Comparative ‘omics analyses differentiateMycobacterium tuberculosisandMycobacterium bovisand reveal distinct macrophage responses to infection with the human and bovine tubercle bacilli

Abstract

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.ImportanceThe 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.

Transcriptomic Profiles of Monocyte-Derived Macrophages in Response to Escherichia coli is Associated with the Host Genetics

“…The next step was to investigate if the NO-based classification can represent any characteristics beyond the oxidative burst ability of macrophages. It has been shown previously that transcriptomic network of macrophages in conjunction with in-silico analysis can be employed to predict the characteristic and proinflammatory status of macrophages 24,29,30 . Therefore, in the current study, the whole transcriptome of MDMs with opposite NO-based phenotypes was compared during the response to E. coli to identify differentially regulated intra-cellular mechanisms and also to investigate if the DE genes be associated with in-silico-predicted functional characteristics of MDMs.…”

Animal tuberculosis: impact of disease heterogeneity in transmission, diagnosis, and control

“…WGS enables the statistic association of newly reported SNPs, insertions and deletions that may explain certain virulence phenotypes, but also the calculation of indicators of selective pressure exerted on specific virulence genes (Abdelaal et al, 2019; Cheng et al, 2018; Hauer et al, 2019). Besides, virulence phenotype–genotype associations can also be inferred by transcriptomic profiling and differential expression analysis in different strains (Malone et al, 2018).…”

Exploring the zoonotic potential of Mycobacterium bovis using variant calling approaches

“…M.bovis is also zoonotic and can spread from animals to humans, is an identi ed public health problem globally and is also known to have intrinsic drug resistance towards several drug molecules [5][6][7][8]. M.bovis infection in humans is identical with that of M.tuberculosis infection, differing only in being non-transmissible among immunocompetent hosts [7,9]. Infection due to M.bovis, causing Bovine Tuberculosis (BTB) is recognized as a One Health problem in certain parts of the globe where cattle-oriented domestication is practised.…”