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SRP108025
Homo sapiens
12 Downloadable Samples
Illumina HiSeq 2500
Description
Human respiratory syncytial virus (hRSV) is a major cause of morbidity and mortality in the pediatric, elderly, and immune compromised populations. A gap in our understanding of hRSVdisease pathology is the interplay between virally encoded immune antagonists and host components that limit hRSV replication. hRSV encodes for non-structural (NS) proteins that are important immune antagonists; however, the role of these proteins in viral pathogenesis is incompletely understood. Here we report the crystal structure of hRSV NS1 protein, which suggests that NS1 is a structural paralog of hRSV matrix (M) protein. Comparative analysis of the shared structural fold with M revealed regions unique to NS1. Studies on NS1 WT or mutant alone or in recombinant RSVs demonstrate that structural regions unique to NS1 contribute to modulation of host responses, including inhibition of type I IFN responses, suppression of dendritic cell maturation, and promotion of inflammatory responses. Transcriptional profiles of A549 cells infected with recombinant RSVs show significant differences in multiple host pathways, suggesting that NS1 may have a greater role in regulating host responses than previously appreciated. These results provide a framework to target NS1 for therapeutic development to limit hRSV associated morbidity and mortality. Overall design: 12 samples where analysed. A549 cell line was infected with mock, hRSV or mutated hRSV virus. Samples are: control mock-infected (2 replicas), hRSV wild-type NS1 infected (3 replicas), hRSV NS1 1-118 infected (3 replicas), hRSV NS1 L132A/L133A infected (2 replicas) and hRSV NS1 Y125A infected (2 replicas). Libraries was prepared for 96 h.p.i.
Publication Title
Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses.
Sample Metadata Fields
Cell line, Subject
View Samples- Mus musculus
- 14 Downloadable Samples
- Illumina HiSeq 2500
Description
The emergence of multidrug resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, resistant to the frontline anti-tubercular drugs rifampicin and isoniazid, forces treatment with less effective and toxic second-line drugs and stands to derail TB control efforts. However, the immune response to MDR Mtb infection remains poorly understood. Here, we determined the RNA transcriptional profile of in vitro generated macrophages to infection with either drug susceptible Mtb HN878 or MDR Mtb W_7642 infection. Overall design: Bone marrow-derived macrophages (BMDMs) from WT and Il1r1–/– mice were derived in 7 days in GM-CSF supplemented complete DMEM. Cells were infected with either Mtb HN878 or Mtb W_7642 (multiplicity of infection = 1) and RNA samples collected after 6 days.
Publication Title
Mycobacterium tuberculosis carrying a rifampicin drug resistance mutation reprograms macrophage metabolism through cell wall lipid changes.
Sample Metadata Fields
Cell line, Subject
View Samples- Danio rerio
- 6 Downloadable Samples
- IlluminaHiSeq2000
Description
The goal of this study is to compare gene expression levels in the livers of larval Tg(fabp10:nls-mcherry) exposed to 1 mM inorganic arsenic from 4-120 hpf to the unexposed siblings. Samples were collected from Tg(fabp10:nls-mcherry) zebrafish larvae that were derived from incrossed parents of the same strain. The background of transgenic lines were typically from mixed outcrosses of the transgenics to AB, TAB5, and TAB14 strains when regenerating the lines as the working stocks aged. All samples were collected at approximately 120 hpf - natural spawning at 8:30-9:00AM EST on day zero, samples were collected at 8-10AM EST on day 5. Overall design: 10-20 livers from 5dpf embryos were pooled per sample of either control or 1 mM inorganic arsenic exposed Tg(fabp10:nls-mcherry) zebrafish larvae and RNA was extracted using the Zymo Quick-RNA Micro Kit with on-column DNase treatment. Libraries were prepared according to Illumina Truseq RNA sample prep kit, version 2, followed by Ribo-Zero Gold treatment.
Publication Title
Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
Interplay between metabolic state of the cell and its ability to undergo immunological activation has been recently recognized as a treasure chest of novel fundamental regulatory principles. Itaconate, and its membrane permeable derivative dimethyl itaconate (DI) were recently shown to selectively inhibit subset of cytokines during macrophage activation (e.g. Il1b, il6, Il12b but not TNF), yet the precise mechanism of this effect remained unclear. We find that selectivity of DI action stems from the inhibitory effects of electrophilic stress exerted by DI on IkB-zeta protein translation, leading to selective control of the secondary wave of Nfkb-signaling. Mechanistically, DI leads to glutathione depletion and subsequent activation of both Nrf2-dependent and Nrf2-independent stress responses. We find that IkB-zeta regulation is carried out in Nrf2-independent manner, and identify Atf3 as a key mediator of DI effects on IkB-zeta/IL6. This inhibitory effect is conserved across species and cell types, as evident from inhibition of IkB-zeta production in activating human monocytes and IL-17A stimulated keratinocytes of both human and mice. Finally, DI administration in vivo ameliorated IL17/IkB-zeta-driven skin pathology in the mouse model of psoriasis, highlighting therapeutic potential of this regulatory pathway. Overall design: Bone marrow-derived macrophages (BMDMs) from WT and Nrf2–/– mice were derived in 7 days in MCSF supplemented complete RPMI. Some samples cells were stimulated with 250 uM DimethylItaconate(DI) for 12 hours prior to collection for RNA-seq.
Publication Title
Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Mus musculus
- 3 Downloadable Samples
- Illumina HiSeq 2500
Description
We report the first RNA-Seq experiments profiling of FancC deficiency in B cells. Overall design: RNA-Seq of FancC-dependent gene signatures in mouse mature B cells
Publication Title
Loss of Fancc Impairs Antibody-Secreting Cell Differentiation in Mice through Deregulating the Wnt Signaling Pathway.
Sample Metadata Fields
Subject
View Samples- Macaca mulatta
- 10 Downloadable Samples
Affymetrix Rhesus Macaque Genome Array (rhesus)
Description
Hyperimmune activation is one of the strong predictors of disease progression during pathogenic immunodeficiency virus infections and is mediated in part by sustained type I interferon (IFN) signaling. Combination antiretroviral therapy suppresses hyperimmune activation only partially in HIV-infected individuals. Here, we show that blockade of Programmed Death-1 (PD-1) during chonic SIV infection significantly reduces the expression of transcripts associated with type I IFN signaling in the blood and colorectal tissue of rhesus macaques (RM). The effect of PD-1 blockade on type I IFN signaling was durable and persisted under high viremia, a condition that is seen in nonprogressive SIV infection in their natural hosts. The reduced type I IFN signaling was associated with enhanced expression of some of the junction-associated genes in the colorectal tissue and a profound decrease in LPS levels in plasma suggesting a possible repair of gut associated junctions and decreased microbial translocation. The reduced type I IFN signaling was also associated with enhanced immunity against gut resident pathogenic bacteria, control of gut associated opportunistic infections and survival of SIV-infected RMs. These results reveal novel mechanisms by which PD-1 blockade enhances survival of SIV-infected RMs and have implications for development of novel therapeutic approaches to control HIV/AIDS.
Publication Title
PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Treatment
View Samples- Macaca mulatta, Cercocebus atys
- 8 Downloadable Samples
- Affymetrix Rhesus Macaque Genome Array (rhesus)
Description
In SIV/HIV infection, the gastrointestinal tissue dominates as an important site due to the impact of massive mucosal CD4 depletion and immune activation-induced tissue pathology. Unlike AIDS-susceptible rhesus macaques, natural hosts do not progress to AIDS and resolve immune activation earlier. Here, we examine the role of dendritic cells in mediating immune activation and disease progression. We demonstrate that plasmacytoid dendritic cells (pDC) in the blood upregulate 7-integrin and are rapidly recruited to the colorectum following a pathogenic SIV infection in rhesus macaques. These pDC were capable of producing proinflammatory cytokines and primed a Tc1 response in vitro. Consistent with the upregulation of 7-integrin on pDC, in vivo blockade of 47-integrin dampened pDC recruitment to the colorectum and resulted in reduced immune activation. The upregulation of 7-integrin expression on pDC in the blood was also observed in HIV-infected humans but not in chronically SIV-infected sooty mangabeys that show low levels of immune activation. Our results uncover a new mechanism by which pDC influence immune activation in colorectal tissue following pathogenic immunodeficiency virus infections.
Publication Title
Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
We report the application of RNA-seq analysis for high-throughput profiling of murine lungs infected with Aspergillus fumigatus. We compared the lung transcription of wildtype murine lungs and lungs from mice deficient in metabolic cytokine adiponectin. Overall design: Examination of 2 different mice strain and comparison of lung transcripts in response to Aspergillus fumigatus infection.
Publication Title
The Metabolic Cytokine Adiponectin Inhibits Inflammatory Lung Pathology in Invasive Aspergillosis.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
We sought to find molecular signatures of the SGZ cell types, and to characterize the molecular pathways and transcription factor cascades that define the neurogenic niche. We used laser capture microdissection and DNA microarrays to profile gene expression in the inner (SGZ) and outer portions of the dentate gyrus (DG). Since the vast majority of the cells in the DG are mature granule cells, we compared the expression of the inner and outer portions to reveal molecular markers for the less numerous populations of the SGZ.
Publication Title
Conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates.
Sample Metadata Fields
Sex, Specimen part
View Samples- Macaca mulatta
- 12 Downloadable Samples
- Affymetrix Rhesus Macaque Genome Array (rhesus)
Description
CD8+ T-cells inhibit virus replication in SIV-infected rhesus macaques (RM). However, it is not clear how SIV infection is controlled in germinal center during chronic SIV infection and limited information exists on the characteristics of CXCR5+ CD8 T cells during chronic SIV/HIV infection. In this study, we used functional genomics to investigate characteristic features and potential mechanisms of CXCR5+ and CXCR5- SIV specific CD8 T cells for the control of pathogenic SIV infection. Six chronically SIV infected RMs, three SIVE660 infected and three SIV mac251 infected that are positive for Mamu A01 allele were selected and SIV-specific CXCR5+ and CXCR5- CD8 T cells were sorted based on CXCR5 expression. RNA from sorted cells were extracted and microarray were performed and analysed. Principal component analysis demonstrated that overall gene expression difference between CXCR5+ and CXCR5- SIV-specific CD8 T cells. Interestingly, the CXCR5+ CD8 T cells revealed a distinct gene signature pattern when compared to CXCR5- CD8 T cells. Unlike the CXCR5- CD8 T cells, the CXCR5+ CD8 T cells expressed higher levels of genes associated with Tfh CD4 T cells such as the master transcription factor Bcl6, CD200, and CTLA4 as well as markers associated with Th2 CD4 T cells such as IL-4R (CD124), CCR4, STAT6, NFATC, and IL-10. Effector molecules typically observed in cytotoxic CD8 T cells such as granzyme A, B, and K were expressed at lower levels on CXCR5+ CD8 T cells compared to their CXCR5- counterparts. CXCR5+ CD8 T cells also expressed higher levels of molecules associated with co-stimulation/antigen presentation such as CD40, CD83, 41BBL and MAMU-DRA. The CXCR5+ CD8 also expressed higher levels of inhibitory receptors such as CD200 and SPRY2 but lower levels of other inhibitory receptors CD160 and CD244. The functional consequence of the expression of these molecules is yet to be determined. Additionally, CXCR5+ CD8 T cells expressed higher levels of the anti-apoptotic gene Bcl-2 and lower levels of the pro-apoptotic gene annexin, suggestive of their better survival potential during chronic SIV infection. Collectively, these results demonstrate that SIV specific CXCR5+ CD8 T cells possess a unique gene expression signature compared to SIV-specific CXCR5- CD8 T cells.
Publication Title
Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection.
Sample Metadata Fields
Specimen part
View Samples