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.
Highlights
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in children under 5 years of age worldwide and is hallmarked by potentially life-threatening bronchiolitis and pneumonia [1, 2]
We feel the results of this study demonstrate that maternal RSV infection conveys lasting effects on postnatal offspring immunity, which coincide with elevated nerve growth factor (NGF) expression and airway smooth muscle contractility during recurrent early-life RSV LRTI
To determine if maternal infection with Red fluorescent protein-expressing recombinant RSV (rrRSV) impacts the development of postnatal offspring immunity during early-life rrRSV infections, we bred Fischer-344 rats and confirmed pregnancy through vaginal swabbing to time gestation
Summary
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in children under 5 years of age worldwide and is hallmarked by potentially life-threatening bronchiolitis and pneumonia [1, 2]. Strong epidemiologic evidence associates infant RSV LRTI with increased risk of wheezing episodes and asthma later in life [3,4,5,6,7,8]. Despite this relationship, the exact mechanisms by which early life RSV LRTI predispose to chronic airway dysfunction remain poorly understood. Chronic airway dysfunction developing after early-life RSV LRTI results from virusdriven modulation of local nerve growth factor (NGF) expression leading to increased neurotransmitters release and neuronal hyperreactivity [12,13,14]. The same study demonstrated the presence of a transplacental route of RSV transmission, the ability of this virus to infect fetal lower airway epithelium, and non-specific airway hyperreactivity (AHR) during postnatal RSV reinfection [15]
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