Mycobacterium abscessus is an emerging pathogen causing pulmonary infections in those with inflammatory lung disorders, such as Cystic Fibrosis (CF), and is associated with the highest fatality rate among rapidly growing mycobacteria (RGM). Phenotypically, MAB manifests as either a Smooth (MAB-S) or a Rough (MAB-R) morphotype, which differ in their levels of cell wall glycopeptidolipids (GPLs) and in their pathogenicity in vivo. As one of the primary immune cells encountered by MAB, we sought to examine the early transcriptional events within macrophages, following infection with both MAB-S or MAB-R. We sampled the small RNA (sRNA) transcriptome of THP-1-derived macrophages infected with both MAB-R and MAB-S at 1, 4 and 24 hours post-infection (hpi) using RNA-seq. MAB-S elicited a more robust transcriptional response at the miRNA level, reflecting higher cytokine levels in culture supernatants. However, and a direct comparison identified no differentially expressed miRNAs between MAB-R- and MAB-S-infected cells. Most of the induced miRNAs have previously been associated with mycobacterial infection and overall miRNA expression patterns were similarly highly correlated between the morphotypes. Overall design: THP-1-derived macrophages were infected in parallel with the MAB-R and MAB-S morphotypes. Poly-A selected RNAs were purified and sequenced at 1, 4 and 24 hours post-infection, and compared with uninfected controls.
High-throughput transcriptomics reveals common and strain-specific responses of human macrophages to infection with Mycobacterium abscessus Smooth and Rough variants.
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View SamplesNon-typhoidal Salmonella (NTS) are among of the most important food-borne pathogens. Recently, a highly invasive multi-drug resistant S. Typhimurium of a distinct multilocus sequence type (MLST), ST313, has emerged across sub-Saharan Africa as a major cause of lethal bacteraemia in children and immunosuppressed adults. Encounters between dendritic cells (DCs) and invading bacteria determine the course of infection but whether or how ST313 might usurp DC mediated defence has not been reported. Here we utilised fluorescently labelled invasive and non-invasive strains of Salmonella combined with single-cell RNA sequencing to study the transcriptomes of individual infected and bystander DCs. The transcriptomes displayed a repertoire of cell instrinsic and extrinsic innate response states that differed between invasive and non-invasive strains. Gene expression heterogeneity was increased in DCs challenged with invasive Salmonella. DCs exposed but not harbouring invasive Salmonella exhibited a hyper-activated profile that likely facilitates trafficking of infected cells and dissemination of internalised intact bacteria. In contrast, invasive Salmonella containing DCs demonstrate reprogramming of trafficking genes required to avoid autophagic destruction. Furthermore, these cells displayed differential expression of tolerogenic IL10 and MARCH1 enabling CD83 mediated adaptive immune evasion. Altogether our data illustrate pathogen cell-to cell variability directed by a Salmonella invasive strain highlighting potential mechanisms of host adaption with implications for dissemination in vivo. Overall design: Single-cell RNA sequencing (SMARTSeq2) of 373 human monocyte derived dendritic cells infected with S. Typhimurium strain LT2 or D23580 or left uninfected
Invasive Salmonella exploits divergent immune evasion strategies in infected and bystander dendritic cell subsets.
Subject, Time
View SamplesNon-typhoidal Salmonella (NTS) are among of the most important food-borne pathogens. Recently, a highly invasive multi-drug resistant S. Typhimurium of a distinct multilocus sequence type (MLST), ST313, has emerged across sub-Saharan Africa as a major cause of lethal bacteraemia in children and immunosuppressed adults. Encounters between dendritic cells (DCs) and invading bacteria determine the course of infection but whether or how ST313 might usurp DC mediated defence has not been reported. Here we utilised fluorescently labelled invasive and non-invasive strains of Salmonella combined with single-cell RNA sequencing to study the transcriptomes of individual infected and bystander DCs. The transcriptomes displayed a repertoire of cell instrinsic and extrinsic innate response states that differed between invasive and non-invasive strains. Gene expression heterogeneity was increased in DCs challenged with invasive Salmonella. DCs exposed but not harbouring invasive Salmonella exhibited a hyper-activated profile that likely facilitates trafficking of infected cells and dissemination of internalised intact bacteria. In contrast, invasive Salmonella containing DCs demonstrate reprogramming of trafficking genes required to avoid autophagic destruction. Furthermore, these cells displayed differential expression of tolerogenic IL10 and MARCH1 enabling CD83 mediated adaptive immune evasion. Altogether our data illustrate pathogen cell-to cell variability directed by a Salmonella invasive strain highlighting potential mechanisms of host adaption with implications for dissemination in vivo. Overall design: RNA-seq of mini-bulks (5000 cells) of human monocyte derived dendritic cells infected with S. Typhimurium strain LT2 or D23580 or left uninfected
Invasive Salmonella exploits divergent immune evasion strategies in infected and bystander dendritic cell subsets.
Subject, Time
View SamplesRecurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) remains one of the most difficult cancers to treat with limited chemotherapeutic options. Here, we describe a patient with HNSCC who had complete response to methotrexate (MTX) after progressing on multiple cytotoxic agents; cetuximab, a monoclonal antibody (mAb) against Epidermal Growth Factor Receptor (EGFR), and AMG 479, a mAb against Insulin-like Growth Factor-1 Receptor (IGF-1R).
Insulin-like growth factor-1 receptor inhibitor, AMG-479, in cetuximab-refractory head and neck squamous cell carcinoma.
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View SamplesIn order to gain insight into the poorly understood pathophysiology of the myelodysplastic syndromes (MDS), we have determined the gene expression profiles of the CD34+ cells of 55 MDS patients using the Affymetrix GeneChip U133 Plus2.0 platform
Gene expression profiles of CD34+ cells in myelodysplastic syndromes: involvement of interferon-stimulated genes and correlation to FAB subtype and karyotype.
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View SamplesAPs were isolated from naïve skin and day 5wounds from dorsal skin wound beds of 7-9 weeks old using FACS. This experiment describes changes in AP gene expression associated with injury and subsequent tissue repair. Overall design: APs were isolated by FACS.
Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair.
Sex, Age, Cell line, Subject
View SamplesCells were isolated from day 5wounds from dorsal skin wound beds of 7-9 weeks old using FACS. This experiment describes the gene expression profile associated with different immune cell subsets during tissue repair. Overall design: Cells were isolated by FACS.
Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair.
Sex, Age, Cell line, Subject
View SamplesWe performed mRNA transcriptional profiling on Drosophila S3 cells after 4 hours treatment with novel lipid storage inhibitors belonging to three different chemotypes. Overall design: Profiling of RNA expression after treatment with three pairs of active/inactive compounds or DMSO as a control in triplicates and without treatment in the presence/absence of oleic acid in sextuplicate.
A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics.
Cell line, Subject, Compound
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