Systemic Dysregulation Of Cellular Immune Responses To H1n1 Infection During Pregnancy

Abstract The 2009 H1N1 flu pandemic demonstrated that pregnant women infected with influenza were at risk for severe respiratory distress and premature-rupture-of-membranes (PROM), leading to high incidence of hospitalization, preterm births and small for gestation age (SGA) neonates. We utilize a syngeneic BALB/c pregnant mouse model which recapitulates clinical phenotypes shown during influenza infection of pregnant women. Pregnant mice sublethally infected (0.5xLD50) with pandemic H1N1 A/California/07/09 showed higher viral titers and delayed viral clearance relative to non-pregnant mice, and increased incidence of stillbirths and SGA offspring. Lymphocytes isolated at days 7 and 14 from lungs and spleens of infected pregnant and non-pregnant female mice were analyzed for H1N1 A/Ca/07/09 specific IL-4 and IFN-γ responses. Pregnancy delayed influenza-specific cytokine secretion at the site of infection, indicating systemic dysregulation of anti-viral responses. Lymphocytes from draining mediastinal lymph nodes, spleens and lungs were used to quantify activation of B cells in germinal centers (GC), maturation into antibody secreting cells and memory B cells, and mucosal homing to lung tissue following infection. Pregnancy decreased maturation of GC+ B cells in the spleen and migration of plasma cells from the spleen to the lungs. Infected pregnant mice generated equivalent serum influenza-specific neutralizing antibody titers and increased IgA antibody secreting cells (ASC) in the lungs 6 weeks post-infection relative to infected non-pregnant mice, indicating a potential role in pregnancy favoring the development of mucosal immunity in response to prolonged viral exposure.