A research team led by ULiège scientists has published a groundbreaking study on malignant catarrhal fever (MCF). This disease is caused by the alcelaphine gammaherpesvirus 1 (AlHV-1), which infects its natural host, the wildebeest. This study sheds light on the mechanisms by which this virus, which is asymptomatic and latent in the wildebeest, causes an oligoclonal expansion of CD8+ T lymphocytes in cattle, leading to the development of MCF.
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n 2013, the research team had already demonstrated (1) that malignant catarrhal fever (MCF), which is fatal in cattle, only develops if the AlHV-1 virus can maintain a latent state replicating its viral genome in CD8+ T lymphocytes without producing viral particles.
In this new study, we used high-throughput sequencing approaches on CD8+ T lymphocytes from sick cattle, compared with healthy animals," explains Benjamin Dewals, a researcher at FARAH and lecturer in the Department of Infectious and Parasitic Diseases at the Faculty of Veterinary Medicine. We were able to characterise the T lymphocyte repertoire (TCR sequencing) as well as the expression of cellular and viral genes specifically regulated during infection".
Discovery of a crucial viral gene
Thanks to these analyses, the team identified a viral gene coding for a protein, called A10, potentially involved in the intracellular signalling of infected cells. This protein turned out to be essential for the development of the disease without affecting viral replication in cell culture", explains Meijiao Gong, PhD student at ULiège and first author of the article published in PNAS (2). In addition, we have shown that phosphorylation of A10 alters the phenotype of T lymphocytes, causing their proliferation and the development of MCF".
The results obtained provide an in-depth description of the reprogramming of CD8+ T cells during infection with AlHV-1 and identify A10 as a key element in the development of MCF. This discovery opens up new perspectives for understanding the mechanisms of malignant lymphoproliferation induced by herpesviruses and provides a promising basis for the development of an effective vaccine against this bovine disease.
"This study represents a significant step forward in our understanding of malignant catarrhal fever and offers hope for the development of a vaccine capable of protecting cattle against this devastating disease," concludes Benjamin Dewals.
Multi-omics analysis of circulating CD8 T lymphocytes isolated from healthy cattle (Mock), infected with an attenuated (73DEL ), or virulent (WT) strain of AlHV-1 inducing MCF . Sequencing data (TCR-seq, RNA-seq, ATAC-seq, and scRNA-V(D)J-seq) determined that MCF is characterized by an oligoclonal expansion of highly activated T lymphocytes displaying a phenotype close to exhaustion. Among the viral genes expressed in CD8 T lymphocytes, the A10 protein was shown to be responsible for the constitutive alteration in the activation of latently infected T lymphocytes, leading to the development of MCF. Credit : University of Liège
* A gammaherpesvirus (Gammaherpesvirinae) is a type of virus belonging to the herpesvirus subfamily, which is a large family of double-stranded DNA viruses. Gammaherpesviruses are distinguished from other subfamilies by several unique characteristics and are of great interest in virology and medicine due to their ability to establish latent infections and cause chronic diseases and cancers. Gammaherpesviruses provide valuable models for studying the mechanisms of viral latency, cellular transformation, and interactions between viruses and the host immune system.
(1) Palmeira et al., An essential role for gamma-herpesvirus latency-associated nuclear antigen homolog in an acute lymphoproliferative disease of cattle, Proceedings of the National Academy of Sciences of the United States of America (PNAS) 2013.
(2) Meijiao Gong, Françoise Myster, Abdulkader Azouz, Guillem Sanchez Sanchez, Shifang, Li, Benoit Charloteaux, Bin Yang, Jenn Nichols, Lucas Lefevre, Justine Javaux, Sylvain, Leemans, Olivier Nivelles, Willem van Camp, Stefan Roels, Laurent Mostin, Thierry van den, Berg, Andrew J. Davison, Laurent Gillet, Tim Connelley, David Vermijlen , Stanislas, Goriely, Alain Vanderplasschen, Benjamin G. Dewals, Unraveling clonal CD8 T cell expansion and discovery of novel factors in γ-herpesvirus-induced lymphomagenesis, PNAS, 2024
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