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Abstract :
[en] Among gammaherpesvirus, the Macavirus genus is composed of viruses associated to malignant catarrhal fever (MCF) and other phylogenetically related viruses. MCF is a frequently fatal lymphoproliferative disease. Three macaviruses inducing MCF have been entirely sequenced: alcelaphine herpesvirus 2 (AlHV-2), ovine herpesvirus 2 (OvHV-2) and alcelaphine herpesvirus 1 (AlHV-1). Sheep carries OvHV-2 asymptomatically while wildebeest is infected with AlHV-1 without developing any clinical signs or lesions. Both viruses represent the most studied macaviruses. In susceptible ruminants, OvHV-2 and AlHV-1 induce the sheep-associated form and the wildebeest-derived form of MCF (WD-MCF), respectively. Economic consequences of WD-MCF are significant in sub-Saharan Africa. WD-MCF is characterized by the proliferation and infiltration of lymphoblastoid T cells surrounding blood vessels and can be considered as a model for peripheral T cell lymphoma caused by a virus. Rabbits are used as experimental model to study MCF. This species develops clinical signs and lesions that they are indistinguishable from those observed in other susceptible species. Until recently, available data on WD-MCF pathogenesis were limited to the simple description clinical signs and lesions. Recently, it was demonstrated that CD8+ T cells proliferate and that this cellular expansion is associated with a severe increase of the viral load in PBMC and lymphoid organs (Dewals et al., 2008). The cloning of the AlHV-1 genome as an infectious and pathogenic bacterial artificial chromosome (BAC) has greatly facilitated the study of individual gene of AlHV-1 (Dewals et al., 2006). Among herpesviruses, viral semaphorins can only be found in members of the Macavirus genus. OvHV 2 encodes Ov3, and AlHV-2 and AlHV-1 encode A3, both genes encoding a semaphorin homolog. Semaphorins are proteins characterized by a conserved amino-terminal domain, the SEMA domain. The roles of the semaphorins on cytoskeleton dynamics have been widely studied. Viral semaphorins could mediate immune evasion mechanisms or viral dissemination and could be involved in specific properties of macaviruses.
The first study of the present thesis was dedicated to the investigation of the pathogenesis of WD-MCF and the role of latency. We investigated the distribution of the AlHV-1 infection in the lesions and demonstrated that the infiltration of CD8+ T cells in different lymphoid and non-lymphoid organs and tissues is directly associated with a non-productive viral infection. The second study focused on the A3 gene of AlHV-1 and its potential functions during WD-MCF. We showed that the A3 gene is expressed during the early phase of the viral infection and encodes a functional semaphorin that was termed AlHV-sema. AlHV-sema was able to induce cell retraction. Despite the observed independent acquisition of pox- and herpesvirus semaphorins, AlHV-sema inhibited phagocytosis by dendritic cells and migration to the draining lymph node through mechanisms similar to poxvirus semaphorin. AlHV-sema could also facilitate viral dissemination or confer immune evasion functions. Next, we investigated whether AlHV-sema could affect WD-MCF induction. We did not observe any effect of the absence of AlHV-sema expression during the development of WD-MCF after rabbit nasal infection.
Macaviruses are swine and ruminant gammaherpesviruses responsible for a latent asymptomatic infection in their natural species. The development of MCF in other ruminant susceptible species is due to cross-species transmission. During evolution, the gene selection in susceptible species is certainly reduced due to the fact that these species are dead-end hosts. Thus, it is difficult to address the role of AlHV-1 specific genes in MCF as these genes have evolved in other species. Nevertheless, we brought in this work important insight for our understanding of the pathogenesis of WD-MCF and we identified AlHV-sema as a potential immunoevasion factor.
DEWALS B., MYSTER F., PALMEIRA L., GILLET L., ACKERMANN M., VANDERPLASSCHEN A. Ex vivo bioluminescence detection of alcelaphine herpesvirus 1 infection during malignant catarrhal fever. J. Virol., 2011, 85, 6941-6954.
MYSTER F., PALMEIRA L., SOREL O., BOUILLENNE F., DEPAUW E., SCHWARTZ-CORNIL I., VANDERPLASSCHEN A., DEWALS B.G. Viral semaphorin inhibits dendritic cell phagocytosis and migration but is not essential for gamma-herpesvirus-induced lymphoproliferation in malignant catarrhal fever. J. Virol., 2015.
