Novel MVA Vector Expressing Anti-apoptotic gene, B13R, Delays Apoptosis and Enhances Humoral Responses
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ABSTRACT:
PROVIDER: PRJNA490556 | ENA |
REPOSITORIES: ENA
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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:Whole blood transcriptomics analysis of healthy individuals, immunized with the MVA-B vaccine via transcutaneous or intramuscular route. We define an early gene expression profile, detected at day 1 and day 7 after immunization, that is associated with the development of either MVA specific humoral or CD8 T cell responses. We used System Biology approach to analyse vaccine efficacy in order to find innate predictive biomarkers of the quality of adaptive responses for potential clinical use in the future. Moreover, from a methodological point of view this study increases knowledges on how vaccine route(s) can affect resulting immune responses and into mechanisms involved in the induction of humoral and cellular immunity to vaccine.
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Project description:The female reproductive tract is one of the major mucosal invasion site of HIV-1. This site has been neglected in previous HIV-1 vaccine studies. Immune responses in the female reproductive tract after systemic vaccination remain to be characterized. Using a modified vaccinia virus Ankara (MVA) as a vaccine model, we characterized specific immune responses in all compartments of the female reproductive tract (FRT) of non-human primates after systemic vaccination. Memory T cells were preferentially found in the lower tract (vagina and cervix), whereas antigen-presenting cells and innate lymphoid cells were mainly located in the upper tract (uterus and fallopian tubes). This compartmentalisation of immune cells in the FRT was supported by transcriptomic analyses and correlation network. Polyfunctional MVA-specific CD8+ T cells were detected in the blood, lymph nodes, vagina, cervix, uterus and fallopian tubes. Anti-MVA IgG and IgA were detected in cervicovaginal fluid after a second vaccine dose. Systemic vaccination with an MVA vector thus elicits cellular and antibody responses in the female reproductive tract.
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Project description:RNA-seq analysis of ID8.OVA.Vegf/GFP omental metastases treated intraperitoneally with MVA expressing a tumor-associated antigen (TAA), CD40L and/or CD137L.
2022-07-19 | GSE196024 | GEO
Project description:Based on RNA-seq technology, we studies gene expression profiles in BMDC before and after MVA or MVAΔE5R infection. We identified genes which expression dependent on cGAS comparing WT and cGAS-/- cells after MVA infection. The difference genes bewteen MVA and MVAΔ5R were also identified.
2022-10-06 | GSE185431 | GEO
Project description:Route of immunization can markedly influence the quality of immune response. Here, we show that intradermal (ID) but not intramuscular (IM) modified vaccinia Ankara (MVA) vaccinations provide protection from acquisition of intravaginal tier2 SHIV challenges in female macaques. Both routes of vaccination induced comparable levels of serum IgG with neutralizing and non-neutralizing activities. The protection in MVA-ID group correlated positively with serum neutralizing and antibody-dependent phagocytic activities, and envelope-specific vaginal IgA; while the limited protection in MVA-IM group correlated only with serum neutralizing activity. MVA-ID immunizations induced greater germinal center Tfh and B cell responses, reduced the ratio of Th1 to Tfh cells in blood and showed lower activation of intermediate monocytes and inflammasome compared to MVA-IM immunizations. This lower innate activation correlated negatively with induction of Tfh responses. These data demonstrate that the MVA-ID vaccinations protect against intravaginal SHIV challenges by modulating the innate and T helper responses.
2023-07-27 | GSE219118 | GEO
Project description:Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations, increased chromosome missegregation, and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1L1012P mutation in mice (BubR1L1002P) and combined it with two other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wildtype protein, respectively. Whereas, BubR1X753/L1002P and BubR1H/X753 mice die prematurely, BubR1H/L1002P mice are viable and exhibit many MVA features, including cancer predisposition and various progeroid phenotypes, including short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a similar reduction in total BubR1 and spectrum of MVA phenotypes as BubR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype (SASP) complexity. Additionally, mice harboring heterozygous BUBR1 MVA variants developed mild MVA pathologies later in life, with alleles conferring unique phenotypic profiles. Together, these data demonstrate that subtle BUBR1 allelic effects contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations, independent of aneuploidy rates and BUBR1 protein levels.
2020-02-04 | GSE134781 | GEO
Project description:Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations, increased chromosome missegregation, and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1L1012P mutation in mice (BubR1L1002P) and combined it with two other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wildtype protein, respectively. Whereas, BubR1X753/L1002P and BubR1H/X753 mice die prematurely, BubR1H/L1002P mice are viable and exhibit many MVA features, including cancer predisposition and various progeroid phenotypes, including short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a similar reduction in total BubR1 and spectrum of MVA phenotypes as BubR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype (SASP) complexity. Additionally, mice harboring heterozygous BUBR1 MVA variants developed mild MVA pathologies later in life, with alleles conferring unique phenotypic profiles. Together, these data demonstrate that subtle BUBR1 allelic effects contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations, independent of aneuploidy rates and BUBR1 protein levels.
2020-02-04 | GSE134780 | GEO
Project description:Modified vaccinia Ankara (MVA) is a live, attenuated human smallpox vaccine and a vector for the development of new vaccines against infectious diseases and cancer. Efficient activation of the immune system by MVA partially relies on its encounter with dendritic cells (DCs). MVA infection of DCs leads to multiple outcomes, including cytokine production, activation of costimulatory molecules for T cell stimulation, and cell death. Here, we examined how these diverse responses are orchestrated in human DCs. Single-cell analyses revealed that the response to MVA infection in DCs was limited to early viral gene expression. In response to the early events in the viral cycle, we found that DCs grouped into three distinct clusters. A cluster of infected cells sensed the MVA genome by the intracellular innate immunity pathway mediated by cGAS, STING, TBK1, and IRF3 and subsequently produced inflammatory cytokines. In response to these cytokines, a cluster of noninfected bystander cells increased costimulatory molecule expression. A separate cluster of infected cells underwent caspase-dependent apoptosis. Induction of apoptosis persisted after inhibition of innate immunity pathway mediators independently of previously described IRF-dependent or replication-dependent pathways and was a response to early MVA gene expression. Together, our study identified multiple mechanisms that underlie the interactions of MVA with human DCs.
2021-08-25 | GSE153835 | GEO