Metabolic Reprogramming of Nasal Airway Epithelial Cells Following Infant Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is a seasonal mucosal pathogen that infects the ciliated respiratory epithelium and results in the most severe morbidity in the first six months of life. RSV is a common cause of acute respiratory infection during infancy and is an important early-life risk factor strongly associated with asthma development. While this association has been repeatedly demonstrated, limited progress has been made on the mechanistic understanding in humans of the contribution of infant RSV infection to airway epithelial dysfunction. An active infection of epithelial cells with RSV in vitro results in heightened central metabolism and overall hypermetabolic state; however, little is known about whether natural infection with RSV in vivo results in lasting metabolic reprogramming of the airway epithelium in infancy. To address this gap, we performed functional metabolomics, 13C glucose metabolic flux analysis, and RNA-seq gene expression analysis of nasal airway epithelial cells (NAECs) sampled from infants between 2–3 years of age, with RSV infection or not during the first year of life. We found that RSV infection in infancy was associated with lasting epithelial metabolic reprogramming, which was characterized by (1) significant increase in glucose uptake and differential utilization of glucose by epithelium; (2) altered preferences for metabolism of several carbon and energy sources; and (3) significant sexual dimorphism in metabolic parameters, with RSV-induced metabolic changes most pronounced in male epithelium. In summary, our study supports the proposed phenomenon of metabolic reprogramming of epithelial cells associated with RSV infection in infancy and opens exciting new venues for pursuing mechanisms of RSV-induced epithelial barrier dysfunction in early life.

White Spot Syndrome Virus Triggers a Glycolytic Pathway in Shrimp Immune Cells (Hemocytes) to Benefit Its Replication

“…Furthermore, the glycolytic flux may have subsequently entered the TCA cycle, as the citrate (Cit) and isocitrate (Ict) were both increased 30 min after tracer injection ( Figures 5A, B ). Respiratory syncytial virus (RSV) infection caused a greater glycolytic flux being dedicated to the pentose phosphate pathway and TCA cycle ( 41 ). The fate of glycolysis differed in hepatitis B virus (HBV) infection; in that case, glucose was incorporated into the pentose phosphate pathway and hexosamine biosynthesis rather than TCA cycle ( 42 ).…”

Viral genetic determinants of prolonged respiratory syncytial virus infection among infants in a healthy term birth cohort

“…It is also possible that strains harbouring G protein p.E123K/D and p.P218T/S/L variants are cleared more slowly and foster an immune environment of low-level chronic stimulation or exhaustion. We previously demonstrated that infants infected with RSV in their first year of life have dampened subsequent antiviral immune responses in early childhood [49] as well as changes in airway epithelial cell metabolism [34].…”

“…It is possible that strains harbouring G protein p.E123K/D and p.P218T/S/L variants are cleared more slowly and foster an immune environment of low-level chronic stimulation or exhaustion. We previously demonstrated that infants infected with RSV in their first year of life have dampened subsequent antiviral immune responses in early childhood [36] as well as changes in airway epithelial cell metabolism [37]. Altered immune responses are expected in extended infections by G protein variant strains [35], and we observed differences in the acute antiviral response between subjects with resolved and prolonged infection, specifically increased levels of types 1 and 2 IFN in nasal secretions; however, we could not make causal inference about variant sequences because of confounding by co-linearity of these polymorphisms with RSV antigenic group.…”

“…As infant RSV infection stimulates an acute antiviral response and also results in decreased barrier function of the airway epithelium [34], we tested for association between host interferon (IFN) response and the amino acid (REF/ALT) identified as the viral variant associated with prolonged infection. A Wilcoxon test was performed to compare IFN- γ , and IFN- α , between RSV amino acid positions, with adjustment for the same covariates as in the main analysis.…”

RELA∙8-Oxoguanine DNA Glycosylase1 Is an Epigenetic Regulatory Complex Coordinating the Hexosamine Biosynthetic Pathway in RSV Infection

“…More recently, it has been observed that RSV replication upregulates glucose influx, induces aerobic glycolysis and increases lactic acid generation in epithelial cells. These metabolic adaptations may aid in enhanced nucleoside synthesis and energy needs for viral replication [ 25 , 26 ]. We have extended this work with our finding that RSV infection induces the hexosamine biosynthetic pathway (HBP) [ 16 ].…”