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See detailA gammaherpesvirus infection protects against allergic asthma.
Machiels, Bénédicte ULg; Dourcy, Mickael ULg; Sabatel, Catherine ULg et al

Poster (2014, December 12)

The “hygiene hypothesis” proposes that the augmentation of allergic diseases in developed countries could be linked to a reduced exposure to infections during childhood. Surprisingly, the potential ... [more ▼]

The “hygiene hypothesis” proposes that the augmentation of allergic diseases in developed countries could be linked to a reduced exposure to infections during childhood. Surprisingly, the potential protective role of herpesvirus infections against allergy development has never been addressed directly. In this study, we used the Murid herpesvirus 4 (MuHV-4) to study the impact of a persistent gammaherpesvirus infection on the development of House Dust Mites (HDM)-induced allergic asthma. Our results revealed that MuHV-4 infection affects both the sensitization and the challenging phases of HDM-induced airway allergy. In particular, we highlighted that MuHV-4 infection strongly impacts the lung innate immune response. Indeed, while the dendritic cells remained competent to uptake antigens and to migrate to the draining lymph nodes, MuHV-4 infection impaired their ability to trigger HDM sensitization. In the future, these results could allow us to develop strategies to prevent the development of TH2-skewed responses against respiratory allergens. [less ▲]

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See detailSchistosoma mansoni egg-induced inflammation inhibits γ-herpesvirus replication
Dougall, Annette ULg; Rolot, Marion ULg; Vanderplasschen, Alain ULg et al

Poster (2014, December)

Geographically, S. mansoni overlaps with human γ-herpesvirus infections such as Kaposi’s sarcoma-associated herpesvirus. The strongly regulated Th2-type immune response generated during infection by S ... [more ▼]

Geographically, S. mansoni overlaps with human γ-herpesvirus infections such as Kaposi’s sarcoma-associated herpesvirus. The strongly regulated Th2-type immune response generated during infection by S. mansoni may jeopardize or improve the host’s ability to generate effective immunity against co-infecting pathogens, such as viruses. Here, we have trialled two approaches using murine herpesvirus-4 (MuHV-4). The first used a S. mansoni egg model to induce lung granulomas followed by intranasal infection with the MuHV-4-luc+ recombinant virus. Alternatively, we naturally infected mice with S. mansoni cercariae to induce a systemic Th2-type response and granulomas in the liver and intestine before intranasal MuHV-4-luc+ infection. We observed in both models a significant reduction of MuHV-4 replication in the lungs at day 5 and 7 pi associated with reduced weight loss caused by MuHV-4 infection. These results indicate that helminth induce Th2-type responses could inhibit and protect against viral infection. [less ▲]

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See detailThe A2 gene of alcelaphine herpesvirus-1 is a transcriptional regulator affecting cytotoxicity in virus-infected T cells but is not required for malignant catarrhal fever induction in rabbits.
Parameswaran, Nevi; Dewals, Benjamin G ULg; Giles, Tom C. et al

in Virus research (2014)

Alcelaphine herpesvirus-1 (AlHV-1) causes malignant catarrhal fever (MCF). The A2 gene of AlHV-1 is a member of the bZIP transcription factor family. We wished to determine whether A2 is a virulence gene ... [more ▼]

Alcelaphine herpesvirus-1 (AlHV-1) causes malignant catarrhal fever (MCF). The A2 gene of AlHV-1 is a member of the bZIP transcription factor family. We wished to determine whether A2 is a virulence gene or not and whether it is involved in pathogenesis by interference with host transcription pathways. An A2 gene knockout (A2DeltaAlHV-1) virus, revertant (A2revAlHV-1) virus, and wild-type virus (wtAlHV-1) were used to infect three groups of rabbits. A2DeltaAlHV-1-infected rabbits succumbed to MCF, albeit with a delayed onset compared to the control groups, so A2 is not a critical virulence factor. Differential gene transcription analysis by RNAseq and qRT-PCR validation of a selection of these was performed in infected large granular lymphocyte (LGL) T cells obtained in culture from the MCF-affected animals. A2 was involved in the transcriptional regulation of immunological, cell cycle and apoptosis pathways. In particular, there was a bias towards gammadelta T cell receptor (TCR) expression and downregulation of alphabeta TCR. TCR signalling, apoptosis, cell cycle, IFN-gamma and NFAT pathways were affected. Of particular interest was partial inhibition of the cytotoxicity-associated pathways involving perforin and the granzymes A and B in the A2DeltaAlHV-1-infected LGLs compared to controls. In functional assays, A2DeltaAlHV-1-infected LGLs were significantly less cytotoxic than wtAlHV-1- and A2revAlHV-1-infected LGLs using rabbit corneal epithelial cells (SIRC) as targets. This implies that A2 is involved in a pathway enhancing the expression of LGL cytotoxicity. This is important as virus-infected T cell cytotoxicity in vivo has been suggested as a potential mechanism of disease induction in MCF. [less ▲]

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See detailIL-4Ralpha-associated antigen processing by B cells promotes immunity in Nippostrongylus brasiliensis infection.
Horsnell, William G. C.; Darby, Matthew G.; Hoving, Jennifer C. et al

in PLoS pathogens (2013), 9(10), 1003662

In this study, B cell function in protective T(H)2 immunity against N. brasiliensis infection was investigated. Protection against secondary infection depended on IL-4Ralpha and IL-13; but not IL-4 ... [more ▼]

In this study, B cell function in protective T(H)2 immunity against N. brasiliensis infection was investigated. Protection against secondary infection depended on IL-4Ralpha and IL-13; but not IL-4. Protection did not associate with parasite specific antibody responses. Re-infection of B cell-specific IL-4Ralpha(-)/(-) mice resulted in increased worm burdens compared to control mice, despite their equivalent capacity to control primary infection. Impaired protection correlated with reduced lymphocyte IL-13 production and B cell MHC class II and CD86 surface expression. Adoptive transfer of in vivo N. brasiliensis primed IL-4Ralpha expressing B cells into naive BALB/c mice, but not IL-4Ralpha or IL-13 deficient B cells, conferred protection against primary N. brasiliensis infection. This protection required MHC class II compatibility on B cells suggesting cognate interactions by B cells with CD4(+) T cells were important to co-ordinate immunity. Furthermore, the rapid nature of these protective effects by B cells suggested non-BCR mediated mechanisms, such as via Toll Like Receptors, was involved, and this was supported by transfer experiments using antigen pulsed Myd88(-)/(-) B cells. These data suggest TLR dependent antigen processing by IL-4Ralpha-responsive B cells producing IL-13 contribute significantly to CD4(+) T cell-mediated protective immunity against N. brasiliensis infection. [less ▲]

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See detailLung-resident CD4 T cells are sufficient for IL-4Ralpha-dependent recall immunity to Nippostrongylus brasiliensis infection.
Thawer, S. G.; Horsnell, W. Gc; Darby, M. et al

in Mucosal Immunology (2013)

Immunity to Nippostrongylus brasiliensis reinfection requires pulmonary CD4+ T-cell responses. We examined whether secondary lymphoid recruited or pre-existing lung CD4+ T-cell populations coordinated ... [more ▼]

Immunity to Nippostrongylus brasiliensis reinfection requires pulmonary CD4+ T-cell responses. We examined whether secondary lymphoid recruited or pre-existing lung CD4+ T-cell populations coordinated this immunity. To do this, we blocked T-cell egress from lymph nodes using Fingolimod (FTY720). This impaired host ability to resolve a primary infection but did not change effectiveness of recall immunity. Associated with this effective recall immunity was the expansion and T helper type 2 polarization of a pre-existing pulmonary CD4+ T-cell population. LTbetaR-Ig (lymphotoxin beta-receptor fusion protein)-mediated disruption of stromal cell organization of immune cells did not disrupt this recall immunity, suggesting that protection was mediated by a pulmonary interstitial residing CD4+ T-cell population. Adoptive transfer of N. brasiliensis-experienced pulmonary CD4+ T cells from FTY720-treated wild-type or T-cell interleukin (IL)-4Ralpha-deficient mice demonstrated protection to be IL-4Ralpha dependent. These results show that pre-existing CD4+ T cells can drive effective recall immunity to N. brasiliensis infection independently of T-cell recruitment from secondary lymphoid organs.Mucosal Immunology advance online publication 19 June 2013; doi:10.1038/mi.2013.40. [less ▲]

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See detailAn essential role for gamma-herpesvirus latency-associated nuclear antigen homolog in an acute lymphoproliferative disease of cattle.
Palmeira, Leonor; Sorel, Océane ULg; Van Campe, Willem et al

in Proceedings of the National Academy of Sciences of the United States of America (2013)

Wildebeests carry asymptomatically alcelaphine herpesvirus 1 (AlHV-1), a gamma-herpesvirus inducing malignant catarrhal fever (MCF) to several ruminant species (including cattle). This acute and lethal ... [more ▼]

Wildebeests carry asymptomatically alcelaphine herpesvirus 1 (AlHV-1), a gamma-herpesvirus inducing malignant catarrhal fever (MCF) to several ruminant species (including cattle). This acute and lethal lymphoproliferative disease occurs after a prolonged asymptomatic incubation period after transmission. Our recent findings with the rabbit model indicated that AlHV-1 infection is not productive during MCF. Here, we investigated whether latency establishment could explain this apparent absence of productive infection and sought to determine its role in MCF pathogenesis. First, whole-genome cellular and viral gene expression analyses were performed in lymph nodes of MCF-developing calves. Whereas a severe disruption in cellular genes was observed, only 10% of the entire AlHV-1 genome was expressed, contrasting with the 45% observed during productive infection in vitro. In vivo, the expressed viral genes included the latency-associated nuclear antigen homolog ORF73 but none of the regions known to be essential for productive infection. Next, genomic conformation analyses revealed that AlHV-1 was essentially episomal, further suggesting that MCF might be the consequence of a latent infection rather than abortive lytic infection. This hypothesis was further supported by the high frequencies of infected CD8+ T cells during MCF using immunodetection of ORF73 protein and single-cell RT-PCR approaches. Finally, the role of latency-associated ORF73 was addressed. A lack of ORF73 did not impair initial virus replication in vivo, but it rendered AlHV-1 unable to induce MCF and persist in vivo and conferred protection against a lethal challenge with a WT virus. Together, these findings suggest that a latent infection is essential for MCF induction. [less ▲]

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See detailCis-acting inhibition of MHC class I-restricted epitope presentation by Alcelaphine herpesvirus 1 genome maintenance protein
Sorel, Océane ULg; Myster, Françoise ULg; Vanderplasschen, Alain ULg et al

Poster (2013, January 18)

γ-Herpesviruses persist as latent episomes in actively dividing lymphocytes. Their consequent need to express a viral genome maintenance protein (GMP) during latency presents a potential immune target ... [more ▼]

γ-Herpesviruses persist as latent episomes in actively dividing lymphocytes. Their consequent need to express a viral genome maintenance protein (GMP) during latency presents a potential immune target. However, the GMPs from several γ-herpesviruses have evolved related strategies to limit their own MHC class I epitope presentation to cytotoxic T lymphocytes (CTLs). Alcelaphine herpesvirus 1 (AlHV-1) is a γ-herpesvirus that persists asymptomatically in its natural host, the wildebeest. However, AlHV-1 transmission to a large number of susceptible ruminants, including cattle, results in the development of a lethal lymphoproliferative disease named malignant catarrhal fever (MCF). We recently observed that the AlHV-1 GMP-homologue encoded by ORF73 is highly expressed during MCF and that the impairment of its expression renders AlHV-1 unable to induce MCF. With its 1300 aa, AlHV-1 ORF73 is the largest γ-herpesvirus GMP described to date and contains a large acidic internal repeat region that could be involved in the cis-acting CTL evasion mechanism. Here, we sought to determine the CTL evasion properties of AlHV-1 ORF73. We first performed bioinformatic analyses to characterize the protein domains. Then, we used an in vitro assay to demonstrate that ORF73 severely limits the presentation at the cell surface of an MHC class I-restricted epitope linked to ORF73 in cis. These results suggest that AlHV-1 has developed mechanisms to evade cytotoxic anti-viral response during latency. The exact mechanisms explaining the presentation defect remain to be deciphered as well as the role of the cis-acting CTL evasion mechanism of ORF73 in the pathogenesis of MCF. [less ▲]

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See detailLa forme africaine du coryza gangreneux est une maladie lymphoproliférative létale causée par l’herpèsvirus alcélaphin 1
Myster, Françoise ULg; Sorel, Océane ULg; Palmeira, Leonor et al

in Virologie (2012), 16(5), 299-314

Les gammaherpèsvirus comprennent des virus pouvant induire des maladies lymphoprolifératives et des tumeurs. Ceux-ci peuvent également per- sister à long terme en l’absence de toute manifestation ... [more ▼]

Les gammaherpèsvirus comprennent des virus pouvant induire des maladies lymphoprolifératives et des tumeurs. Ceux-ci peuvent également per- sister à long terme en l’absence de toute manifestation pathologique chez leur hôte naturel. Parmi les gammaherpèsvirus, l’herpèsvirus alcélaphin 1 (AlHV-1) appartient au genre des Macavirus et infecte son hôte naturel, le gnou (Conno- chaetes spp.) de manière asymptomatique. Par ailleurs, lors de sa transmission à de nombreuses espèces sensibles appartenant à l’ordre des artiodactyles, l’AlHV- 1 induit une maladie lymphoproliférative létale dénommée forme africaine du coryza gangreneux (FACG). Le contrôle de cette maladie dans les régions où l’AlHV-1 est endémique est important et dépend directement de la compréhen- sion des mécanismes pathogéniques responsables de l’induction de la FACG. Le but de cette revue est de synthétiser les connaissances actuelles sur l’AlHV-1 et la FACG avec un intérêt particulier porté aux mécanismes par lesquels l’AlHV- 1 induit la maladie. Parmi les différents modèles pathogéniques, nous discuterons du rôle particulier de la latence virale sur base des données actuelles. Enfin, la relation évolutive entre le gnou, l’AlHV-1 et les espèces sensibles à la FACG sera abordée. [less ▲]

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See detailInvestigation on the Role of the Viral Semaphorin encoded by the A3 Gene of Alcelaphine Herpesvirus 1 in the Induction of Malignant Catarrhal Fever
Myster, Françoise ULg; Palmeira, Leonor ULg; Vanderplasschen, Alain ULg et al

Poster (2011, July)

Alcelaphine herpesvirus 1 (AlHV-1) is a gammaherpesvirus carried by wildebeest asymptomatically. AlHV-1 is however responsible for the development of malignant catarrhal fever (MCF) when cross-species ... [more ▼]

Alcelaphine herpesvirus 1 (AlHV-1) is a gammaherpesvirus carried by wildebeest asymptomatically. AlHV-1 is however responsible for the development of malignant catarrhal fever (MCF) when cross-species transmitted to a variety of ruminant susceptible species. Wildebeest-derived (WD)-MCF is a fatal lymphoproliferative and degenerative disease of ruminants. Experimentally, WD-MCF can be reproduced in rabbits. A3 ORF encodes a putative semaphorin homolog protein, named AlHV-sema. Semaphorins are secreted and membrane-associated proteins characterized by a conserved ‘Sema’ domain. Initially identified as guidance factors assisting axons pathfinding during neural development, semaphorins have been shown over the last decade to have significant functions in various processes of immunoregulation. Phylogenetic analyses revealed that AlHV-sema and mammals Sema7A have a common ancestor and that AlHV-Sema has evolved independently of other viral semaphorins. Further bioinformatics analyses demonstrated that AlHV-Sema and cellular Sema7A share a highly similar tridimensional structure. In order to investigate the role of AlHV-Sema in WD-MCF induction, we used the AlHV-1 BAC clone and produced a strain deleted for A3 and a revertant strain. The strain deleted for A3 replicated comparably to the wild-type parental strain in vitro. In vivo, rabbits infected with the strain deleted for A3 developed WD-MCF with a small but significant delay compared to those infected with the parental and revertant strains. Deletion of A3 did not affect the increase of viral genomic charge over time in peripheral blood and in lymph nodes at time of death and the major histopathological lesions were present in all groups. Though infection with wild-type and revertant strains resulted in the inversion of CD8 over CD4 ratio and increased IFN- production in lymphoid tissues at time of death, both parameters were significantly reduced after infection with the A3 deleted strain. Together, these results suggest that AlHV-Sema play a role in the host response to AlHV-1 infection. [less ▲]

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See detailCharacterization of ovine herpesvirus 2-induced malignant catarrhal fever in rabbits
Li, Hong; Cunha, Cristina W.; Gailbreath, Katherine L. et al

in Veterinary Microbiology (2011), 150(3-4), 270-7

Malignant catarrhal fever (MCF) is a frequently fatal lymphoproliferative disease syndrome primarily of ruminant species, caused by gammaherpesviruses in the genus Macavirus. Ovine herpesvirus 2 (OvHV-2 ... [more ▼]

Malignant catarrhal fever (MCF) is a frequently fatal lymphoproliferative disease syndrome primarily of ruminant species, caused by gammaherpesviruses in the genus Macavirus. Ovine herpesvirus 2 (OvHV-2), carried by sheep, causes sheep-associated MCF worldwide, while Alcelaphine herpesvirus 1 (AlHV-1), carried by wildebeest, causes wildebeest-associated MCF, mainly in Africa. Diseases in rabbits can be induced by both viruses, which are clinically and pathologically similar; however, recent studies revealed different expression of viral genes associated with latency or lytic replication during clinical disease between the two viruses. In this study, we further characterized experimentally induced MCF in rabbits by nebulization with OvHV-2 from sheep nasal secretions to elucidate the course of viral replication, along with in vivo incorporation of 5-Bromo-2’-Deoxyuridine (BrdU), to evaluate lymphoproliferation. All six rabbits nebulized with OvHV-2 developed MCF between 24 and 29 days post infection. OvHV-2 DNA levels in peripheral blood leukocytes (PBL) remained undetectable during the incubation period and increased dramatically a few days before onset of clinical signs. During the clinical stage, we found that predominantly lytic gene expression was detected in PBL and tissues, and both T and B cells were proliferating. The data showed that the viral gene expression profile and lymphoproliferation in rabbits with OvHV-2 induced MCF were different from that in rabbits with AlHV-1 induced MCF, suggesting that OvHV-2 and AlHV-1 may play a different role in MCF pathogenesis. [less ▲]

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See detailCharacterization of ovine herpesvirus 2-induced malignant catarrhal fever in rabbits
Li; Cunha, C.W.; Gailbreath, K.L. et al

in Veterinary Microbiology (2011), 2

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See detailEx vivo bioluminescent detection of Alcelaphine herpesvirus 1 infection during malignant catarrhal fever.
Dewals, Benjamin G ULg; Myster, Françoise ULg; Palmeira, Leonor ULg et al

in Journal of Virology (2011), 85(14), 6941-54

Alcelaphine herpesvirus 1 (AlHV-1), carried by wildebeest asymptomatically, causes malignant catarrhal fever (WD-MCF) when cross-species transmitted to a variety of susceptible species of the Artiodactyla ... [more ▼]

Alcelaphine herpesvirus 1 (AlHV-1), carried by wildebeest asymptomatically, causes malignant catarrhal fever (WD-MCF) when cross-species transmitted to a variety of susceptible species of the Artiodactyla order. Experimentally, WD-MCF can be reproduced in rabbits. WD-MCF is described as a combination of lymphoproliferation and degenerative lesions in virtually all organs and caused by unknown mechanisms. Recently, we demonstrated that WD-MCF is associated with the proliferation of CD8(+) cells supporting a latent type of infection in lymphoid tissues. Here, we investigated the macroscopic distribution of AlHV-1 infection using ex vivo bioluminescence imaging in rabbit to determine whether it correlates with the distribution of lesions in lymphoid and non-lymphoid organs. To reach that goal, a recombinant AlHV-1 strain was produced by insertion of a luciferase expression cassette (luc) in an intergenic region. In vitro, the reconstituted AlHV-1 luc(+) strain replicated comparably to the parental strain and luciferase activity was detected by bioluminescence imaging. In vivo, rabbits infected with the AlHV-1 luc(+) strain developed WD-MCF comparably to the parental wild-type strain with hyperthermia and increase of both CD8(+) T cells frequencies and viral genomic charge over time in peripheral blood mononuclear cells and in lymph nodes at time of euthanasia. Bioluminescent imaging revealed that AlHV-1 infection could be detected ex vivo in lymphoid organs but also in lung, liver and kidney during WD-MCF, demonstrating that AlHV-1 infection is prevalent in tissue lesions. Finally, we show that the infiltrating mononuclear leukocytes in non-lymphoid organs are mainly CD8(+) T cells and that latency is predominant during WD-MCF. [less ▲]

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See detailBovine Herpesvirus 4 Bo10 gene encodes a nonessential viral envelope protein that regulates viral tropism through both positive and negative effects.
Machiels, Bénédicte ULg; Lété, Céline ULg; Defays, Katalin et al

in Journal of Virology (2011), 85(2), 1011-1024

All gammaherpesviruses encode a glycoprotein positionally homologous to the Epstein-Barr virus gp350 and the Kaposi's Sarcoma associated herpesvirus (KSHV) K8.1. In this study, we characterized that of ... [more ▼]

All gammaherpesviruses encode a glycoprotein positionally homologous to the Epstein-Barr virus gp350 and the Kaposi's Sarcoma associated herpesvirus (KSHV) K8.1. In this study, we characterized that of Bovine Herpesvirus-4 (BoHV-4), encoded by the Bo10 gene. We identified a 180 kDa gene product, gp180, which was incorporated into the virion envelope. A Bo10 deletion virus was viable, but showed a growth deficit associated with reduced binding to epithelial cells. This seemed to reflect an interaction of gp180 with glycosaminoglycans (GAGs), since the Bo10 mutant was both less infectious for GAG(+) cells than the wild-type and more infectious for GAG(-) cells. However, we could not identify a direct interaction between gp180 and GAGs, implying that any direct interaction must be of low affinity. This function of gp180 was very similar to that previously identified for the Murid Herpesvirus 4 gp150, and also to the Epstein-Barr virus gp350 that promotes CD21(+) cell infection and inhibits CD21(-) cell infection. We propose that such proteins generally regulate virion attachment both by binding to cells and by covering another receptor-binding protein until they are displaced. Thus they regulate viral tropism both positively and negatively depending upon the presence or absence of their receptor. [less ▲]

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See detailMalignant catarrhal fever induced by Alcelaphine herpesvirus 1 is characterized by an expansion of activated CD3+CD8+CD4- T cells expressing a cytotoxic phenotype in both lymphoid and non-lymphoid tissues.
Dewals, Benjamin G ULg; Vanderplasschen, Alain ULg

in Veterinary research (2011), 42(1), 95

ABSTRACT: Alcelaphine herpesvirus 1 (AlHV-1) is carried by wildebeest asymptomatically. It causes a fatal lymphoproliferative disease named wildebeest-derived malignant catarrhal fever (WD-MCF) when cross ... [more ▼]

ABSTRACT: Alcelaphine herpesvirus 1 (AlHV-1) is carried by wildebeest asymptomatically. It causes a fatal lymphoproliferative disease named wildebeest-derived malignant catarrhal fever (WD-MCF) when cross-species transmitted to a variety of susceptible species of the Artiodactyla order. WD-MCF can be reproduced experimentally in rabbits. In a previous report, we demonstrated that WD-MCF induced by AlHV-1 is associated with a severe proliferation of CD8+ T cells in the lymphoid tissues. Here, we further studied the mononuclear leukocytic populations in both the lymphoid (throughout the infection and at time of euthanasia) and non-lymphoid (at time of euthanasia) organs during WD-MCF induced experimentally in rabbits. To reach that goal, we performed multi-colour flow cytometry stainings. The results obtained demonstrate that the development of WD-MCF correlates in peripheral blood with a severe increase of CD8+ cell percentages; and that CD3+CD8+CD4- T cells were the predominant cell type in both lymphoid and non-lymphoid organs at time of euthanasia. Further characterization of the mononuclear leukocytes isolated from both lymphoid and non-lymphoid tissues revealed that the CD8+ T cells express high levels of the activation markers CD25 and CD44, produce high amount of gamma-interferon (IFN-gamma) and perforin, and showed a reduction of interleukin-2 (IL-2) gene expression. These data demonstrate that the development of WD-MCF is associated with the expansion and infiltration of activated and cytotoxic CD3+CD8+CD4- T cells secreting high amount of IFN-gamma but low IL-2. [less ▲]

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See detailThe A3 gene of Alcelaphine herpesvirus 1 encodes a viral semaphorin that is non-essential for the induction of malignant catarrhal fever
Myster, Françoise ULg; Palmeira, Leonor ULg; Vanderplasschen, Alain ULg et al

Conference (2010, November)

Alcelaphine herpesvirus 1 (AlHV-1) is a γ-Herpesvirus carried by wildebeest asymptomatically. AlHV-1 is however responsible for the development of malignant catarrhal fever (MCF) when cross-species ... [more ▼]

Alcelaphine herpesvirus 1 (AlHV-1) is a γ-Herpesvirus carried by wildebeest asymptomatically. AlHV-1 is however responsible for the development of malignant catarrhal fever (MCF) when cross-species transmitted to a variety of ruminant susceptible species. Wildebeest-derived (WD)-MCF is a frequently fatal lymphoproliferative and degenerative disease of ruminants. Experimentally, WD-MCF can be reproduced in rabbits. The A3 open reading frame (ORF) of the AlHV-1 encodes a putative semaphorin homolog protein, thereafter named AlHV-sema. Semaphorins are secreted and membrane-associated proteins characterized by a conserved amino-terminal ‘Sema’ domain. Initially identified as guidance factors that assist axons pathfinding during neural development, semaphorins have been shown over the last decade to have significant functions in various processes of immunoregulation. Bioinformatics analyses revealed that AlHV-sema has a high homology to the cellular Sema7A. Besides its roles in neural development, Sema7A has been shown to play pivotal functions in the regulation of cytokine secretion and as a tumor suppressor. In order to investigate whether AlHV-Sema could play a role in the pathogenesis of WD-MCF, we used the AlHV-1 BAC clone and produced a strain deleted for A3 and a revertant strain. The strain deleted for A3 replicated comparably to the wild-type parental strain in vitro. In vivo, rabbits infected with the strain deleted for A3 developed WD-MCF similarly to that observed with the parental strain with both severely increased CD8+ T cell frequencies and viral genomic charge over time in peripheral blood and in lymph nodes at time of death, as well as indistinguishable histopathological lesions in lymphoid organs and in liver, lung and kidney. In conclusion, this study demonstrates that AlHV-sema is not essential for the induction of WD-MCF in rabbits. [less ▲]

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