[en] Alcelaphine gammaherpesvirus 1 (AlHV-1) asymptomatically persists in its natural host, the wildebeest. However, cross-species transmission to cattle results in the induction of an acute and lethal peripheral T cell lymphoma-like disease (PTCL), named malignant catarrhal fever (MCF). Our previous findings demonstrated an essential role for viral genome maintenance in infected CD8+ T lymphocytes but the exact mechanism(s) leading to lymphoproliferation and MCF remained unknown. To decipher how AlHV-1 dysregulates T lymphocytes, we first examined the global phenotypic changes in circulating CD8+ T cells after experimental infection of calves. T cell receptor repertoire together with transcriptomics and epigenomics analyses demonstrated an oligoclonal expansion of infected CD8+ T cells displaying effector and exhaustion gene signatures, including GZMA, GNLY, PD-1, and TOX2 expression. Then, among viral genes expressed in infected CD8+ T cells, we uncovered A10 that encodes a transmembrane signaling protein displaying multiple tyrosine residues, with predicted ITAM and SH3 motifs. Impaired A10 expression did not affect AlHV-1 replication in vitro but rendered AlHV-1 unable to induce MCF. Furthermore, A10 was phosphorylated in T lymphocytes in vitro and affected T cell signaling. Finally, while AlHV-1 mutants expressing mutated forms of A10 devoid of ITAM or SH3 motifs (or both) were able to induce MCF, a recombinant virus expressing a mutated form of A10 unable to phosphorylate its tyrosine residues resulted in the lack of MCF and protected against a wild-type virus challenge. Thus, we could characterize the nature of this γ-herpesvirus-induced PTCL-like disease and identify an essential mechanism explaining its development.
Disciplines :
Veterinary medicine & animal health
Author, co-author :
Gong, Meijiao ✱; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH)
Myster, Françoise ✱; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires (DMI) > Vaccinologie vétérinaire
Azouz, Abdulkader; Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium ; Center for Research in Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium
Sanchez Sanchez, Guillem; Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium ; Center for Research in Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium ; Department of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles, Brussels 1050, Belgium ; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), WEL Research Institute, Wavre 1300, Belgium
Li, Shifang ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH)
CHARLOTEAUX, Benoit ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
Yang, Bin ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Nichols, Jenna ; Medical Research Council (MRC)-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom
Lefevre, Lucas; The Roslin Institute, The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom
Javaux, Justine ; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires (DMI) > Immunologie vétérinaire
Leemans, Sylvain ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Nivelles, Olivier ; Université de Liège - ULiège > GIGA > GIGA Research (AFT)
van Campe, Willem; Sciensano, Scientific Directorate Infectious Diseases in Animals, Experimental Center Machelen, Machelen 1830, Belgium
Roels, Stefan ; Sciensano, Scientific Directorate Infectious Diseases in Animals, Experimental Center Machelen, Machelen 1830, Belgium
Mostin, Laurent ; Sciensano, Scientific Directorate Infectious Diseases in Animals, Experimental Center Machelen, Machelen 1830, Belgium
van den Berg, Thierry; Sciensano, Scientific Directorate Infectious Diseases in Animals, Experimental Center Machelen, Machelen 1830, Belgium
Davison, Andrew J ; Medical Research Council (MRC)-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom
Gillet, Laurent ; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires (DMI) > Vaccinologie vétérinaire
Connelley, Timothy; The Roslin Institute, The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom
Vermijlen, David ; Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium ; Center for Research in Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium ; Department of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles, Brussels 1050, Belgium ; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), WEL Research Institute, Wavre 1300, Belgium
Goriely, Stanislas; Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium ; Center for Research in Immunology, Université Libre de Bruxelles, Gosselies 6041, Belgium
Vanderplasschen, Alain ; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires (DMI) > Immunologie vétérinaire ; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), WEL Research Institute, Wavre 1300, Belgium
Dewals, Benjamin G ; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires (DMI) > Immunologie vétérinaire ; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), WEL Research Institute, Wavre 1300, Belgium
F.R.S.-FNRS - Fonds de la Recherche Scientifique WELBIO - Walloon Excellence in Life Sciences and Biotechnology ERDF - European Regional Development Fund
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