Rescue of CD8+ T cell vaccine memory in mice following sublethal g radiation exposure
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE64434 | GEO | 2015/09/01
SECONDARY ACCESSION(S): PRJNA271035
REPOSITORIES: GEO
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Project description:In two disparate models, we show that rapid revaccination following sublethal gamma radiation exposure rescues memory CD8+ T cell Responses. To investigate the mechanism of rescue we performed RNA microarray analyses to identify whether there was a genetic “signature” of rescue. mRNA was obtained from whole spleens 6 hrs after revaccination with LM-DActA at D1 and D4 PI for RNA microarray analysis
2015-09-01 | E-GEOD-64434 | biostudies-arrayexpress
Project description:Sublethal γ irradiation eliminates CD8+ T cell mediated memory responses. In this work, we explored how these memory responses could be rescued in the aftermath of such exposure. We utilized two models of CD8+ T cell mediated immunity: a mouse model of Listeria monocytogenes (LM) infection in which CD8+ T cells specific for LM expressed antigens (Listeriolysin O, LLO) can be tracked, and a murine skin graft model in which CD8+ T cells mediate rejection across a MHC class I (D(d)) disparity. In the LM immunized mice, LL0 specific CD8+ T memory cells were lost on irradiation, preserved with rapid revaccination with an attenuated strain 1-3 days post-irradiation (PI), and these mice survived a subsequent wild type LM challenge. A genetic "signature of rescue" identified a group of immune-associated mRNA maintained or upregulated following irradiation and rescue. A number of these factors, including IL-36γ, dectin-2 (Clec4n), and mir101c are upregulated rapidly after exposure of mice to sublethal γ radiation alone and are sustained by early, but not later rescue. Such factors will be evaluated as potential therapeutics to replace individual vaccines for global rescue of CD8+ T memory cell responses following sublethal γ irradiation. The skin allograft model mirrored that of the LM model in that the accelerated D(d) skin allograft rejection response was lost in mice exposed to sublethal γ radiation, but infusion of allogeneic D(d) expressing bone marrow cells 1-4 days PI preserved the CD8+ T memory mediated accelerated rejection response, further suggesting that innate immune responses may not always be essential to rescue of CD8+ memory T cells following γ irradiation.
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Project description:Increased use of nuclear reactors and radioactive materials for energy production and proliferation of nuclear weaponry increases risk of radiation exposure or nuclear accidents. Development of radiation countermeasures for the diagnosis, prognosis, and radiation treatment are trailing behind, and knowledge of the deleterious radiation effects on health and responses to exposure at the molecular, cellular, and systems biology level are still not fully understood. In this work, skin biopsies collected at h2, d4, d7, d21, and d28 from mice exposed to 1, 3, 6, 20Gy of whole-body x-ray ionizing radiation were used in a transcriptomic approach to evaluate the potential of radiation-induced transcriptional alterations in diagnosis and prognosis of a radiation event. Mice exposed to 20Gy were euthanized under the humane endpoint of an IACUC approved study protocol at d7 while mice that received 1, 3, 6Gy survived the full 28 days time course. Sammon plot analysis showed a clear separation of samples based on survival and timepoints within lethal (20Gy) and in the sublethal (1, 3, 6Gy) IR doses. Differences in the numbers, regulation mode, and fold change of significantly differentially transcribed genes (SDTGs, p < 0.05 and FC > 2) were identified between lethal and sublethal doses. Down and upregulation dominated transcriptomes during the first post-exposure week, respectively. Numbers of SDTGs and percentages of upregulated SDTGs revealed stationary transcription and low upregulation percentages after lethal dose in contrary to transcription responses that were dynamic and largely upregulated after exposure to sublethal doses. Longitudinal variations in numbers of up/downregulated SDTGs suggested delayed and extended responses with increasing IR doses in the sublethal range with lethal-like responses in late time points suggesting more than a single-phase response. This was supported further by the distributions of common and unique genes across the TPs within each dose. Several genes with potential use as markers for radiation exposure and dosimetric applications were identified. Pathways enrichment analysis showed strong modulations of immune responses, fibrosis development, detoxification responses, hematological responses, skin reactions, neurological system disruptions, maintenance of gastric mucosa, and cell survival, migration, and proliferation pathways. The majority of the identified pathways were predicted activated after sublethal and inactivated after lethal exposures, particularly during the first post-exposure week.
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Project description:Despite the widespread use of antiseptics such as chlorhexidine digluconate (CHX) in dental practice and oral care, the risks of potential resistance toward antiseptics in oral bacteria have only been highlighted very recently. Since the molecular mechanisms behind antiseptic resistance or adaptation are not entirely clear yet and the bacterial stress response has not been investigated systematically so far, the aim of the present study was to investigate the transcriptomic stress response in Streptococcus mutans after treatment with CHX using RNA sequencing. Planktonic cultures of stationary phase S. mutans were treated with a sublethal dose of CHX (125 µg/mL) for 5 min. After treatment, RNA was extracted, and RNA sequencing was performed on the Illumina NextSeq 500. Differential expressed genes were analyzed and validated by qRT-PCR. The analysis of the differential gene expression following pathway analysis revealed a considerable number of genes and pathways significantly regulated in S. mutans after sublethal treatment with CHX. In summary, expression of 423 genes was up-regulated and 295 genes down-regulated after CHX treatment. Analysis of differentially expressed genes and significantly regulated pathways showed regulation of genes involved in purine nucleotide synthesis, biofilm formation, transport systems and stress responses. In conclusion, these results show an overview of the transcriptomic stress response in S. mutans upon exposure to CHX and give an insight in potential mechanisms that may result in development of resistances.
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Project description:Purpose: In order to clarify the molecular response mechanism of Tetranychus truncatus to sublethal concentrations of abamectin. Methods: We sequenced the transcriptome of Tetranychus truncatus treated with sublethal concentration of abamectin and control. Results: we provide a comprehensive transcriptome resource for Tetranychus truncatus derived from treating with sublethal concentration abamectin and control. Conclusions: The new genomic resources and data that we present in this study for Tetranychus truncatus will substantially facilitate molecular studies of underlying mechanisms involved in abamectin resistance.
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Project description:Radiation therapy is commonly used to treat glioblastoma multiforme (GBM) brain tumor. Ionizing radiation (IR) induces dose- specific variations in transcriptional programs, implicating they are tightly regulated and critical components in the tumor response and survival. Yet, our understanding of the downstream molecular events triggered by lethal vs sublethal IR doses is limited. Herein, we report that variations in the genetic programs are positively and functionally correlated with the exposure to lethal or sublethal IR doses. Genome architecture analysis revealed that gene regulation is spatially and temporally coordinated with DNA repair kinetics. Radiation-activated genes were pre-positioned in active sub-nuclear compartments and were up-regulated following DNA damage response, while the DNA repair activity shifted to the inactive heterochromatic spatial compartments. The IR dose affected the levels of DNA damage repair and transcription modulation, but not the order of events, which was linked to their spatial nuclear positioning. Thus, distinct coordinated temporal dynamics of DNA damage repair and transcription reprogramming in the active and inactive sub-nuclear compartments highlight the importance of high-order genome organization in synchronizing the molecular events following IR.
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Project description:Radiation therapy is commonly used to treat glioblastoma multiforme (GBM) brain tumor. Ionizing radiation (IR) induces dose- specific variations in transcriptional programs, implicating they are tightly regulated and critical components in the tumor response and survival. Yet, our understanding of the downstream molecular events triggered by lethal vs sublethal IR doses is limited. Herein, we report that variations in the genetic programs are positively and functionally correlated with the exposure to lethal or sublethal IR doses. Genome architecture analysis revealed that gene regulation is spatially and temporally coordinated with DNA repair kinetics. Radiation-activated genes were pre-positioned in active sub-nuclear compartments and were up-regulated following DNA damage response, while the DNA repair activity shifted to the inactive heterochromatic spatial compartments. The IR dose affected the levels of DNA damage repair and transcription modulation, but not the order of events, which was linked to their spatial nuclear positioning. Thus, distinct coordinated temporal dynamics of DNA damage repair and transcription reprogramming in the active and inactive sub-nuclear compartments highlight the importance of high-order genome organization in synchronizing the molecular events following IR.
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