Ursolic acid moderates Th17-mediated immunity in respiratory syncytial virus infections of young cattle

Abstract

Abstract Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease in infants and young children. Bovine RSV is a common cause of respiratory disease in young cattle with high genetic and immunological similarity to human RSV, making it a relevant clinical model. While RSV is highly prevalent in both humans and cattle, the disease pathogenesis remains poorly understood and therapeutic options are limited. Th17-mediated immunity is intrinsically linked to RSV infections and characterized by the production of the inflammatory cytokine IL-17A; however, excessive IL-17 production may contribute to immunopathology by exacerbating neutrophil recruitment and activation in the lungs. Herein, we sought to elucidate the role of Th17-mediated immune responses by inhibiting Th17 cell differentiation with ursolic acid (UA), a small molecule agonist of the RORγt transcription factor. Calves were prophylactically treated with UA before being challenged with aerosolized bovine RSV. Challenged calves were monitored for clinical disease, gross and microscopic lung pathology, and immunologic responses in the periphery and respiratory tract. Local and systemic neutrophils and monocytes were analyzed for phagocytic and oxidative burst functions. Cellular adaptive immune responses were measured in the peripheral blood and airways by antigen recall assays. Our results suggest that UA-treatment may result in reduced RSV-associated immunopathology by shifting the immune response from Th17-mediated immunity to a more productive Th1-mediated immune response.