Differential induction of apoptosis, IFN signaling and phagocytosis in macrophages infected with a panel of attenuated and non-attenuated poxviruses
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE79159 | GEO | 2016/03/14
SECONDARY ACCESSION(S): PRJNA315062
REPOSITORIES: GEO
Similar Datasets
Project description:Similarities as well as differences were found in macrophages infected with different virus strains, particularly at the expression level of immunomodulatory genes, but infection with MVA was particularly efficient in triggering changes in gene expression associated with increased activation of innate immunity. Two-condition experiment, uninfected vs. infected cells. Biological replicates: 6 control replicates, 3 infected replicates.
2016-03-14 | E-GEOD-79159 | biostudies-arrayexpress
Project description:Due to the essential role macrophages play in antiviral immunity, it is important to understand the intracellular and molecular processes that occur in macrophages following infection with various strains of vaccinia virus, particularly those used as vaccine vectors. Similarities as well as differences were found in macrophages infected with different poxvirus strains, particularly at the level of virus-induced apoptosis and the expression of immunomodulatory genes, as determined by microarray analyses. Interestingly, the attenuated modified vaccinia Ankara virus (MVA) was particularly efficient in triggering apoptosis and beta interferon (IFN-?) secretion and in inducing changes in the expression of genes associated with increased activation of innate immunity, setting it apart from the other five vaccinia virus strains tested. Taken together, these results increase our understanding of how these viruses interact with human macrophages, at the cellular and molecular levels, and suggest mechanisms that may underlie their utility as recombinant vaccine vectors.Our studies clearly demonstrate that there are substantial biological differences in the patterns of cellular gene expression between macrophages infected with different poxvirus strains and that these changes are due specifically to infection with the distinct viruses. For example, a clear induction in IFN-? mRNA was observed after infection with MVA but not with other poxviruses. Importantly, antiviral bioassays confirmed that MVA-infected macrophages secreted a high level of biologically active type I IFN. Similarly, the phagocytic capacity of macrophages was also specifically increased after infection with MVA. Although the main scope of this study was not to test the vaccine potential of MVA as there are several groups in the field working extensively on this aspect, the characteristics/phenotypes we observed at the in vitro level clearly highlight the inherent advantages that MVA possesses in comparison to other poxvirus strains.
| S-EPMC4019115 | biostudies-literature
Project description:Modified vaccinia virus Ankara (MVA) has been explored as a vaccine vector for use against infectious diseases and cancer. MVA is an immunogenic, attenuated poxvirus capable of eliciting robust cellular and humoral responses in pre-clinical animal models and in patients. However, upon infection with MVA, cells undergo rapid apoptosis leading to faster clearance of recombinant antigens. The fragmentation of the anti-apoptotic gene B13R in MVA could contribute to this effect. Here, we replaced the fragmented B13R with a functional version and observed that MVA-B13R infected HeLa cells and muscle cell lines delayed caspase 3 activation compared to MVA indicating slower progression of apoptosis. For immunogenicity studies, mice were intramuscularly immunized with recombinant MVA or MVA-B13R expressing SIV Gag, Pol and HIV Env (SHIV). We observed higher Env-specific humoral responses from MVA-B13R SHIV compared to MVA SHIV mice. To determine differences in the innate immune response that may have contributed to the augmented humoral response, we performed RNA-Seq analysis on draining lymph node cells after immunization. Gene set enrichment analysis from day 1 after immunization showed that MVA-B13R SHIV immunizations were associated with a negative enrichment for type I and II interferon responses compared to MVA SHIV mice indicating MVA-B13R SHIV induces a delayed anti-viral interferon response that may lead to the enhanced humoral response observed. Taken together, these results demonstrate that restoring B13R functionality in MVA significantly delays MVA-induced apoptosis, augments Env-specific antibody responses, and is associated with reduced interferon-alpha and interferon-gamma responses induced after vaccination.
2018-11-27 | GSE119884 | GEO
Project description:Acute myocardial infarction (AMI) is one of the leading causes of death. It is particularly important to predict malignant ventricular arrhythmia (MVA) timely and accurately in patients with AMI. This study aimed to explore biomarkers and to reveal possible mechanisms of MVA in AMI for clinical diagnosis. Blood samples from 190 human subjects were collected to reveal the differentially expressed proteins (DEPs) in three comparisons (AMI/control, AMI+MVA/control, and AMI+MVA/AMI) in proteomics with bioinformatics analysis and validated in new cohorts. The diagnostic value of candidate DEPs predicting AMI+MVA was also evaluated by the receiver operating characteristic curve (ROC). A total of 8,365 peptides and 460 proteins from the LC-MS/MS analysis were identified with 90 in AMI/control, 94 in AMI+MVA/control, and 43 in AMI+MVA/AMI identified as DEPs. TGFBI level had notable decreasing trend in AMI+MVA (161.9 ± 19.0 ng/ml) compared with AMI (P<0.0001) or control (P<0.0001). vWF level in AMI+MVA patients was significantly higher than that in AMI patients (P<0.01) and control (P<0.0001). ROC analysis showed that TGFBI and vWF had the strong and potential value of predicting MVA in AMI. By constructing proteomics profile to identify the protein characteristics this study found that decreased TGFBI and increased vWF are the characteristics of proteins in the MVA patients with AMI. These findings provide new insight into the diagnosis and pathogenesis of the development of MVA. Further, decreased TGFBI and increased vWF are potential predicting biomarkers for diagnosis of MVA in AMI patients.
2024-01-26 | PXD041535 | Pride
Project description:The mechanisms of aging-related oocyte aneuploidy remain elusive. Hi-C and SMART-seq revealed aging-related decreases in chromosome condensation, particularly for genomic regions proximal to the centromeres, accompanied with disrupted meiosis-associated gene expression in metaphase I (MI) aged oocytes. Further transcriptomic analysis showed that oocyte meiotic maturation was correlated with robust increases in mevalonate (MVA) pathway gene expression in young oocyte-surrounding granulosa cells (GCs), which was largely downregulated in aged GCs. Inhibtion of MVA metabolism in GCs by statins resulted in marked meiotic defects and aneuploidy in young cumulus-oocyte complexes (COCs). Conversely, supplementation with the MVA isoprenoid geranylgeraniol ameliorated meiotic defects and aneuploidy in aged COCs. Meanwhile, geranylgeraniol also activated LHR/EGF signaling in aged GCs and then enhanced the meiosis-associated gene expression in oocytes. Generally, the MVA pathway in GCs is a critical regulator of meiotic maturation and euploidy in oocytes.
2023-02-26 | GSE212860 | GEO
Project description:Viral vectors are being used for the treatment of cancer. Yet their efficacy varies among tumors and their use poses challenges in immunosuppressed patients, underscoring the need for alternatives. We report striking antitumoral effects by a nonlytic viral vector based on attenuated lymphocytic choriomeningitis virus (r3LCMV). We show in multiple tumor models that injection of tumor-bearing mice with this novel vector results in improved tumor control and survival. Importantly, r3LCMV also improved tumor control in immunodeficient Rag1-/- mice. Single cell RNA-Seq analyses, antibody blockade experiments, and KO models revealed a critical role for host IFN-I in the antitumoral efficacy of r3LCMV vectors. Collectively, these data demonstrate potent antitumoral effects by a replication-attenuated LCMV vector and unveil mechanisms underlying its antitumoral efficacy.
| S-EPMC10723415 | biostudies-literature
Project description:Cultured epidermal keratinocyte controls used for IFNg, TNFa and IL1 treatment. Interferon (IFN)-gamma, is a multifunctional, immunomodulatory cytokine with cell type-specific antiviral activities, particularly important in skin, where it is implicated in many diseases ranging from warts to psoriasis and cancer. Since epidermis is our first line of defence against many viruses, we investigated the molecular processes regulated by IFN-gamma in keratinocytes using DNA microarrays. We identified the IFN-gamma-regulated keratinocyte-specific genes in keratinocytes, IFN-gamma-induced tight junction proteins, presumably to deny viruses paracellular routes of infection. Furthermore, differing from published data, we find that IFN-gamma suppressed the expression of keratinocytes differentiation markers including desmosomal proteins, cornified envelope components and suprabasal cytokeratins. Inhibition of differentiation may interfere with the epidermal tropism of viruses that require differentiating cells for growth, for example, papillomaviruses. As in other cell types, IFN-gamma induced HLA, cell adhesion and proteasome proteins, facilitating leukocyte attraction and antigen-presentation by keratinocytes. IFN-gamma also induced chemokine/cytokines specific for mononuclear cells. IFN-gamma suppressed the expression of over 100 genes responsible for cell cycle, DNA replication and RNA metabolism, thereby shutting down many nuclear processes and denying viruses a healthy cell in which to replicate. Thus, uniquely in keratinocytes, IFN-gamma initiates a well-organized molecular programme boosting host antiviral defences, obstructing viral entry, suppressing cell proliferation and impeding differentiation.
2007-10-26 | E-GEOD-440 | biostudies-arrayexpress
Project description:In the adult hippocampus, neuroprogenitor cells in the subgranular zone (SGZ) of the dentate gyrus give rise to newborn neuroblasts. However, only a small subset of these cells integrates into the hippocampal circuitry as mature neurons at the end of a 4 week period. Here, we show that the majority of the newborn cells undergo death by apoptosis in the first 1 to 4 days of their life, during the transition from amplifying neuroprogenitors to neuroblasts. These apoptotic newborn cells are rapidly cleared out through phagocytosis by unchallenged microglia present in the adult SGZ niche. Phagocytosis by the microglia is efficient and undeterred by increased age or inflammatory challenge. Our results suggest that the main critical period of newborn cell survival occurs within a few days of birth and reveal a new role for microglia in maintaining the homeostasis of the baseline neurogenic cascade.
| S-EPMC4008496 | biostudies-literature
Project description:Modified vaccinia Ankara (MVA) immunisation is being deployed to curb the current outbreak of mpox in multiple countries1. Originally authorized for vaccination against smallpox, MVA is a vaccinia virus (VACV) strain that does not replicate in human cells or cause serious adverse events. Here, we conducted a highly multiplexed proteomic analysis2 to quantify >9,000 cellular proteins and ~80% of viral proteins at five time points throughout MVA infection of human cells3. 690 human proteins were down-regulated >2-fold by MVA, revealing a substantial remodelling of the host proteome. >25% of these MVA targets, including multiple components of the nuclear pore complex (NPC), were not shared with VACV-Western Reserve4, which is derived from a first generation smallpox vaccine associated with serious adverse events. Using pharmacological inhibition of viral DNA replication and heat-inactivated virions, we discovered that post-replicative gene expression is necessary for the downregulation of NPC proteins and for elements of MVA antagonism of innate immune sensing. Our approach thus provides the first global view of the impact of MVA infection on the host proteome, offers insights into how MVA interacts with the antiviral defences and identifies cellular mechanisms that may underpin the abortive infection of human cells. These discoveries will prove vital to the rational design of future generations of vaccines.
2023-10-11 | PXD039034 | Pride
Project description:Background: Tyrosine kinase inhibitor (TKI) resistance is a significant factor exacerbating the burden on chronic myeloid leukemia (CML) patients and impacting clinical efficacy. The main goal is to offer new insights into overcoming drug resistance in treating CML. Methods: (IM) resistant K562/IM cells were generated using gradient induction. Responses to IM, lycorine, and autophagy modulators were assessed using CCK-8. Protein expression of Beclin-1, Atg5, LC3, Caspase-3, P62, Bax, Bcl-2, and P-gp was detected using Western blot. Lycorine-induced apoptosis and cell cycle changes were evaluated through flow cytometry, while autophagy alterations were detected using Monodansylcadaverine(MDC) staining. In the K562/IM mice model, Non-obese diabetic severe combined immunodeficent(NOD-SCID) mice were subcutaneously inoculated with K562/IM cells. After 17 days of lycorine injection, assessments included tumor size, Hematoxylin-eosin(HE) staining, and Ki67 expression. Results: After 72 hours of IM treatment, K562/IM cells showed a 55.86-fold increase in drug resistance compared to K562 cells. Lycorine treatment for 24 hours inhibited cell proliferation and induced G0/G1 phase cell cycle arrest and apoptosis in both K562 and K562/IM cells. MDC staining indicated reduced autophagy in K562/IM cells, mitigated by lycorine. In vivo experiments demonstrated reduced tumor size and Ki67 proliferation index in the lycorine treatment group (K562+L, K562/IM+L) compared to the control group, particularly in the drug-resistant group. However, no significant change in Ki67 was observed in the K562 group after lycorine treatment. Conclusion: In summary, K562/IM cells displayed heightened autophagy levels compared to K562 cells. Lycorine effectively impeded the proliferation of K562/IM cells through diverse mechanisms, including reduced autophagy, enhanced apoptosis, and induced cell cycle arrest.
2024-05-20 | GSE267522 | GEO