Respiratory syncytial virus (RSV) is a leading cause of severe acute lower respiratory tract infection in infants and children worldwide. Severe RSV bronchiolitis as a child is also a critical risk factor in the development of wheezing and allergic asthma later in life. Bovine RSV (BRSV) is closely related to human RSV and a significant cause of morbidity in young cattle. BRSV infection in calves displays many striking similarities to HRSV infection in humans, and cattle are an outbred population that is naturally susceptible to BRSV infection. Further, calves with severe BRSV infection are also prone to the development of virus-associated allergic airway disease, thus mimicking the association between RSV bronchiolitis and development of allergic asthma that is observed in humans. Therefore, BRSV infection in calves represents an excellent model for studying RSV infection, antiviral immunity and the development of virus-associated allergic airway disease in children. Interleukin-17A (IL-17) is an inflammatory cytokine that plays an important role in neutrophil recruitment and activation. It is primarily produced by activated CD4 T cells, termed Th17 cells, and activated gamma delta T cells. IL-17 is increased in children and rodents with severe RSV infection; and in calves with severe BRSV infection. Reports from mice about the role of IL-17 during RSV infection are contradictory, and studies from humans are limited and primarily correlative; therefore, it is currently unclear if IL-17 and Th17 immunity is beneficial or detrimental to the host during RSV infection or during the development of RSV-associated allergic airway disease. The neonatal calf represents a tractable model of the infant immune system, and is a natural host for BRSV that closely mimics critical aspects of disease pathogenesis and immunity in humans with RSV. Therefore, the calf is an ideal model for determining the effect of IL-17 on RSV disease. The experiments in Aim 1 are designed to determine how pharmacologic inhibition of IL-17 production effects disease outcome and immunity during uncomplicated BRSV infection in the neonatal calf. The experiments in Aim 2 are designed to determine how inhibition of IL-17 production effects the development of RSV-associated allergic airway disease in the neonatal calf. Much of our knowledge of RSV infection and immunity stems from studies in rodents and adult animals; however, the experiments proposed here will study a natural host-pathogen interaction and will examine the response in the neonate, the same population commonly targeted by severe disease. It is anticipated that these studies will have a positive impact by identifying a role for IL-17 in protecting or harming the host during severe RSV infection, and by identifying IL-17 and Th17 responses as possible targets for the development of therapeutic intervention strategies to be used in patients with severe RSV bronchiolitis.
Respiratory syncytial virus (RSV) is a leading cause of severe acute lower respiratory tract infection in infants and children worldwide. Severe RSV infection as a child is also a significant risk factor for development of wheezing and allergic airway disease later in life. These studies will use the natural host-pathogen model of bovine RSV infection in neonatal calves to determine the role of Interleukin-17 on disease pathogenesis and immunity during RSV infection, and on the development of virus-associated allergic airway disease.
