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Asthma is an airway inflammatory disease that is mediated by T effector (Teff) cells, specifically Th2 and Th17 cells. As disease increases in severity, there is a shift towards a higher Th17 response. Treatment of asthmatic patients include the use of glucocorticoid (GC) steroids. These drugs are effective at controlling inflammation in mild cases but as disease severity increases towards neutrophilic disease there is resistance by Th17 cells to effects of the drugs. A key therapeutic objective is to identify either alternative treatments for asthma or targets that make Th17 cells more susceptible to GCs. Studies have shown cells which have increased glycolysis and oxidative phosphorylation are more resistant to the effects of GCs. In this study we show, that in the murine model of airway inflammation there are differences in the expression of metabolic proteins between Th2 and Th17 cells that are present in the lung. This has been seen in cells that have higher amounts glucose uptake. These results imply that the higher glucose utilization of Th17 cells and their metabolic flexibility may contribute to their resistance to the effects of GCs. We also show by CyTOF of PBMCs that individuals with asthma have increased expression of metabolic associated proteins compared to control individuals in their CD4 cells. These data support the metabolic shift observed in our in vitro studies.

Airway mucus is a hallmark of respiratory syncytial virus (RSV) lower respiratory tract illness. Laboratory RSV strains (A2, Long, and Line 19) differentially induce airway mucus production in mice. We tested whether RSV strains differ in pathogenesis by screening low passage RSV clinical isolates for mucogenicity and virulence in BALB/c mice. RSV clinical isolates induced variable disease severity. Infection of BALB/c mice with clinical isolate RSV A2001/2-20 (2-20) resulted in greater disease severity and higher lung IL-13 levels than infection with RSV laboratory strains and other clinical isolates. Like the line 19 strain, 2-20 induced airway mucin expression in BALB/c mice and resulted in higher viral antigen levels in the bronchiolar epithelium than A2. 2-20 caused epithelial desquamation, airway hyperresponsiveness, and increased breathing effort in BALB/c mice. We hypothesize that the fusion (F) protein of 2-20 contributes to this phenotype. We generated a chimeric RSV by replacing the F gene of A2 with the F gene of 2-20. A2-2-20F grew to similar levels as 2-20 in mouse and human cells in vitro. In BALB/c mice, the A2-2-20F exhibited viral loads similar to 2-20 over a time course and showed comparable mucin levels to 2-20. We established a mouse model of clinical isolate strain-dependent RSV pathogenesis that recapitulates key features of RSV disease. Identification of virulence factors of RSV 2-20 may contribute to our understanding of RSV disease mechanisms.