title: Viral semaphorin inhibits dendritic cell phagocytosis and migration but is not essential for gammaherpesvirus-induced lymphoproliferation in malignant catarrhal fever.
abstract: Viral semaphorins are semaphorin 7A (sema7A) mimics found in pox- and herpesviruses. Among herpesviruses, semaphorins are encoded by gammaherpesviruses of the Macavirus genus only. Alcelaphine herpesvirus 1 (AlHV-1) is a macavirus that persistently infects wildebeest asymptomatically but induces malignant catarrhal fever (MCF) when transmitted to several species of susceptible ruminants and the rabbit model. MCF is caused by the activation/proliferation of latently infected T lymphocytes. Viral semaphorins have been suggested to mediate immune evasion mechanisms and/or directly alter host T cell function. We studied AlHV-sema, the viral semaphorin encoded by the A3 gene of AlHV-1. Phylogenetic analyses revealed independent acquisition of pox- and herpesvirus semaphorins, suggesting that these proteins might have distinct functions. AlHV-sema showed a predicted three-dimensional structure very similar to sema7A and conserved key residues in sema7A-plexinC1 interaction. Expression analyses revealed that AlHV-sema is a secreted 93-kDa glycoprotein expressed during the early phase of virus replication. Purified AlHV-sema was able to bind to fibroblasts and dendritic cells and induce F-actin condensation and cell retraction through a plexinC1 and Rho/cofilin-dependent mechanism. Cytoskeleton rearrangement was further associated with inhibition of phagocytosis by dendritic cells and migration to the draining lymph node. Next, we generated recombinant viruses and demonstrated that the lack of A3 did not significantly affect virus growth in vitro and did not impair MCF induction and associated lymphoproliferative lesions. In conclusion, AlHV-sema has immune evasion functions through mechanisms similar to poxvirus semaphorin but is not directly involved in host T cell activation during MCF.
  
  
  OBJECTIVE
  Whereas most poxviruses encode viral semaphorins, semaphorin-like genes have only been identified in few gammaherpesviruses belonging to the Macavirus genus. Alcelaphine herpesvirus 1 (AlHV-1) is a macavirus carried asymptomatically by wildebeest but induces a latency-associated lymphoproliferative disease of T lymphocytes in various ruminant species, namely, malignant catarrhal fever (MCF). Viral semaphorins have been hypothesized to have immune evasion functions and/or be involved in activating latently infected T cells. We present evidence that the viral semaphorin AlHV-sema inhibits dendritic cell phagocytosis and migration to the draining lymph node, both being indispensable mechanisms for protective antiviral responses. Next, we engineered recombinant viruses unable to express AlHV-sema and demonstrated that this protein is dispensable for the induction of MCF. In conclusion, this study suggests that herpesvirus and poxvirus semaphorins have independently evolved similar functions to thwart the immune system of the host while AlHV-sema is not directly involved in MCF-associated T-cell activation.
authors.affiliation: Fundamental and Applied Research in Animals and Health, Laboratory of Immunology-Vaccinology, University of Liège, Liège, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Myster
authors.affiliation: Fundamental and Applied Research in Animals and Health, Laboratory of Immunology-Vaccinology, University of Liège, Liège, Belgium GIGA-Research, Unit of Animal Genomics, University of Liège, Liège, Belgium.
authors.forename: Leonor
authors.initials: L
authors.lastname: Palmeira
authors.affiliation: Fundamental and Applied Research in Animals and Health, Laboratory of Immunology-Vaccinology, University of Liège, Liège, Belgium.
authors.forename: Océane
authors.initials: O
authors.lastname: Sorel
authors.affiliation: Centre for Protein Engineering, University of Liège, Liège, Belgium.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bouillenne
authors.affiliation: Mass Spectrometry Laboratory, Department of Chemistry, University of Liège, Liège, Belgium.
authors.forename: Edwin
authors.initials: E
authors.lastname: DePauw
authors.affiliation: Virologie et Immunologie Moléculaires, UR892 INRA, Jouy-en-Josas Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schwartz-Cornil
authors.affiliation: Fundamental and Applied Research in Animals and Health, Laboratory of Immunology-Vaccinology, University of Liège, Liège, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Vanderplasschen
authors.affiliation: Fundamental and Applied Research in Animals and Health, Laboratory of Immunology-Vaccinology, University of Liège, Liège, Belgium bgdewals@ulg.ac.be.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Dewals
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D005347:Fibroblasts / Q000187:drug effects; D018142:Gammaherpesvirinae / Q000235:genetics / Q000276:immunology*; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D008214:Lymphocytes / Q000502:physiology*; D008304:Malignant Catarrh / Q000276:immunology / Q000821:virology*; D010587:Phagocytosis; D010802:Phylogeny; D011487:Protein Conformation; D039961:Semaphorins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D017386:Sequence Homology, Amino Acid
chemical_list: D039961:Semaphorins