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. IMPORTANCEWhereas 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. Semaphorins are members of a large family of secreted, membrane-anchored and transmembrane glycoproteins that can be f...

Genomic duplication and translocation of reactivation transactivator and bZIP-homolog genes is a conserved event in alcelaphine herpesvirus 1

“…Bovine turbinate fibroblasts (BT, ATCC CRL-1390) and MacT-Cre cells2634 were cultured in Dulbecco’s modified essential medium (D-MEM, Invitrogen Corporation). Madin-Darby bovine kidney cells (MDBK, ATCC CCL-22) were cultured in modified essential medium (MEM).…”

“…The entire genome of strain C500 has been cloned from low-passage, virulent virus as a bacterial artificial chromosome (BAC), in which infectivity and pathogenicity have been shown to be preserved24. The BAC clone is therefore an invaluable tool for studying the biology and pathogenesis of MCF78252627. The overall genome of strain C500 has been shown to be present in the BAC clone24, but the full sequence, and therefore the possible existence of undetected genetic changes, has not been determined.…”

The Genome of a Tortoise Herpesvirus (Testudinid Herpesvirus 3) Has a Novel Structure and Contains a Large Region That Is Not Required for Replication In Vitro or Virulence In Vivo

“…5B). Together, these data suggested that the TeHV-3 TE7 protein might also signal through Plexin-C1 and function similarly to other viral SEMAs (56). As for the TE8 protein, its sequence exhibits most of the residues found in the two family signature motifs characteristic of all cellular IL-10s:…”

“…The finding that the TeHV-3 TE7 and TE8 genes encode SEMA and IL-10 homologs, respectively, is particularly interesting for the following reasons. First, SEMA homologs have been reported in the family Herpesviridae only in the Macavirus genus of subfamily Gammaherpesvirinae (56). Second, although numerous IL-10 homologs have been described in the subfamilies Betaherpesvirinae and Gammaherpesvirinae (42), they have not been reported in the subfamily Alphaherpesvirinae.…”

Semaphorin 7A Promotes Chemokine-Driven Dendritic Cell Migration

“…Furthermore, the secreted viral semaphorins from pox and herpes viruses, which harbor some degree of homology to Sema7A, were demonstrated to affect DC adhesion, migration, and phagocytosis by acting on the cytoskeleton through plexin C1 (34,35).…”