Alternative mechanisms for respiratory syncytial virus (RSV) infection and persistence: could RSV be transmitted through the placenta and persist into developing fetal lungs?

Abstract

Purpose of review: Respiratory syncytial virus (RSV) represents the most common respiratory pathogen observed worldwide in infants and young children and may play a role in the inception of recurrent wheezing and asthma in childhood. We discuss herein the recent hypothesis that RSV vertically transmitted from the mother to the fetus in utero causes persistent structural and functional changes in the developing lungs of the offspring, thereby predisposing to postnatal airway obstruction.

Recent findings: A number of observations in humans support the notion that extrapulmonary tissues may be infected hematogenously by RSV and harbor this virus allowing the persistence of latent infection. More recent data from animal models suggest that RSV can be transmitted across the placenta from the respiratory tract of the mother to that of the fetus, and persist in the lungs both during development, as well as during adulthood. Vertical RSV infection is associated with dysregulation of crucial neurotrophic pathways during ontogenesis, leading to aberrant parasympathetic innervation and airway hyperreactivity after postnatal reinfection.

Summary: These new data challenge the current paradigm that acquisition of RSV infection occurs only after birth and shift attention to the prenatal effects of the virus, with the potential to result in more severe and lasting consequences by interfering with crucial developmental processes. The most immediate implication is that prophylactic strategies targeted to the mother-fetus dyad may reduce the incidence of postviral sequelae like childhood wheezing and asthma.

Figure 1. RSV detection in naïve human BMSC

Eleven primary human BMSC lines derived from pediatric or adult donors were screened by RT-PCR using primers specific for the nucleocapsid (N) protein of RSV. Five of the 8 adult-derived BMSC lines (63%) and all 3 children-derived ones (100%) yielded a 380 bp product (top) whose sequence shared > 95% homology with the RSV genome (bottom). Homologous base pairs are marked by asterisks.

Figure 2. Propagation of vertically transmitted RSV

Magnified at 60×, extracts of whole fetuses are shown that were delivered from dams inoculated with recombinant RSV (rrRSV; bottom row) or from pathogen-free controls (top row) and co-cultured with human airway epithelial cells. The micrographs show red fluorescence in the cytoplasm of cells exposed to fetal extracts from rrRSV-infected dams, confirming the presence of actively replicating infectious virus associated with markedly increased green nerve growth factor (NGF) immunoreactivity.

Figure 3. Innervation of RSV-infected fetal airways

Confocal microscopy showing acetylcholine immunoreactivity (green) in the subepithelial neural plexus lining the lumen of fetal airways exposed in utero to RSV (asterisks). As a consequence, when pups delivered from RSV-infected dams were reinfected postnatally (group R+R) their airways became significantly hyperresponsive to electrical field stimulation of cholinergic nerves. In contrast, airway responses from pathogen-free pups delivered from pathogen-free dams (group C+C) were not affected by either prenatal (group R+C) or postnatal RSV infection (group C+R).

Figure 4. Fetal programming of asthmatic airways

What makes our lungs prone to develop disease? Of course, genetic traits inherited from our parents are important role. But also the quantity and quality of food our mother eats, the pollution in the air she breathes, the infections she suffers during gestation will play a critical role throughout our life, perhaps even more important than genetics. In particular, prenatal events like the intrauterine exposure to viruses with specific tropism for the developing respiratory epithelium will cause a shift in the trajectory of structural and functional airway development toward a hyperreactive phenotype. The resulting neonatal phenotype may predispose the child to aberrant responses to common respiratory infections and airborne irritants, thereby increasing the risk of obstructive lung disease later in life. Postnatal events, such as exposure to indoor and outdoor pollutants and allergens, can further shift the equilibrium of the adult phenotype by exacerbating airway inflammation and hyperreactivity.