Prenatal Exposure to Respiratory Syncytial Virus Alters Postnatal Immunity and Airway Smooth Muscle Contractility during Early-Life Reinfections

Abstract

Maternal viral infections can have pathological effects on the developing fetus which last long after birth. Recently, maternal-fetal transmission of respiratory syncytial virus (RSV) was shown to cause postnatal airway hyperreactivity (AHR) during primary early-life reinfection; however, the influence of prenatal exposure to RSV on offspring airway immunity and smooth muscle contractility during recurrent postnatal reinfections remains unknown. Therefore, we sought to determine whether maternal RSV infection impairs specific aspects of cell-mediated offspring immunity during early-life reinfections and the mechanisms leading to AHR. Red fluorescent protein-expressing recombinant RSV (rrRSV) was inoculated into pregnant rat dams at midterm, followed by primary and secondary postnatal rrRSV inoculations of their offspring at early-life time points. Pups and weanlings were tested for specific lower airway leukocyte populations by flow cytometry; serum cytokine/chemokine concentrations by multiplex ELISA and neurotrophins concentrations by standard ELISA; and ex vivo lower airway smooth muscle (ASM) contraction by physiological tissue bath. Pups born to RSV-infected mothers displayed elevated total CD3+ T cells largely lacking CD4+ and CD8+ surface expression after both primary and secondary postnatal rrRSV infection. Cytokine/chemokine analyses revealed reduced IFN-γ, IL-2, IL-12, IL-17A, IL-18, and TNF-α, as well as elevated nerve growth factor (NGF) expression. Prenatal exposure to RSV also increased ASM reactivity and contractility during early-life rrRSV infection compared to non-exposed controls. We conclude that maternal RSV infection can predispose offspring to postnatal lower airways dysfunction by altering immunity development, NGF signaling, and ASM contraction during early-life RSV reinfections.

Respiratory syncytial virus seropositivity at birth is associated with adverse neonatal respiratory outcomes

“…Determining outcomes originating from maternal symptoms occurring in the first or second trimester would be difficult to discern, but findings in our rat model suggest that the implications for the fetus and offspring could be more severe due to the induction of immune tolerance by exposure to viral antigens during the pre-immune phase of ontogenesis. 34 Indeed, other congenital infections occurring during fetal development are known to induce immune tolerance or altered immune response. 35,36 Another novel and important finding of this study is that newborns with evidence of prenatal RSV exposure tend to have adverse…”

Effects of maternal−fetal transmission of viruses and other environmental agents on lung development

“…Until our 2013 publication proposing for the first time that RSV could spread hematogenously from the infected airways of a pregnant mother to the lungs of her unborn child via the placenta (4), it was universally accepted that fetal lungs were protected from maternal respiratory infections during gestation. Since then, our research has provided proof of concept that this central axiom of respiratory medicine (the "sterile womb dogma") is incorrect, first using cellular and animal models (4)(5)(6) and more recently also with human studies (7).…”

Detection of respiratory syncytial virus (RSV) at birth in a newborn with respiratory distress

“…6 Expanding on these findings, RSV has been shown recently to spread across the rodent placenta from the respiratory tract of an infected dam to the lungs of the fetus. [7][8][9] However, so far vertical transmission of this virus has been demonstrated in animal models, but never in humans. Herein, we describe a case of RSV infection documented at birth in the peripheral blood of a human newborn with onset of severe respiratory distress immediately after delivery from a mother with serological and clinical evidence of RSV infection during pregnancy.…”