Biology subjects

Smyth, A.

Publications and source records attributed to Smyth, A..

4 recordsLinked to original sources

bioRxiv2024

A robust brain network for sustained attention from adolescence to adulthood that predicts later substance use

Substance use, including cigarettes and cannabis, is associated with poorer sustained attention in late adolescence and early adulthood. Previous studies were predominantly cross-sectional or under-powered and could not indicate if impairment in sustained attention was a predictor of substance-use or a marker of the inclination to engage in such behaviour. This study explored the relationship between sustained attention and substance use across a longitudinal span from ages 14 to 23 in over 1,000 participants. Behaviours and brain connectivity associated with diminished sustained attention at age 14 predicted subsequent increases in cannabis and cigarette smoking, establishing sustained attention as a robust biomarker for vulnerability to substance use. Individual differences in network strength relevant to sustained attention were preserved across developmental stages and sustained attention networks generalized to participants in an external dataset. In summary, brain networks of sustained attention are robust, consistent, and able to predict aspects of later substance use. TeaserA robust brain network for sustained attention at age 14 predicts cigarette and cannabis use from ages 14 to 23.

neuroscience↗

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↗

bioRxiv2019

Mycobacterium riyadhense clinical isolates provide insights into ancestry and adaptive evolution in tuberculosis

Current evolutionary scenarios posit the emergence of Mycobacterium tuberculosis, the deadliest bacterial pathogen for humans globally, from an environmental saprophyte through a cumulative process of genome adaptation. Mycobacterium riyadhense is a novel non-tuberculous mycobacterium (NTM) that is being increasingly isolated from human clinical cases with tuberculosis (TB)-like symptoms in various parts of the world. We provide evidence here that M. riyadhense is likely a missing link in our understanding of the evolution of M. tuberculosis. To elucidate the genomic hallmarks that define the evolutionary relationship between M. riyadhense and other mycobacterial species, including members of the Mycobacterium tuberculosis complex (MTBC), eight clinical isolates of M. riyadhense were sequenced and analyzed. We show, among other features, that M. riyadhense shares a large number of conserved orthologues with the MTBC; contains linear and circular plasmids carrying type IV and type VII secretion systems; and shows expansion of toxin/anti-toxin pairs. We conclude that M. riyadhense is an emerging mycobacterial pathogen that shares a common ancestor with members of the MTBC and that can serve as an experimental model to study the evolution and pathogenesis of tubercle bacilli.\n\nAuthor summaryMycobacterium tuberculosis is one of the most prolific infectious killers in humans and is a member of the Mycobacterium tuberculosis complex (MTBC) - a group of genetically related pathogens that cause tuberculosis (TB) in mammalian species. It is postulated that MTBC has evolved from a free-living environmental ancestor into an obligate pathogen. In this evolutionary context, a comprehensive understanding of the genomic hallmarks of the free-living environmental ancestors of the MTBC is of particular scientific interest for better understanding of the evolution of the MTBC. Mycobacterium riyadhense is a novel environmental mycobacterium, first isolated in 2009 in a hospital in Riyadh, that is increasingly being isolated from clinical cases with typical tuberculosis (TB)-like symptoms in humans. In this study, we report the characterization of eight clinical isolates of M. riyadhense, compare their genomes to members of the MTBC, and provide a comprehensive insight into the adaptive changes associated with the evolution of the MTBC from environmental mycobacteria. We show that M. riyadhense is one of the closest known environmental mycobacteria related to the MTBC, and we provide several lines of molecular evidence that M. riyadhense is likely the missing link in the evolution of M. tuberculosis. It shares a common ancestor with members of the MTBC that have evolved through a process of genome reduction, expansion of toxin/antitoxin (T/A) gene systems, and ultimately host adaptation.

evolutionary biology↗

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↗