Abstract
We have shown that respiratory syncytial virus (RSV) can spread hematogenously from infected airways of a pregnant woman to the developing fetal lungs in utero. This study sought to measure RSV replication, cytopathic effects, and protein expression in human lung organoids (HLOs) reproducing architecture and transcriptional profiles of human fetal lungs during the 1st trimester of gestation. HLOs derived from human pluripotent stem cells were microinjected after 50 or 100 days in culture with medium or recombinant RSV-A2 expressing the red fluorescent protein gene (rrRSV). Infection was monitored by fluorescent microscopy and PCR. Immunohistochemistry and proteomic analysis were performed. RSV infected HLOs in a dose- and time-dependent manner. RSV-infected HLOs increased expression of CC10 (Club cells), but had sparse FOXJ1 (ciliated cells). Disruption of F-actin cytoskeleton was consistent with proteomic data showing a significant increase in Rho GTPases proteins. RSV upregulated the transient receptor potential vanilloid 1 (TRPV1) channel and, while β2 adrenergic receptor (β2AR) expression was decreased overall, its phosphorylated form increased. Our data suggest that prenatal RSV infection produces profound changes in fetal lungs’ architecture and expression profiles and maybe an essential precursor of chronic airway dysfunction. expression profiles, and possibly be an important precursor of chronic airway dysfunction.
Highlights
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, with nearly every child being infected by 2 years of age during seasonal outbreaks occurring worldwide in winter months [1]
Previous data have shown that human lung organoids (HLOs) grown under the same conditions described were assessed for transcriptional activity by publicly available RNAseq datasets compared to human fetal lungs representing a range of gestational stages
We show that these HLOs using the protocols outlined in the Method section replicated the 3D architecture and cell composition of human lungs, including ciliated, epithelial, mesenchymal, goblet and Club cells (Fig 1)
Summary
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, with nearly every child being infected by 2 years of age during seasonal outbreaks occurring worldwide in winter months [1]. Because of the limited duration and strength of the anamnestic immune response to this virus, RSV infections recur. RSV infection of human fetal lungs 3D organoids study design, data collection and analysis, decision to publish, or preparation of the manuscript
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