Biology subjects

Vickers, A.

Publications and source records attributed to Vickers, A..

5 recordsLinked to original sources

bioRxiv2026

Population-level genome sequencing reveals distinct Mycobacterium tuberculosis intrahost mutational trajectories in simian immunodeficiency virus co-infected and antiretroviral treated non-human primates

Whole genome sequencing of Mycobacterium tuberculosis (Mtb) populations from clinical samples has increasingly identified genes undergoing selection within and between hosts that drive differential infection and treatment outcomes. However, the intrahost Mtb mutational landscape--especially in the context of human immunodeficiency virus coinfection and antiretroviral therapy (ART)--remains less clear, as do the potential impacts of such mutations on Mtb infection dynamics. Here, we performed whole genome sequencing of Mtb populations isolated from 477 infected tissues across 20 non-human primates, including animals co-infected with simian immunodeficiency virus (SIV) with or without virological suppression by ART. We identified 116 mutations that emerged during infection, including those that are overrepresented within individual tissues and a subset that are shared across tissues during Mtb dissemination. We further find differential mutation trajectories across treatment groups, with higher mutation rate and bacterial outgrowth in SIV-infected hosts and increased prevalence of oxidative damage-associated mutations in coinfected animals on ART. Finally, we demonstrate a common pattern of mutation in Mtb lipid metabolism and polyketide synthase genes and identify a subset of NHP-derived mutations that have also independently arisen in human clinical isolates. Together, our population-based sequencing uncovers Mtb diversification during early infection, captures discrete bacterial dissemination events and infers differential immune pressures faced by Mtb in the setting of SIV-Mtb coinfection and ART suppression. ImportanceTuberculosis remains a leading cause of death worldwide, especially in people living with HIV. How HIV infection and antiretroviral therapy impacts Mycobacterium tuberculosis (Mtb) intrahost evolution remains unclear. Using whole genome sequencing from hundreds of infected tissues from non-human primates, we find that simian immunodeficiency virus co-infected hosts and those receiving antiretroviral therapy exact different immune pressures on Mtb leading to different mutation rates and types of DNA damage that are incurred. Mtb mutations were enriched in genes involved in lipid metabolisms and some of these are also seen in human TB strains. This work highlights the role of immune pressure to alter bacterial pathways that may enable Mtb adaptation to the host.

microbiology↗

bioRxiv2024

Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a leading cause of death by an infectious disease globally, with no efficacious vaccine. Antibodies are implicated in Mtb control, but the mechanisms of antibody action remain poorly understood. We assembled a library of TB monoclonal antibodies (mAb) and screened for the ability to restrict Mtb in mice, identifying protective antibodies targeting known and novel antigens. To dissect the mechanism of mAb-mediated Mtb restriction, we optimized a protective lipoarabinomannan-specific mAb through Fc-swapping. In vivo analysis of these Fc-variants revealed a critical role for Fc-effector function in Mtb restriction. Restrictive Fc-variants altered distribution of Mtb across innate immune cells. Single-cell transcriptomics highlighted distinctly activated molecular circuitry within innate immune cell subpopulations, highlighting early activation of neutrophils as a key signature of mAb-mediated Mtb restriction. Therefore, improved antibody-mediated restriction of Mtb is associated with reorganization of the tissue-level immune response to infection and depends on the collaboration of antibody Fab and Fc.

immunology↗

bioRxiv2018

High-throughput micro-patterning platform reveals Nodal-dependent dissection of peri-gastrulation-associated versus pre-neurulation associated fate patterning

In vitro models of post-implantation human development are valuable to the fields of regenerative medicine and developmental biology. Here, we report characterization of a robust in vitro platform that enabled high-content screening of multiple human pluripotent stem cell (hPSC) lines for their ability to undergo peri-gastrulation-like fate patterning upon BMP4 treatment of geometrically-confined colonies and observed significant heterogeneity in their differentiation propensities along a gastrulation associable and neuralization associable axis. This cell line associated heterogeneity was found to be attributable to endogenous nodal expression, with upregulation of Nodal correlated with expression of a gastrulation-associated gene profile, and Nodal downregulation correlated with a neurulation-associated gene profile expression. We harness this knowledge to establish a platform of pre-neurulation-like fate patterning in geometrically confined hPSC colonies that arises due to a stepwise activation of reaction-diffusion and positional-information. Our work identifies a Nodal signalling dependent switch in peri-gastrulation versus pre-neurulation-associated fate patterning in hPSC cells, provides a technology to robustly assay hPSC differentiation outcomes, and suggests conserved mechanisms of self-organized fate specification in differentiating epiblast and ectodermal tissues.

developmental biology↗

bioRxiv2018

Smoking induces coordinated DNA methylation and gene expression changes in adipose tissue with consequences for metabolic health

Tobacco smoking is a risk factor for multiple diseases, including cardiovascular disease and diabetes. Many smoking-associated signals have been detected in the blood methylome, but the extent to which these changes are widespread to metabolically relevant tissues, and impact gene expression or cardio-metabolic health, remains unclear.\n\nWe investigated smoking-associated DNA methylation and gene expression variation in adipose tissue from 542 healthy female twins with available well-characterized cardio-metabolic phenotype profiles. We identified 42 smoking-methylation and 42 smoking-expression signals, where five genes (AHRR, CYP1A1, CYP1B1, CYTL1, F2RL3) were both hypo-methylated and up-regulated in smokers. We replicated and validated a proportion of the signals in blood, adipose, skin, and lung tissue datasets, identifying tissue-shared effects. Smoking leaves systemic imprints on DNA methylation after smoking cessation, with stronger but shorter-lived effects on gene expression. We tested for associations between the observed smoking signals and several adiposity phenotypes that constitute cardio-metabolic disease risk. Visceral fat and android/gynoid ratio were associated with methylation at smoking-markers with functional impacts on expression, such as CYP1A1, and in signals shared across tissues, such as NOTCH1. At smoking-signals BHLHE40 and AHRR DNA methylation and gene expression levels in current smokers were predictive of future gain in visceral fat upon smoking cessation.\n\nOur results provide the first comprehensive characterization of coordinated DNA methylation and gene expression markers of smoking in adipose tissue, a subset of which link to human cardio-metabolic health and may give insights into the wide ranging risk effects of smoking across the body.\n\nAuthor SummaryTobacco smoking is the strongest environmental risk factor for human disease. Here, we investigate how smoking systemically changes methylome and transcriptome signatures in multiple tissues in the human body. We observe strong and coordinated epigenetic and gene expression changes in adipose tissue, some of which are mirrored in blood, skin, and lung tissue. Smoking leaves a strong short-lived impact on gene expression levels, while methylation changes are long-lasting after smoking cessation. We investigated if these changes observed in a metabolically-relevant (adipose) tissue had impacts on human disease, and observed strong associations with cardio-metabolic disease traits. Some of the smoking signals could predict future gain in obesity and cardio-metabolic disease risk in current smokers who subsequently go on to quit smoking. Our results provide novel insights into understanding the widespread health consequence of smoking outside the lung.

genomics↗

bioRxiv2018

Identifying the genetic basis of variation in cell behaviour in human iPS cell lines from healthy donors

Large cohorts of human iPSCs from healthy donors are potentially a powerful tool for investigating the relationship between genetic variants and cellular phenotypes. Here we integrate high content imaging, gene expression and DNA sequence datasets for over 100 human iPSC lines to identify the genetic basis of inter-individual variability in cell behaviour. By applying a dimensionality reduction approach, Probabilistic Estimation of Expression Residuals (PEER), we identified genes that correlated in expression with intrinsic (genetic) and extrinsic (ECM) factors. However, variation in mRNA levels could not account for outlier cell behaviour. Instead, we identified rare, deleterious SNVs in the coding sequence of genes involved in ECM adhesion that occurred in cell lines that were outliers for one or more phenotypes such as cell spreading. These also correlated with altered germ layer differentiation on micropatterned surfaces. Our study thus establishes a strategy for integrating genetic and cell biological measurements for high-throughput analysis.

cell biology↗