Severity of bovine tuberculosis is associated with innate immune-biased transcriptional signatures of whole blood in early weeks after experimental Mycobacterium bovis infection

Authors: WIARDA, JAYNE - Orise Fellow; Boggiatto, Paola; Bayles, Darrell; WATERS, RAY - Retired Non ARS Employee; Thacker, Tyler; Palmer, Mitchell

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/16/2020
Publication Date: 11/9/2020
Citation: Wiarda, J.E., Boggiatto, P.M., Bayles, D.O., Waters, R.W., Thacker, T.C., Palmer, M.V. 2020. Severity of bovine tuberculosis is associated with innate immune-biased transcriptional signatures of whole blood in early weeks after experimental Mycobacterium bovis infection. PLoS ONE. 15(11). https://doi.org/10.1371/journal.pone.0239938.
DOI: https://doi.org/10.1371/journal.pone.0239938

Interpretive Summary: Mycobacterium bovis is the primary causative agent of bovine tuberculosis and is capable of infecting humans, resulting in zoonotic tuberculosis. The global burden due to its impact on both animal and human health is staggering, with an estimated 50 million cattle infected and a financial loss of $3 billion annually. Improving our understanding of the host immune response to infection with M. bovis would facilitate the development of much needed diagnostics and therapeutic interventions, including vaccines. In this manuscript, we utilized RNA sequencing in order to obtain global information regarding the immune response to M. bovis infection from whole blood samples. Our data demonstrates a specific pattern of gene expression in animals with clinical disease, which correlates to active tuberculosis in humans, which, to our knowledge, has not previously been show before in cattle. This work will be of interest to scientists, regulatory personnel, and producers as a safe approach to the control of animal tuberculosis.

Technical Abstract: Worldwide, bovine tuberculosis is a disease that impacts both animal and human health alike. Consequently, there is a need to improve understanding of disease dynamics, identification of infected animals, and characterization of immune that result in protection. The goal of this study was to assess transcriptional changes occurring in early weeks following experimental Mycobacterium bovis infection in cattle. Analysis of RNA-sequencing data from whole blood revealed two distinct transcriptional clusters of infected cattle at both 4- and 10-weeks post-infection. Transcriptional clustering of infected animals correlated with disease severity, with cattle more transcriptionally divergent from uninfected cohorts exhibiting more severe disease. At 4-weeks post-infection, 25 genes were commonly upregulated in both infected clusters of cattle compared to uninfected cohorts; however, by 10-weeks post-infection, differential gene expression could only be observed when comparing more severely affected cattle to those uninfected, indicating transcriptional divergence of the two infected clusters of cattle over time. Biological processes and cell type enrichment analyses revealed overrepresentation of innate immune-related processes and cell types in infected animals, with overrepresentation being of greater magnitude in cattle with more severe disease. Collectively, our findings indicate two distinct transcriptional profiles occur in cattle following M. bovis infection, corresponding to clinical manifestation of disease and innate immune biases.