Clearance of a persistent picornavirus infection is associated with enhanced pro-apoptotic and cellular immune responses
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ABSTRACT:
PROVIDER: PRJNA408127 | ENA |
REPOSITORIES: ENA
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Project description:Immunomodulatory mechanisms associated with clearance versus persistence of foot-and-mouth disease virus (FMDV) in micro-dissected compartments of the bovine nasopharynx were investigated using qRT-PCR and whole transcriptome microarray. Analysis of tissue samples obtained by laser capture microdissection (LCM) during transitional and persistent phases of infection demonstrated significant differences in transcriptome profiles of animals that cleared infection versus those that became persistently infected carriers. The combined output of the analyses suggested that clearance of FMDV from the nasopharyngeal mucosa is associated with an activated cellular immune response. This was supported by induction of Th1-associated mediators and upregulation of multiple targets associated with activation of T cell-mediated cytotoxicity in tissues from animals that cleared infection. Contrastingly, the pattern of gene regulation in FMDV carriers during transitional and persistent phases of infection suggested inhibition of T cell activation and promotion of Th2 polarization. Regulation of genes associated with apoptosis or cellular proliferation suggested inhibition of apoptotic pathways and promotion of cellular proliferation associated with FMDV persistence while the opposite patterns were found in animals that cleared infection. The findings presented herein emphasize the critical importance of Th1-mediated cellular immunity for clearance of persistent FMDV infection. Additionally, the strong antibody-mediated immune response that is induced during acute infection may impair efficient clearance of intra-cellular virus, thereby promoting FMDV persistence. Thus, a critical balance between Th1 and Th2 -mediated immunity is essential for successful clearance of FMDV infection and should be considered for development of next-generation vaccines and antiviral products.
2017-12-19 | GSE104058 | GEO
Project description:Long-term persistent viral infections cause substantial morbidity and associated economic losses in human and veterinary contexts. Yet, the mechanisms associated with establishment of persistent infections are poorly elucidated. We investigated immunomodulatory mechanisms associated with clearance versus persistence of foot-and-mouth disease virus (FMDV) in micro-dissected compartments of the bovine nasopharynx by microarray. The use of laser-capture microdissection allowed elucidation of differential gene regulation within distinct anatomic compartments critical to FMDV infection. Analysis of samples from transitional and persistent phases of infection demonstrated significant differences in transcriptome profiles of animals that cleared infection versus those that became persistently infected carriers. Specifically, it was demonstrated that clearance of FMDV from the nasopharyngeal mucosa was associated with upregulation of targets associated with activation of T cell-mediated immunity. Contrastingly, gene regulation in FMDV carriers suggested inhibition of T cell activation and promotion of Th2 polarization. These findings were corroborated by immunofluorescence microscopy which demonstrated relative abundance of CD8+?T cells in the nasopharyngeal mucosa in association with clearance of FMDV. The findings presented herein emphasize that a critical balance between Th1 and Th2 -mediated immunity is essential for successful clearance of FMDV infection and should be considered for development of next-generation vaccines and antiviral products.
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Project description:Although apoptotic cells (ACs) contain nucleic acids that can be recognized by Toll-like receptors (TLRs), engulfment of ACs does not initiate inflammation in healthy organisms. To better understand this phenomenon, we identified and characterized macrophage populations that continually engulf ACs in several distinct tissues. These macrophages share characteristics compatible with immunologically silent clearance of ACs, including high expression of AC recognition receptors, low expression of TLR9, and reduced TLR responsiveness to nucleic acids. When removed from tissues, these macrophages lose many of these characteristics and generate inflammatory responses to AC-derived nucleic acids, suggesting that cues from the tissue microenvironment are required to program macrophages for silent AC clearance. We show that KLF2 and KLF4 control expression of many genes within this AC clearance program. Coordinated expression of AC receptors with genes that limit responses to nucleic acids may represent a central feature of tissue macrophages that ensures maintenance of homeostasis.
2017-11-15 | GSE93820 | GEO
Project description:TNF-Related Apoptosis Inducing Ligand (TRAIL) binds to and activates death receptors to stimulate caspase-8 and apoptosis with higher efficiency in cancer than normal cells but the development of apoptosis resistance has limited its clinical efficacy. We found that stable, but not transient knockdown of the ABL tyrosine kinase enhanced the apoptotic response to TRAIL. Re-expression of Abl, but not its nuclear import- or kinase-defective mutant, in the ABL-knockdown cells re-established apoptosis suppression. TRAIL is known to stimulate caspase-8 ubiquitination (Ub-C8), which can facilitate caspase-8 activation or degradation by the lysosomes. In the ABL-knockdown cells, we found a higher basal level of Ub-C8 that was not further increased by lysosomal inhibition. Re-expression of Abl in the ABL-knockdown cells reduced the basal Ub-C8, correlating with apoptosis suppression. We found that lysosomal inhibition by chloroquine (CQ) could also enhance TRAIL-induced apoptosis. However, this pro-apoptotic effect of CQ was lost in the ABL-knockdown cells but restored by Abl re-expression. Interestingly, kinase inhibition at the time of TRAIL stimulation was not sufficient to enhance apoptosis. Instead, persistent treatment for several days with imatinib, an ABL kinase inhibitor, was required to cause the enhanced and the CQ-insensitive apoptotic response to TRAIL. Together, these results show that persistent loss of nuclear ABL tyrosine kinase function can sensitize cells to TRAIL and suggest that long-term exposure to the FDA-approved ABL kinase inhibitors may potentiate apoptotic response to TRAIL-based cancer therapy.
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Project description:Goal: Determine the role of microglia in the antiviral response during neurotropic picornavirus infection of C57BL/6J and SJL/J mice and whether absence of microglia would affect CD4 and CD8 T cell functions. Methods: Brains from C57BL/6J and SJL/J mice treated with PLX5622 (to deplete microlgia) or control diet were harvested at 6 days post TMEV-infection. CD4+ T cells and CD8+ T cells were obtained using Easy Sep Mouse CD4+ T cell isolation Kit and Easy Sep Mouse CD8+ T cell isolation Kit (Stemcell). RNA was obtained using RNeasy (QIAGEN) and Illumina TruSeq stranded RNA Kit with Ribo-Zero Gold was then utilized to prepare cDNA library for RNA-seq. Results: Our results demonstrate strain-specific effects of the CSF1R-microglia axis in the context of neurotropic viral infection as well as inherent differences in microglial antigen presentation and subsequent T cell crosstalk that contribute to susceptibility to neurotropic picornavirus infection.
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Project description:While Nanos-mediated maintenance of germ cells in Drosophila and mice has been related to regulation of apoptosis, the relevance of these findings to human physiology is uncertain. We show here that the NM_199461.4(NANOS1_v001):c.[100C>A;240_242del]; NM_199461.4(NANOS1_i001):p.[(Pro34Thr);(Ser83del)] double mutation, which has previously been associated with a lack of germ cells in the testes of infertile patients, causes NANOS1 to functionally switch from being anti-apoptotic to pro-apoptotic in the human male germ cell line TCam-2.
2019-08-01 | GSE134802 | GEO