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| Status |
Public on May 01, 2024 |
| Title |
Deep sequencing after alcelaphine gammaherpesvirus 1 infection reveals the nature of CD8+ T cell expansion and identify an essential viral protein for fatal bovine malignant catarrhal fever [ATAC-seq] |
| Organism |
Bos taurus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Alcelaphine gammaherpesvirus 1 (AlHV-1) is a member of the Gammaherpesvirinae subfamily and establishes asymptomatic latent infection in its natural host species, the wildebeest. Cross-species transmission to various ruminant species including cattle can occur, resulting in the induction of malignant catarrhal fever (MCF), a deadly peripheral T cell lymphoproliferative disease. Here, we experimentally infected calves to confirm that AlHV-1 latency-associated gene expression is essential for persistent infection of CD8+ T cells and MCF development. Then, deep sequencing of the T cell receptor repertoire revealed an oligoclonal expansion of peripheral CD8+ T cells during bovine MCF, associated with transcriptomic and epigenetic changes identified by (sc)RNA-seq and ATAC-seq analyses which indicated a mixed effector/memory and exhaustion phenotype of infected cells in vivo. Analysis of the viral genome transcription identified viral genomic regions being expressed in infected CD8+ T cells, such as the region predicted to encode the gene A10. A10 encodes a transmembrane signaling protein displaying multiple tyrosine residues, with predicted ITAM and SH3 motifs. We could demonstrate that impaired expression of A10 did not affect AlHV-1 replication in vitro but rendered AlHV-1 unable to induce MCF in the rabbit experimental model, and we showed that A10 is phosphorylated in T lymphocytes in vitro and affects T cell signaling. Finally, while AlHV-1 viruses expressing mutated forms of A10 devoid of ITAM and/or SH3 motifs could induce MCF, an A10 knock-in viral mutant unable to phosphorylate tyrosine residues resulted in the absence of MCF development. Overall, we identified AlHV-1-induced phenotypic changes in CD8+ T cells during MCF and demonstrated that A10 expression in infected CD8+ T lymphocytes results in the dysregulation of T cell signaling and MCF.
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| Overall design |
Bovine PBMC were isolated from veinous blood collected from the jugular vein. PBMCs were subjected to a microbead-based negative selection protocol to isolate CD8 T cells.
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| Contributor(s) |
Gong M, Myster F, Azouz A, Sanchez Sanchez G, Nichols J, Lefevre L, Li S, Charloteaux B, Yang B, Javaux J, Leemans S, Nivelles O, van Campe W, Roels S, Mostin L, van den Bergh T, Davison AJ, Gillet L, Connelley T, Vermijlen D, Goriely S, Vanderplasschen A, Dewals BG |
| Citation missing |
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| Submission date |
Jan 19, 2024 |
| Last update date |
May 01, 2024 |
| Contact name |
Abdulkader AZOUZ |
| E-mail(s) |
Abdulkader.azouz@ulb.be
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| Organization name |
Université Libre de Bruxelles
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| Street address |
Rue Adrienne Bolland, 8
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| City |
GOSSELIES |
| ZIP/Postal code |
6041 |
| Country |
Belgium |
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| Platforms (1) |
| GPL26012 |
Illumina NovaSeq 6000 (Bos taurus) |
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| Samples (13)
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| This SubSeries is part of SuperSeries: |
| GSE253729 |
Deep sequencing after alcelaphine gammaherpesvirus 1 infection reveals the nature of CD8+ T cell expansion and identify an essential viral protein for fatal bovine malignant catarrhal fever |
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| Relations |
| BioProject |
PRJNA1066838 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE253727_RAW.tar |
2.1 Gb |
(http)(custom) |
TAR (of BIGWIG) |
SRA Run Selector |
| Raw data are available in SRA |
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