Abstract
Bovine tuberculosis, caused by infection with members of the Mycobacterium tuberculosis complex, particularly Mycobacterium bovis, is a major endemic disease affecting cattle populations worldwide, despite the implementation of stringent surveillance and control programs in many countries. The development of high-throughput functional genomics technologies, including RNA sequencing, has enabled detailed analysis of the host transcriptome to M. bovis infection, particularly at the macrophage and peripheral blood level. In the present study, we have analysed the transcriptome of bovine whole peripheral blood samples collected at −1 week pre-infection and +1, +2, +6, +10, and +12 weeks post-infection time points. Differentially expressed genes were catalogued and evaluated at each post-infection time point relative to the −1 week pre-infection time point and used for the identification of putative candidate host transcriptional biomarkers for M. bovis infection. Differentially expressed gene sets were also used for examination of cellular pathways associated with the host response to M. bovis infection, construction of de novo gene interaction networks enriched for host differentially expressed genes, and time-series analyses to identify functionally important groups of genes displaying similar patterns of expression across the infection time course. A notable outcome of these analyses was identification of a 19-gene transcriptional biosignature of infection consisting of genes increased in expression across the time course from +1 week to +12 weeks post-infection.
Highlights
Bovine tuberculosis (BTB) is caused by Mycobacterium bovis and other intracellular bacterial pathogens of the Mycobacterium tuberculosis complex (MTBC), which display 99.9% DNA sequence identity at the genome level [1,2,3]
This yielded a mean of 15.4 ± 1.7 million filtered reads (91.5%) that uniquely mapped to this bovine genome build with a mean mapped length of 195.6 ± 0.6 bp; a mean of 0.77 ± 0.19 million reads (4.6%) that mapped to multiple genomic locations and 0.67 ± 0.17 million reads (3.9%) that did not map to any genomic location
In support of this, using RNA sequencing (RNA-seq), we have shown that CXCL8 increases in expression in bovine alveolar macrophages (AMs) infected with either M. tuberculosis or M. bovis across a 48-h time course [101]
Summary
Bovine tuberculosis (BTB) is caused by Mycobacterium bovis and other intracellular bacterial pathogens of the Mycobacterium tuberculosis complex (MTBC), which display 99.9% DNA sequence identity at the genome level [1,2,3]. Each member of the MTBC has a distinctive host spectrum, such that tuberculosis (TB) affects a wide range of mammals including humans [4]. Tuberculous mycobacteria—primarily M. bovis and M. tuberculosis, the main cause of human TB—are generally inhaled from the environment within aerosol droplets and are phagocytosed by host alveolar macrophages (AMs); infection is normally initiated within, and restricted to, lung tissues [12,13,14,15]. Tuberculous mycobacteria have evolved a wide range of mechanisms to modulate, suppress, and manipulate specific host immune mechanisms, including inhibition of phagosomal maturation, detoxification of reactive oxygen and nitrogen species (ROS and RNS), repair of ROS- and RNS-induced cellular damage, resistance to antimicrobial and cytokine defences, modulation of antigen presentation, and induction of cellular necrosis and inhibition of apoptosis [16,17,18,19]. The remaining intact mycobacterial cells are confined in granulomas that act to contain the infection, but may, under certain conditions, facilitate expansion and dissemination of mycobacteria to spread infection [20,21,22]
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