Large-scale survey of the bovine upper-respiratory metatranscriptome underscores the complex etiology of bovine respiratory disease

Bovine respiratory disease (BRD) is a major burden to the cattle industry worldwide. It is a complex poly-microbial disease involving viruses, bacteria, and host stressors. In this study, we use publicly available metatranscriptome data from worldwide respiratory sample datasets to simultaneously investigate how the bovine nasal virome, microbiome, and host transcriptome are associated with disease. We detected fourteen BRD-associated virus species in the samples. Most of them, thirteen, were found in both healthy and diseased animals, and twelve of them were found in samples from at least two continents. Viral diversity and abundance differed significantly based on geographic location, and certain viral pairs co-occur non-randomly. Interestingly, some virus species were more abundant in healthy animals. When examining the bovine microbiome, differences in alpha diversity and beta diversity were observed when considering sampling location and disease state. Mannheimia spp. were detected more abundantly in animals with respiratory disease. Host gene expression analysis revealed that animals with respiratory disease have increased expression of immune effector genes and receptors involved in innate immunity and antiviral response, making host gene expression, and not a specific microbe, the best predictor of disease state in our samples. Our results underscore the complex nature of bovine respiratory disease and the fine balance between host mucosal immunity and respiratory microbial species.