BALB/c mouse model of RSV clinical isolate A2001/2-20 pathogenesis

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.