Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1077336 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:To study emergence of resistance to BDGR-49 during infection with Venezuelan equine encephalitis virus (VEEV), mice were treated suboptimal treatment regimen. C3H/HeN mice were prophylactically treated with BDGR-49 2 hours prior to infection for a total of 5 days. Mice were infected with a lethal challenge dose of VEEV TC-83. Following infection mice brains were euthanized on 3-, 5-, 7,9-, and 10-days post-infection and their brains collected and RNA-Seq performed on. RNA-Seq results were used to analyze for viral resistant mutants. Analysis revealed that only one of the mice contained a mutant that is potentially resistant to BDGR-49.
2025-01-06 | GSE277431 | GEO
Project description:Infections by the New World alphaviruses, Eastern Equine encephalitis virus (EEEV), Venezuelan Equine encephalitis virus (VEEV), and Western Equine encephalitis virus (WEEV), cause febrile illness that can progress to fatal disease in humans and equids. Currently there are no FDA-approved antivirals for prophylactic or therapeutic treatment of human infection by these viruses. To combat these infections, we have developed a novel small molecule, BDGR-164, which has subnanomolar potency against VEEV, EEEV, and WEEV. Using an intranasal route of virus infection in a lethal BALB/c model, prophylactic subcutaneous administration of BDGR-164 conferred 100% (VEEV), 88% (EEEV), and 63% (WEEV) survival. To evaluate the ability of BDGR-164 to reduce viral RNA/antigen, inflammation, and pathogenesis, we used RNASeq and histopathology of whole brain at 4 days post-infection (dpi). Viral RNA levels and antigen were reduced significantly in virus-infected and BDGR-164-treated versus virus-infected, sham-treated mice. Moreover, there was a significant reduction in host immune responses associated with inflammatory signaling, immune cell recruitment, and programmed cell death in virus-infected, BDGR-164 treated mice. Cytokine analyses of sera corroborated the reduction in upregulation of the immune response in virus-infected, BDGR-164 treated mice. Limited antiviral resistance to BDGR-164 was detected in one mouse on 4 dpi at NSP2:Y102C. In conclusion, our studies suggest that BDGR-164 has broad and potent prophylactic efficacy against the neurotropic alphaviruses.
2025-01-06 | GSE255795 | GEO
Project description:Brief assessment of VEEV TC-83 Capsid:RNA interactions.
2020-05-25 | GSE132125 | GEO
Project description:Suboptimal prophylactic treatments with BDGR-49 in a lethal VEEV TC-83 mouse model
| PRJNA1162158 | ENA
Project description:Experimental V4020 is derived from VEEV TC-83, a vaccine with a long track record of use in lab and military personnel at risk. V4020 was generated from an infectious DNA clone, secured genetic stability by employing stabilizing mutation at position 120 in the E2 protein, and by rearrangement of structural genes. In this study, serial passages in brain tissues of mice were performed to compare safety and genetic stability of V4020 and TC-83 experimental vaccines. During five serial passages in brain, less severe clinical manifestations and lower viral load were observed in V4020 mice and all animals survived. In contrast, 13.3% of mice met euthanasia criteria during the passages in TC-83 group. At 2 DPI, RNA-Seq analysis of brain tissues revealed that V4020 mice had lower rates of mutations throughout five passages. Higher synonymous mutation ratio was observed in the nsP4 (RdRP) gene of TC-83 compared to V4020 mice. At 2 DPI, both viruses induced different expression profiles of host genes involved into neuro-regeneration. Taken together, these results provide evidence for the improved safety and genetic stability of the experimental V4020 VEEV vaccine in a murine model. While no single nucleotide polymorphisms that have been previously linked to virulence were identified, more neuro-virulence markers were observed in serial passaged TC-83 compared to V4020. This study suggests a complex polygenic basis for neuro-virulent reversion in VEEV live attenuated vaccines and provides evidence for the advanced safety and genetic stability of V4020.
2020-06-01 | GSE142325 | GEO
Project description:Venezuelan, Western and Eastern Equine Encephalitis Virus (VEEV, WEEV and EEEV), genus Alphavirus, causes a febrile illness that may result in fatal neurological disease which has no FDA-approved antivirals for the prevention or treatment. To address this gap, we developed a novel brain-penetrant, small molecule, BDGR-49, which when administered subcutaneously at 6 mg/kg twice per day for 6 days conferred 100% protection against a lethal intranasal challenge of VEEV Trinidad donkey (TrD) in BALB/c mouse model. By eight days post-infection (dpi), viral load in the brain of BDGR-49-treated mice was significantly reduced whereas TrD-infected, sham-treated mice succumbed to disease on 5 dpi. Analysis of the host responses in the brains of VEEV TrD-infected, BDGR-49-treated, mice resulted in a significant reduction in expression of genes in pathways associated with inflammation and cell death.
2025-01-06 | GSE277300 | GEO
Project description:Venezuelan equine encephalitis virus (VEEV) causes a febrile illness that can progress to neurological disease with the possibility of death in human cases. The evaluation and optimization of therapeutics that target brain infections demands knowledge of the host’s response to VEEV, the dynamics of infection, and the potential for within-host evolution of the virus. We hypothesized that selective pressures during infection of the brain may differ temporally and spatially and so we investigated the dynamics of the host response, viral transcript levels, and genetic variation of VEEV TC-83 in eight areas of the brain in mice over 7 days post-infection (dpi). Viral replication increased throughout the brain until 5-6 dpi and decreased thereafter with neurons as the main site of viral replication. Low levels of genetic diversity were noted on 1 dpi, and was followed by an expansion in the genetic diversity of VEEV and nonsynonymous mutations (Ns) that peaked by 5 dpi. The proinflammatory response and the influx of immune cells mirrored the levels of virus and correlated with substantial damage to neurons by 5 dpi and increased activation of microglial cells and astrocytes. The prevalence and dynamics of Ns mutations suggests that the VEEV is under selection within the brain and that progressive neuroinflammation may play a role in acting as a selective pressure.
2023-07-21 | GSE213725 | GEO
Project description:Comparison of multiple passages of VEEV V4020 to VEEV TC-83 at 2 days after intracranial inoculation in BALB/c mice
| PRJNA596646 | ENA
Project description:Broad spectrum efficacy of BDGR-164 against neurotropic alphaviruses and correlates of protection
| PRJNA1076535 | ENA