The impact of viral genotype on pathogenesis and disease severity: respiratory syncytial virus and human rhinoviruses

Abstract

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRI) and viral death in infants. RSV disease in infants is characterized by epithelial desquamation, neutrophilic bronchiolitis and pneumonia and obstructive pulmonary mucus. Human rhinoviruses (HRVs) are by far the most common cause of symptomatic upper respiratory tract infection (URI) in people and are more recently appreciated as a significant cause of LRI. RSV and HRV are also implicated in asthma pathogenesis. Within both RSV and HRV, viral genetic differences play a role in disease severity and/or prevalence in patient populations, and viral genetic differences affect pathogenesis. Here, we review data on how viral genetic differences impact disease using RSV and HRV as examples, including effects on the host immune response. Virus genotype–phenotype relationships can be exploited in the laboratory to gain insight into mechanisms by which respiratory viruses modulate host immune responses and cause disease.

Figure 1

Working model of RSV strain-specific induction of airway mucin expression. (A) Electron micrograph of RSV exhibiting glycoprotein spikes. The sample was cell-free supernatant from RSV A2-infected primary human airway epithelial cells processed for negative staining. The RSV fusion (F) protein is a major spike protein necessary for virus fusion to target cells and for cell-cell fusion in the formation of syncytia. Recent work showed the “mucogenic” strain 2-20 F protein is capable of enhanced fusion compared to the laboratory A2 strain F protein [•43]. (B) Enhanced fusion correlates with the ability to infect the mouse airway epithelium. RSV strain 2-20 infects the BALB/c mouse airway epithelium, resulting in early necrotic cell debris in the airways as well as lung neutrophils [42, •43]. (C) Six days post-infection witih mucogenic RSV 2-20, IL-13-expressing CD4+ T cells are found in the lung [•43]. IL-13 plays a critical role in airway mucin induction by both RSV strains line 19 and 2-20 [35, 42]. (D) Robust PAS+ airways day 8 post-infection in lungs of a mouse infected with RSV 2-20. Digitized H&E-stained section as described [42]. Depletion of neutrophils results in signficantly fewer IL-13-expressing CD4+ T cells in the lung and less airway mucin expression, although the mechanism by which neutrophils promote T_H2 cytokine expression and mucus are unknown.