Metabolic signature combined with changes in proteome and transcriptome shape respiratory syncytial virus infection and response to vaccination in a bovine model.

Abstract

Respiratory syncytial virus (RSV) is a major respiratory disease in infants leading to long-term morbidity. Bovine RSV (bRSV) serves as a clinically translatable large animal model to understand host responses in neonates to vaccination and re-infection enabling straightforward and accessible sample collection not often possible in human infants. This study probes clinically relevant bovine biointerfaces by combining Raman spectroscopy-based metabolic profiling with proteomics and gene expression in nasal fluid, serum, and lung tissues collected from 11 vaccinated (V) and 11 non-vaccinated (NV) neonatal calves following bRSV rechallenge. The analyses showed at Day 7 post-challenge, 16 significant Raman metabolite peaks in nasal fluid, 17 peaks in sera, and 17 peaks in lesioned lung tissue differentiated V from NV calves including features associated with glucose, lipids and fatty acids, and phenylalanine among others. We find that in NV calves systemic metabolic changes were greater than in the V group, and in an exploratory proteomic analysis of a subset of animals (n = 4/group), we identified a complement and innate immune protein signature in NV calves that aligned with metabolic features. In lesioned lung tissue, immune engagement between V and NV calves differed with changes observed in multiple metabolites that tightly correlated with gene expression and showed higher inflammatory cytokine gene expression (IL17A, IL6, IFNγ, IFNβ, IL8) in NV calves. Collectively, our data show an integrative approach enables a comprehensive molecular view of translationally relevant biointerfaces to understand vaccination and reinfection-associated host response. The outcomes of this study can be leveraged in the long-term to understand treatment response in human RSV.

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