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

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.

Reproductive performance of pandemic influenza A virus infected sow herds before and after implementation of a vaccine against the influenza A (H1N1)pdm09 virus

“…Furthermore, the pathogenesis of reproductive disorders subsequent to infection with IAV is not definitively determined. Alterations of the maternal immune system during pregnancy can result in an increased likelihood of influenza virus infection [22]. The few studies examining the effect of infection with IAV during pregnancy were conducted mainly with rodent models [22,23].…”

“…Alterations of the maternal immune system during pregnancy can result in an increased likelihood of influenza virus infection [22]. The few studies examining the effect of infection with IAV during pregnancy were conducted mainly with rodent models [22,23]. Thus, interpretation of these studies is hampered by histological dissimilarities of the rodent placenta and the of swine placenta [24].…”

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

“…Pregnant mouse models, including syngenic mating between like strains of mice and allogenic mating between different strains of mice, yield insights into the altered influenza pathogenesis in pregnant hosts. Reduced viral clearance and eightfold higher viral titers characterize the lungs of syngeneic and allogenic pregnant mice infected during mid-gestation, with allogenic-mated mice showing more severe disease caused by fetal tolerance (van Riel et al 2016;Engels et al 2017;Littauer et al 2017). Increased disease severity is not strain-specific; increased viral loads are observed with influenza B-infected pregnant mice as well (Kim et al 2014).…”

Chronic exposure to arsenite enhances influenza virus infection in cultured cells

“…According to the World Health Organization (WHO), global influenza infection rates range from 1% to 15% every year, resulting in 3‐5 million hospitalizations and approximately 250,000‐500,000 deaths (Fischer, Gong, Bhagwanjee, & Sevransky, ; WHO, ). Several factors, including age extremes, pregnancy and pre‐existing medical conditions, can increase incidence and severity of influenza infection (Kunisaki & Janoff, ; Littauer et al, ; Peltola, Ziegler, & Ruuskanen, ; Ruf & Knuf, ; Whitley & Monto, ).…”