Relationship of bovine &lt;i&gt;NOS2&lt;/i&gt; gene polymorphisms to the risk of bovine tuberculosis in Holstein cattle

Cheng, Yafen; Huang, Chenshen; Tsai, Hsiang‐Jung

doi:10.1292/jvms.15-0295

“…4b ). The core response includes numerous key genes known to be involved in the innate immune response against pathogenic mycobacteria such as: CCL20 [ 75 ]; IL18 , which limits the growth of M. tuberculosis in human macrophages [ 76–78 ]; anti-inflammatory IL10 [ 79 ]; and NOS2 , polymorphisms of which are associated with susceptibility of Holstein cattle to bovine TB [ 80 ] ( Fig. 4c ).…”

Section: Resultsmentioning

confidence: 99%

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

Malone

¹

,

Rue-Albrecht

²

,

Magee

³

et al. 2018

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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 the translational level via RNA-sequencing and SWATH MS. Furthermore, a bovine alveolar macrophage infection time course model was used to investigate the shared and divergent host transcriptomic response to infection with M. tuberculosis H37Rv or M. bovis AF2122/97. 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 H37Rv and M. bovis AF2122/97 infection of bovine alveolar macrophages, in particular cytosolic DNA-sensing pathways at 48 h 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.

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“…The association of enriched pathways such as Cytokine-cytokine receptor interaction, NOD-like receptor signalling and Jak-STAT signalling with this gene subset suggests a robust “core” macrophage response to infection with either mycobacterial species throughout the time course (Fig.4B). The core response includes numerous key genes known to be involved in the innate immune response against pathogenic mycobacteria such as: CCL20 (75); IL18, which limits the growth of M. tuberculosis in human macrophages (76-78); anti-inflammatory IL10 (79); and NOS2, polymorphisms of which are associated with susceptibility of Holstein cattle to bovine TB (80) (Fig.4C). Furthermore, the HIF-1 signalling pathway was significantly enriched for the DE genes common to both infection series; this pathway is associated with regulating a switch in central glucose metabolism during high-energy demanding events, such as infection, in neutrophils and macrophages (81)(Fig.S6A).…”

Section: Resultsmentioning

confidence: 99%

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

Malone

¹

,

Rue-Albrecht

²

,

Magee

³

et al. 2017

Preprint

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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.

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“…Polymorphisms in the human and bovine iNOS genes have also been linked to increased rates of M. tuberculosis and bTB respectively suggesting that variation in the NO response is field relevant434445. Moreover, iNOS-deficient mice are highly susceptible to TB infection, presenting with atypical granulomas that can facilitate mycobacterial reactivation, dissemination and transmission1246.…”

Section: Discussionmentioning

confidence: 99%

Badger macrophages fail to produce nitric oxide, a key anti-mycobacterial effector molecule

Bilham

¹

,

Boyd

²

,

Preston

³

et al. 2017

Sci Rep

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The European badger is recognised as a wildlife reservoir for bovine tuberculosis (bTB); the control of which is complex, costly and controversial. Despite the importance of badgers in bTB and the well-documented role for macrophages as anti-mycobacterial effector cells, badger macrophage (bdMφ) responses remain uncharacterised. Here, we demonstrate that bdMφ fail to produce nitric oxide (NO) or upregulate inducible nitric oxide synthase (iNOS) mRNA following Toll-like receptor (TLR) agonist treatment. BdMφ also failed to make NO after stimulation with recombinant badger interferon gamma (bdIFNγ) or a combination of bdIFNγ and lipopolysaccharide. Exposure of bdMφ to TLR agonists and/or bdIFNγ resulted in upregulated cytokine (IL1β, IL6, IL12 and TNFα) mRNA levels indicating that these critical pathways were otherwise intact. Although stimulation with most TLR agonists resulted in strong cytokine mRNA responses, weaker responses were evident after exposure to TLR9 agonists, potentially due to very low expression of TLR9 in bdMφ. Both NO and TLR9 are important elements of innate immunity to mycobacteria, and these features of bdMφ biology would impair their capacity to resist bTB infection. These findings have significant implications for the development of bTB management strategies, and support the use of vaccination to reduce bTB infection in badgers.

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Relationship of bovine <i>NOS2</i> gene polymorphisms to the risk of bovine tuberculosis in Holstein cattle

Cited by 12 publications

References 36 publications

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

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

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

Badger macrophages fail to produce nitric oxide, a key anti-mycobacterial effector molecule

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