Ingels, J. F. | Search bioRxiv

bioRxiv2020

Respiratory Syncytial Virus Infections Induce Hypermetabolism in Pediatric Upper Airways

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).

systems biology↗

bioRxiv2019

Modulation of longevity by diet, and youthful body weight, but not by weight gain after maturity

Diet and environment profoundly modulate lifespan. We measured longevity as a function of diet and weight gain across a genetically diverse family of mice. We followed 1348 females from two parental strains--C57BL/6J and DBA/2J--and 146 cohorts of BXD isogenic progeny strains (n = 73) across their lifespan on a low fat chow diet (CD, 18% calories from fat) and on a high fat diet (HFD, 60% calories from fat). On average, HFD shortens lifespan by 85 days or 12%, roughly equivalent to an 8-10 year decrease in humans. However, strain variation in the response of diet on longevity is remarkably high, ranging from a longevity loss of 54% in BXD65 to a gain of 37% in BXD8. Baseline weights and early weight gain are both associated with a mean decrease in longevity of [~]4 days/g. By 500 days-of-age, cases fed HFD gained four times as much weight as control on average. However, strain-specific variation was substantial, thus weight gain did not correlate well with lifespan. In summary, high fat had a strong negative effect on longevity, but genetic interactions effects were even stronger. This highlights the unequivocal importance of genetic differences in making dietary recommendations.

genetics↗

bioRxiv2019

The expanded BXD family of mice: A cohort for experimental systems genetics and precision medicine

The challenge of precision medicine is to model complex interactions among DNA variants, sets of phenotypes, and complex environmental factors and confounders. We have expanded the BXD family, creating a powerful and extensible test bed for experimental precision medicine and an ideal cohort to study gene-by-environmental interactions.\n\nThese BXD segregate for over 6 million variants, with a mean minor allele frequency close to 0.5. We have increased the family two-fold to 150 inbred strains, all derived from C57BL/6J and DBA/2J. We have also generated updated and comprehensive genotypes and an unrivaled deep phenome.\n\nApproximately 10,000 recombinations have been located, allowing precision of quantitative trait loci mapping of {+/-}2.0 Mb over much of the genome and {+/-}0.5 Mb for Mendelian loci. The BXD phenome includes more than 100 omics data sets and >7000 quantitative and clinical phenotypes, all of which is publicly available.\n\nThe BXD family is an enduring, collaborative, and replicable resource to test causal and mechanistic links between genomes and phenomes at many stages and under a wide variety of treatments and interventions.

genomics↗