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bioRxiv · 10.1101/2020.07.18.200964

Respiratory Syncytial Virus Infections Induce Hypermetabolism in Pediatric Upper Airways

Rezinciuc, S.·Bezavada, L.·Bahadoran, A.·Ingels, J. F.·Kim, Y.-Y.·Cormier, S. A.·Shulkin, B. L.·Smallwood, H. S.
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Abstract

To determine whether respiratory syncytial virus (RSV) regulates human metabolism, we used positron emission tomography (PET) of patient lungs along with bioenergetics and metabolomics of patient upper airway cells and fluids. We previously found a significant negative monotonic relationship between glucose uptake and respiratory viral infection in 20 pediatric patients (e.g., 70% of infected patients had glucose uptake within 0-3 days). In our recent study, 3 out of 4 patients positive for glucose uptake at later times (>5 days) were positive for RSV infection. At present, the bioenergetics of upper respiratory cells (URCs) from nasal pharyngeal aspirates have not been investigated, and in vitro studies indicate RSV reduces metabolism in cell lines. To define metabolic changes in RSV-infected pediatric patients, we acquired fresh aspirates from 6 pediatric patients. Immediately following aspiration of URCs, we measured the two major energy pathways using an XFe flux analyzer. Glycolysis and mitochondrial respiration were significantly increased in URCs from RSV-infected patients, and mitochondrial respiration was operating at near maximal levels, resulting in loss of cellular capacity to increase respiration with impaired coupling efficiency. Metabolomics analysis of metabolites flushed from the upper airways confirmed a significant increase in TCA cycle intermediates. Taken together, these studies demonstrate RSV induces significant hypermetabolism in pediatric patients lungs and respiratory tract. Thus, hypermetabolism is a potential anti-viral drug target and reveals RSV can regulate human metabolism. Contributions to the fieldMetabolic changes in humans in response to viral infection are largely unknown. In this brief clinical report, we find metabolism is markedly increased in live upper respiratory cells from infants infected with respiratory syncytial virus (RSV) concomitant to changes in metabolites in their upper airway fluids. This sheds light on viral induced hypermetabolism in the airways and offers potential biomarkers for RSV. In addition, this identifies potential therapeutic targets for host directed therapies of aberrant metabolism in RSV. This work has clinical impact as biomarkers and therapeutics for RSV are needed for this pervasive virus that causes infections with long term consequence for some children. Further, advancements in molecular mechanisms underpinning RSV infection biology are constrained by the difficulties in translating model systems to humans as well as relating human studies in adults to infants (Mestas and Hughes, 2004; Papin et al., 2013).

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Rezinciuc, S., Bezavada, L., Bahadoran, A., Ingels, J. F., Kim, Y.-Y., Cormier, S. A., Shulkin, B. L., Smallwood, H. S.. 2020-07-18. Respiratory Syncytial Virus Infections Induce Hypermetabolism in Pediatric Upper Airways. https://doi.org/10.1101/2020.07.18.200964

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