Project description:Human neuronal differentiation alters responsiveness to innate immune stimuli and virus infections. We used microarrays to examine the transcriptional responses of the human BE(2)-C neuroblastoma cell line to infection with western equine encephalitis virus (WEEV).
Project description:Human neuronal differentiation alters responsiveness to innate immune stimuli and virus infections. We used microarrays to examine the transcriptional responses of the human BE(2)-C neuroblastoma cell line to infection with western equine encephalitis virus (WEEV). Experiment Overall Design: Cultured BE(2)-C cells were differentiated with 10 uM all-trans retinoic acid (RA) for 3 weeks and infected with WEEV at an MOI=10 for 6 h, and Affymetrix Human Genome Array U133 Plus 2.0 chips were used to analyze transcript levels.
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.
Project description:Venezuelan equine encephalitis virus (VEEV) is a neurotropic alphavirus that causes neurological disease in both humans and equine. In this study we paired spatial transcriptomics and a mouse model of VEEV to generate a transcriptomic profile of infected or control brains at 6 days post infection. We identified regionally distinct myeloid and lymphocyte populations, contributing to our understanding of the neuroinflammation caused by VEEV.
Project description:Differing from other experimental models, intranasal infection with vaccine strain of Venezuelan equine encephalitis virus, VEEV, (TC83) caused high titer infection in the brain and 90–100% mortality in the C3H/HeN murine model. Intranasal infection with VEEV (TC83) caused persistent viral infection in the brains of mice without functional αβ T-cells (αβ-TCR -/-). While wild-type C57BL/6 mice clear infectious virus in the brain by 13 dpi, αβ-TCR -/- maintain infectious virus in the brain to 92 dpi. To better characterize the susceptibility to disease development in different strains of mice, we have analyzed the gene transcriptomes in the brains of infected mice.