza virus infection in maternal and fetal health, we first infected pregnant mice at day 12 of gestation and non-pregnant controls with a low dose of H1N1 A/Brisbane/59/07

Summary

Introduction

Pregnant women are among the high-risk groups who are more susceptible to seasonal and pandemic influenza viral infections, with pronounced lung immunopathology [2] and increased incidence of complications, such as pre-eclampsia, pneumonia or heart failure during all 3 trimesters of gestation resulting in high hospitalization rates and mortality [1, 3,4,5,6,7,8]. The majority of pregnant women who died of influenza-related illness during the pandemic were infected in the second and third trimesters of pregnancy [10]. Both seasonal and pandemic influenza virus have a substantial impact on the developing fetus. Several studies indicate that infants born to influenza virus-infected mothers have an increased risk of developing health problems later in life ranging from chronic immune diseases to schizophrenia [12, 13]

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