Biology subjects

Gordon, S. V.

Publications and source records attributed to Gordon, S. V..

18 recordsLinked to original sources

bioRxiv2026

Comparative multi-omics of the macrophage response to infection with Mycobacterium tuberculosis complex bacteria reveals pathogen-driven epigenomic reprogramming

BackgroundBovine tuberculosis (bTB) is a chronic infectious disease primarily caused by Mycobacterium bovis, which inflicts significant economic losses on the global livestock industry worldwide and can also cause tuberculosis (TB) disease in other mammalian species, including humans. Alveolar macrophages are the host cells targeted by the pathogen during the early stages of infection. While they play a crucial role in controlling infection, the exact nature of the host-pathogen interaction and the genetic and epigenetic factors that modulate infection outcome remain poorly understood. ResultsHere, we used transcriptomics (RNA-seq), chromatin accessibility (ATAC-seq), and chromatin configuration (ChIP-seq) analyses to examine the effects of intracellular mycobacterial infection on the bovine alveolar macrophage (bAM) transcriptome and epigenome. The primary focus was M. bovis infection, but we also conducted parallel comparative analyses using M. tuberculosis (the primary cause of human TB--hTB), M. bovis BCG (the vaccine strain), and gamma-irradiated (killed) M. bovis. Integration of RNA-seq, ChIP-seq, and ATAC-seq data revealed coordinated remodelling of chromatin accessibility and histone modification landscapes underpinning transcriptional activation of key immune and metabolic pathways in response to infection. The identification of candidate genes, including ERBB4, LRCH1, MRTFA, and RNPC3, through integrative analysis with a genome-wide association study (GWAS) for M. bovis infection susceptibility underscores the functional relevance of these regulatory networks. ConclusionsOur results demonstrate that M. bovis drives extensive reprogramming of the bAM epigenome, distinct from the responses elicited by other members of the M. tuberculosis complex (MTBC). The results of this multi-omics comparison provide new insights into the function of pivotal response genes and support the hypothesis that pathogen-driven epigenetic reprogramming of the bovine host macrophage is key to M. bovis survival. It also identifies molecular targets that may inform genome-enabled breeding strategies to enhance resilience to bTB in cattle.

genomics↗

bioRxiv2025

Accurate and robust classification of Mycobacterium bovis-infected cattle using peripheral blood RNA-seq data

Bovine tuberculosis (bTB) remains recalcitrant to eradication in many endemic countries where current diagnostics are suboptimal. Mycobacterium bovis causes bTB and is closely related to Mycobacterium tuberculosis, which causes human tuberculosis (hTB). Although blood-based mRNA biomarkers identified through machine learning can discriminate hTB-positive from hTB-negative individuals, similar approaches have not been explored for bTB. Here, we use RNA-seq and machine learning to investigate the utility of blood mRNA as a host-response biomarker for bTB. We identify a 30-gene signature and a 273-gene elastic net classifier that differentiate bTB-positive from bTB-negative cattle, achieving area under the curve (AUC) values of 0.986/0.900 for the former and 0.968/0.938 for the latter in training and testing, respectively. Additionally, we show that these classifiers distinguish bTB-positive cattle from cattle infected with other microbial pathogens (AUC [≥] 0.819). These mRNA-based classifiers represent a promising tool for augmenting current diagnostics to advance global bTB eradication efforts.

genomics↗

bioRxiv2025

Genetic control of the transcriptional response to active tuberculosis disease and treatment

Understanding the functional impact of genomic sequence variants is critical for evaluating the role of genetic variation in the host response during tuberculosis (TB) disease and anti-TB treatment (ATT). Hitherto, there have been no genome-wide in vivo response expression quantitative trait loci (reQTL) studies conducted for active TB and ATT. Here, using longitudinal peripheral blood RNA-seq data from n = 48 patients with active TB who underwent ATT, we call sequence variants directly from these transcriptomes and impute them with a multi-ancestry reference panel. Associating our variants with the expression of nearby genes, we characterise thousands of cis-eQTL and hundreds of reQTL. We further show significant changes in cell type proportions during ATT through deconvolution of the bulk RNA-seq data and identify the putative cell type specific nature of cis-eQTL. Our work sheds light on the immunogenetics of TB disease and treatment, while providing a framework for studies using only RNA-seq data.

genetics↗

bioRxiv2024

Integrative genomics sheds light on the immunobiology of tuberculosis in cattle

Mycobacterium bovis causes bovine tuberculosis (bTB), an infectious disease of cattle that poses a zoonotic threat to humans. Research has shown that bTB susceptibility is a heritable trait, and that the peripheral blood (PB) transcriptome is perturbed during bTB disease. Hitherto, no study has integrated PB transcriptomic, genomic and GWAS data to study bTB disease, and little is known about the genomic architecture underpinning the PB transcriptional response to M. bovis infection. Here, we perform transcriptome profiling of PB from 63 control and 60 confirmed M. bovis infected animals and detect 2,592 differently expressed genes that perturb multiple immune response pathways. Leveraging imputed genome-wide SNP data, we characterise thousands of cis- and trans-expression quantitative trait loci (eQTLs) and show that the PB transcriptome is substantially impacted by intrapopulation genomic variation. We integrate our gene expression data with summary statistics from multiple GWAS data sets for bTB susceptibility and perform the first transcriptome-wide association study (TWAS) in the context of tuberculosis disease. From this TWAS, we identify 136 functionally relevant genes (including RGS10, GBP4, TREML2, and RELT) and provide important new omics data for understanding the host response to mycobacterial infections that cause tuberculosis in mammals.

genomics↗

bioRxiv2023

Integrative and comparative genomic analyses of mammalian macrophage responses to intracellular mycobacterial pathogens

Mycobacterium tuberculosis, the causative agent of human tuberculosis (hTB), is currently classed as the thirteenth leading cause of death worldwide. Mycobacterium bovis, a close evolutionary relative of M. tuberculosis, causes bovine tuberculosis (bTB) and is one of the most damaging infectious diseases to livestock agriculture. Previous studies have shown that the pathogenesis of bTB disease is comparable to hTB disease, and that the bovine and human alveolar macrophage (bAM and hAM, respectively) transcriptomes are extensively reprogrammed in response to infection with these intracellular mycobacterial pathogens. However, although M. bovis and M. tuberculosis share over 99% identity at the genome level, the innate immune responses to these pathogens have been shown to be different in human or cattle hosts. In this study, a multi-omics integrative approach was applied to encompass functional genomics and GWAS data sets across the two primary hosts (Bos taurus and Homo sapiens) and both pathogens (M. bovis and M. tuberculosis). Four different experimental infection groups were used, each with parallel non-infected control cells: 1) bAM infected with M. bovis, 2) bAM infected with M. tuberculosis, 3) hAM infected with M. tuberculosis, and 4) human monocyte-derived macrophages (hMDM) infected with M. tuberculosis. RNA-seq data from these experiments 24 hours post-infection (24 hpi) was analysed using three separate computational pipelines: 1) differentially expressed genes, 2) differential gene expression interaction networks, and 3) combined pathway analysis. The results of these analyses were then integrated with high-resolution bovine and human GWAS data sets to detect novel quantitative trait loci (QTLs) for resistance to mycobacterial infection and resilience to disease. Results from this study revealed common and unique response macrophage pathways for both pathogens and identified 32 genes (12 bovine and 20 human) significantly enriched for SNPs associated with disease resistance, the majority of which encode key components of the NF-{kappa}B signalling pathway and that also drive formation of the granuloma.

genomics↗

bioRxiv2022

High-resolution transcriptomics of bovine purified protein derivative-stimulated peripheral blood from cattle infected with Mycobacterium bovis across an experimental time course

ObjectivesImproved bovine tuberculosis (bTB) diagnostics with higher sensitivity and specificity are urgently required. A better understanding of the peripheral blood transcriptional response of Mycobacterium bovis-infected animals after bovine purified protein derivative (PPD-b) stimulation of whole blood--an important component of current bTB diagnostics--will provide new information for development of better diagnostics. MethodsRNA sequencing (RNA-seq) was used to study the peripheral blood transcriptome after stimulation with PPD-b across four time points (-1 wk pre-infection, and +1 wk, +2 wk, and +10 wk post-infection) from a 14-week M. bovis infection time course experiment with ten age-matched Holstein-Friesian cattle. ResultsIn vitro PPD-b stimulation of peripheral blood from M. bovis-infected and non-infected cattle elicited a strong transcriptional response. Comparison of PPD-b stimulated, and unstimulated samples revealed higher expression of genes encoding cytokine receptors, transcription factors, and interferon-inducible proteins. Lower expression was seen for genes encoding proteins involved in antimicrobial activity, C-type lectin receptors, inhibition of signal transduction, and genes encoding metal ion transporters. ConclusionsA transcriptional signature associated with the peripheral blood response to PPD-b stimulation consisting of 170 genes was identified exclusively in the post-infection time points. Therefore, this represents a panel of potential biomarkers of M. bovis infection.

genomics↗

bioRxiv2021

Macrophage Innate Training Induced by IL-4 Activation Enhances OXPHOS Driven Anti-Mycobacterial Responses

Macrophages are a highly adaptive population of innate immune cells. Polarization with IFN{gamma} and LPS into the "classically activated" M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, "alternatively activated" M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

immunology↗

bioRxiv2021

Mycobacterial infection of precision cut lung slices reveals that the type 1 interferon pathway is locally induced by Mycobacterium bovis but not M. tuberculosis in different cattle breeds

Tuberculosis exacts a terrible toll on human and animal health. While Mycobacterium tuberculosis (Mtb) is restricted to humans, Mycobacterium bovis (Mb) is present in a large range of mammalian hosts. In cattle, bovine TB (bTB) is a notifiable disease responsible for important economic losses in developed countries and underestimated zoonosis in the developing world. Early interactions that take place between mycobacteria and the lung tissue early after aerosol infection govern the outcome of the disease. In cattle, these early steps remain poorly characterized. The precision-cut lung slice (PCLS) model preserves the structure and cell diversity of the lung. We developed this model in cattle in order to study the early lung response to mycobacterial infection. In situ imaging of PCLS infected with fluorescent Mb revealed bacilli in the alveolar compartment, adjacent or inside alveolar macrophages (AMPs) and in close contact with pneumocytes. We analyzed the global transcriptional lung inflammation signature following infection of PCLS with Mb and Mtb in two French beef breeds: Blonde dAquitaine and Charolaise. Whereas lungs from the Blonde dAquitaine produced high levels of mediators of neutrophil and monocyte recruitment in response to infection, such signatures were not observed in the Charolaise in our study. In the Blonde dAquitaine lung, whereas the inflammatory response was highly induced by two Mb strains, AF2122 isolated from cattle in the UK and Mb3601 circulating in France, the response against two Mtb strains, H37Rv the reference laboratory strain and BTB1558 isolated from zebu in Ethiopia, was very low. Strikingly, the type I interferon pathway was only induced by Mb but not Mtb strains indicating that this pathway may be involved in mycobacterial virulence and host tropism. Hence, the PCLS model in cattle is a valuable tool to deepen our understanding of early interactions between lung host cells and mycobacteria. It revealed striking differences between cattle breeds and mycobacterial strains. This model could help deciphering biomarkers of resistance versus susceptibility to bTB in cattle as such information is still critically needed for bovine genetic selection programs and would greatly help the global effort to eradicate bTB.

immunology↗

bioRxiv2020

Phylodynamic analysis of an emergent Mycobacterium bovis outbreak in an area with no previously known wildlife infections

Understanding how an emergent pathogen successfully establishes itself and persists in a previously unaffected population is a crucial problem in disease ecology. In multi-host pathogen systems this problem is particularly difficult, as the importance of each host species to transmission is often poorly characterised, and the epidemiology of the disease is complex. Opportunities to observe and analyse such emergent scenarios are few. Here, we exploit a unique dataset combining densely-collected data on the epidemiological and evolutionary characteristics of an outbreak of Mycobacterium bovis (M. bovis, the causative agent of bovine tuberculosis, bTB) in a population of cattle and badgers in an area considered low-risk for bTB, that has no previous record of either persistent infection in cattle, or of any infection in wildlife. We analyse the outbreak dynamics using a combination of mathematical modelling, machine learning and Bayesian evolutionary analyses. Comparison to M. bovis whole-genome sequences from Northern Ireland confirmed this to be a single introduction of the pathogen from the latter region, with evolutionary analysis supporting an introduction directly into the local cattle population at least six years prior to its first discovery in badgers. Once introduced, the evidence supports M. bovis epidemiological dynamics passing through two phases, the first dominated by cattle-to-cattle transmission before becoming established in the local badger population. These findings emphasise the importance of disease surveillance for early containment of outbreaks, in particular for pathogens not causing immediately evident symptoms in the infected host, and highlight the utility of combining dynamic modelling and phylogenetic analyses for understanding the often complex infection dynamics associated with emergent outbreaks.

ecology↗

bioRxiv2020

Integrative genomics of the mammalian alveolar macrophage response to intracellular mycobacteria

Bovine tuberculosis (bTB), caused by infection with Mycobacterium bovis, is a major disease affecting cattle globally as well as being a zoonotic risk to human health. The key innate immune cell that first encounters M. bovis is the alveolar macrophage, previously shown to be substantially reprogrammed during intracellular infection by the pathogen. Here we use multi-omics and network biology approaches to analyse the macrophage transcriptional response to M. bovis infection and identify core infection response pathways and gene modules. These outputs were integrated with results from genome-wide associations of M. bovis infection to enhance the detection of putative genomic variants for disease resistance. Our results show that network-based integration of relevant transcriptomics data can extract additional information from large genome-wide associations and that this approach could also be used to integrate relevant functional genomics outputs with results from genomic association studies for human tuberculosis caused by the related Mycobacterium tuberculosis.

genomics↗

bioRxiv2020

Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation

The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. While Mycobacterium bovis (Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB, M. tuberculosis (Mtb) affects human populations and seldom causes disease in cattle. However, the host and pathogen determinants driving host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed both blood-derived primary human and bovine macrophages (hM{phi} or bM{phi}, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hM{phi} whereas both Mbv and Mtb efficiently replicate in bM{phi}. Specifically, we show that out of the four infection combinations, only the infection of bM{phi} with Mbv promoted the formation of multinucleated cells (MNCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bM{phi} promote macrophage multi-nucleation. Importantly, we extend our in vitro studies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNCs. Our findings implicate MNC formation in the contrasting pathology between Mtb and Mbv for the bovine host, and identify MPB70 from Mbv and extracellular vesicles from bM{phi} as mediators of this process.

microbiology↗

bioRxiv2020

Revisiting the expression signature of pks15/1 unveils regulatory patterns controlling phenolphtiocerol and phenolglycolipid production in pathogenic mycobacteria

One of the most relevant and exclusive characteristics of mycobacteria is its cell wall, composed by mycolic acids. Amid these are two related families of glycosylated lipids, diphthioceranates and phthiocerol dimycocerosate (PDIM) and its variant phenolic glycolipids (PGL). PGL have been associated with cell wall impermeability, phagocytosis, defence against nitrosative and oxidative stress and, supposedly, biofilm formation. In bacteria from the Mycobacterium tuberculosis complex, the biosynthetic pathway of the phenolphthiocerol moiety of PGL depends upon the expression of several genes encoding type I polyketide synthases (PKS), namely ppsA-E and pks15/1 constituting the PDIM + PGL locus, highly conserved in PDIM/PGL-producing strains. Consensus has not been achieved regarding the genetic organization of pks15/1 locus and little effort has been put on the disclosure of its transcriptional signature. Here we explore publicly available datasets of transcriptome data (RNA-seq) from more than 100 experiments in 40 growth conditions to outline the transcriptional structure and signature of pks15/1 and use a differential expression approach to infer the regulatory patterns involving these and related genes. We show that pks1 is highly correlated with fadD22, Rv2949c, lppX, fadD29 and, also, pks6 and pks12, with the first three putatively integrating a polycistronic structure. We evidence dynamic heterogeneity of transcription within the genes involved in phenolphtiocerol and phenolglycolipid production, most exhibiting up-regulation upon acidic pH and antibiotic exposure and down-regulation under hypoxia, dormancy, and low/high iron concentration. We finally propose a model based on transcriptome data in which {sigma}D positively regulates pks1, pks15 and fadD22, while {sigma}B and {sigma}E factors exert negative regulation at an upper level.

genomics↗

bioRxiv2019

Updated functional annotation of the Mycobacterium bovis AF2122/97 reference genome.

Mycobacterium bovis AF2122/97 is the reference strain for the bovine tuberculosis bacillus. We here report an update to the M. bovis AF2122/97 genome annotation to reflect 616 new protein identifications which replace many of the old hypothetical coding sequences and proteins of unknown function in the genome. These changes integrate information from functional assignments of orthologous coding sequences in the Mycobacterium tuberculosis H37Rv genome. We have also added 69 additional new gene names.

microbiology↗

bioRxiv2019

Alveolar macrophage chromatin is uniquely modified to orchestrate host response to Mycobacterium bovis infection

Mycobacterium bovis, the causative pathogen of bovine tuberculosis (bTB), induces extensive reprogramming of the macrophage transcriptome during infection. To identify key transcriptional changes in infected bovine alveolar macrophages (bAM), we have performed both gene expression (RNA-seq) and epigenomic (ChIP-seq) analyses using two key histone modification marks associated with activation (H3K4me3) and repression (H3K27me3). Together with RNA polymerase II (PolII) occupancy data, we show that reprogramming of the bAM transcriptome after M. bovis infection affects key immune response genes. Identification of these genes also facilitated integration of GWAS data, which identified genomic regions and SNPs significantly associated with resilience to infection with M. bovis in cattle.\n\nHighlightsO_LIComprehensive analysis of bovine alveolar macrophage (bAM) transcriptome and chromatin architecture revealed Mycobacterium bovis (M. bovis) induces genome-wide chromatin remodelling in bAM\nC_LIO_LIM. bovis induces transcriptional changes of immune response genes, associated with changes of histone modifications and RNA Polymerase II (PolII) occupancy\nC_LIO_LIGWAS integration of our ChIP study enabled the identification of important SNPs for bovine tuberculosis (bTB) susceptibility\nC_LI\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=69 SRC=\"FIGDIR/small/520098_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (19K):\norg.highwire.dtl.DTLVardef@1946689org.highwire.dtl.DTLVardef@1d7c0aborg.highwire.dtl.DTLVardef@1aa5c1forg.highwire.dtl.DTLVardef@1860ea5_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2018

RNA sequencing (RNA-seq) reveals extremely low levels of reticulocyte-derived globin gene transcripts in peripheral blood from horses (Equus caballus) and cattle (Bos taurus)

RNA-seq has emerged as an important technology for measuring gene expression in peripheral blood samples collected from humans and other vertebrate species. In particular, transcriptomics analyses of whole blood can be used to study immunobiology and develop novel biomarkers of infectious disease. However, an obstacle to these methods in many mammalian species is the presence of reticulocyte-derived globin mRNAs in large quantities, which can complicate RNA-seq library sequencing and impede detection of other mRNA transcripts. A range of supplementary procedures for targeted depletion of globin transcripts have, therefore, been developed to alleviate this problem. Here, we use comparative analyses of RNA-seq data sets generated from human, porcine, equine and bovine peripheral blood to systematically assess the impact of globin mRNA on routine transcriptome profiling of whole blood in cattle and horses. The results of these analyses demonstrate that total RNA isolated from equine and bovine peripheral blood contains very low levels of globin mRNA transcripts, thereby negating the need for globin depletion and greatly simplifying blood-based transcriptomic studies in these two domestic species.

genomics↗

bioRxiv2017

Comparative omics analyses differentiate Mycobacterium tuberculosis and Mycobacterium bovis and reveal distinct macrophage responses to infection with the human and bovine tubercle bacilli

Members of the Mycobacterium tuberculosis complex (MTBC) are the causative agents of tuberculosis in a range of mammals, including humans. A key feature of MTBC pathogens is their high degree of genetic identity, yet distinct host tropism. Notably, while Mycobacterium bovis is highly virulent and pathogenic for cattle, the human pathogen M. tuberculosis is attenuated in cattle. Previous research also suggests that host preference amongst MTBC members has a basis in host innate immune responses. To explore MTBC host tropism, we present in-depth profiling of the MTBC reference strains M. bovis AF2122/97 and M. tuberculosis H37Rv at both the global transcriptional and translational level via RNA-sequencing and SWATH mass spectrometry. Furthermore, a bovine alveolar macrophage infection time course model was employed to investigate the shared and divergent host transcriptomic response to infection with M. tuberculosis or M. bovis. Significant differential expression of virulence-associated pathways between the two bacilli was revealed, including the ESX-1 secretion system. A divergent transcriptional response was observed between M. tuberculosis and M. bovis infection of bovine alveolar macrophages, in particular cytosolic DNA-sensing pathways at 48 hours post-infection, and highlights a distinct engagement of M. bovis with the bovine innate immune system. The work presented here therefore provides a basis for the identification of host innate immune mechanisms subverted by virulent host-adapted mycobacteria to promote their survival during the early stages of infection.\n\nImportanceThe Mycobacterium tuberculosis complex (MTBC) includes the most important global pathogens for humans and animals, namely Mycobacterium tuberculosis and Mycobacterium bovis, respectively. These two exemplar mycobacterial pathogens share a high degree of genetic identity, but the molecular basis for their distinct host preference is unknown. In this work we integrated transcriptomic and proteomic analyses of the pathogens to elucidate global quantitative differences between them at the mRNA and protein level. We then integrated this data with transcriptome analysis of the bovine macrophage response to infection with either pathogen. Increased expression of the ESX-1 virulence system in M. bovis appeared a key driver of an increased cytosolic nucleic acid sensing and interferon response in bovine macrophages infected with M. bovis compared to M. tuberculosis. Our work demonstrates the specificity of host-pathogen interaction and how the subtle interplay between mycobacterial phenotype and host response may underpin host specificity amongst MTBC members.

systems biology↗

bioRxiv2017

Experimental infection of cattle with Mycobacterium tuberculosis isolates shows the attenuation of the human tubercle bacillus for cattle

The Mycobacterium tuberculosis complex (MTBC) is the collective term given to the group of bacteria that cause tuberculosis (TB) in mammals. It has been reported that M. tuberculosis H37Rv, a standard reference MTBC strain, is attenuated in cattle compared to Mycobacterium bovis. However, as M. tuberculosis H37Rv was isolated in the early 1930s, and genetic variants are known to exist, we sought to revisit this question of attenuation of M. tuberculosis for cattle by performing a bovine experimental infection with a recent M. tuberculosis isolate. Here we report infection of cattle using M. bovis AF2122/97, M. tuberculosis H37Rv, and M. tuberculosis BTB1558, the latter isolated in 2008 during a TB surveillance project in Ethiopian cattle. We show that both M. tuberculosis strains caused reduced gross and histopathology in cattle compared to M. bovis. Using M. tuberculosis H37Rv and M. bovis AF2122/97 as the extremes in terms of infection outcome, we used RNA-Seq analysis to explore differences in the peripheral response to infection as a route to identify biomarkers of progressive disease in contrast to a more quiescent, latent infection. Our work shows the attenuation of M. tuberculosis strains for cattle, and emphasizes the potential of the bovine model as a One Health approach to inform human TB biomarker development and post-exposure vaccine development.

immunology↗

bioRxiv2016

Updated reference genome sequence and annotation of Mycobacterium bovis AF2122/97

We report an update to the reference genome of the bovine tuberculosis bacillus Mycobacterium bovis AF2122/97 generated using an integrative multi- omics approach. Updates include 42 new CDS, 14 modified annotations, 26 SNP corrections, and disclosure that the RD900 locus, previously described as absent from the genome, is in fact present.

genomics↗