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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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See detailIL-4Ralpha-responsive smooth muscle cells contribute to initiation of T(H)2 immunity and pulmonary pathology in Nippostrongylus brasiliensis infections.
Horsnell, W. G.; Vira, A.; Kirstein, F. et al

in Mucosal immunology (2010), 4(1), 83-92

Nippostrongylus brasiliensis infections generate pulmonary pathologies that can be associated with strong T(H)2 polarization of the host's immune response. We present data demonstrating N. brasiliensis ... [more ▼]

Nippostrongylus brasiliensis infections generate pulmonary pathologies that can be associated with strong T(H)2 polarization of the host's immune response. We present data demonstrating N. brasiliensis-driven airway mucus production to be dependent on smooth muscle cell interleukin 4 receptor-alpha (IL-4Ralpha) responsiveness. At days 7 and 10 post infection (PI), significant airway mucus production was found in IL-4Ralpha(-/lox) control mice, whereas global knockout (IL-4Ralpha(-/-)) and smooth muscle-specific IL-4Ralpha-deficient mice (SM-MHC(Cre) IL-4Ralpha(-/lox)) showed reduced airway mucus responses. Furthermore, interleukin (IL)-13 and IL-5 cytokine production in SM-MHC(Cre) IL-4Ralpha(-/lox) mice was impaired along with a transient reduction in T-cell numbers in the lung. In vitro treatment of smooth muscle cells with secreted N. brasiliensis excretory-secretory antigen (NES) induced IL-6 production. Decreased protein kinase C (PKC)-dependent smooth muscle cell proliferation associated with cell cycle arrest was found in cells stimulated with NES. Together, these data demonstrate that both IL-4Ralpha and NES-driven responses by smooth muscle cells make important contributions in initiating T(H)2 responses against N. brasiliensis infections.Mucosal Immunology advance online publication 25 August 2010. doi:10.1038/mi.2010.46. [less ▲]

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See detailIL-4R{alpha}-responsive smooth muscle cells increase intestinal hypercontractility and contribute to resistance during acute Schistosomiasis.
Marillier, Reece G; Brombacher, Tiroyaone M; Dewals, Benjamin G ULg et al

in American Journal of Physiology - Gastrointestinal and Liver Physiology (2010), 298(6), 943-51

Interleukin-(IL)-4 and IL-13 signal through heterodimeric receptors containing a common IL-4 receptor-alpha (IL-4Ralpha) subunit, which is important for protection against helminth infections, including ... [more ▼]

Interleukin-(IL)-4 and IL-13 signal through heterodimeric receptors containing a common IL-4 receptor-alpha (IL-4Ralpha) subunit, which is important for protection against helminth infections, including schistosomiasis. Previous studies demonstrated important roles for IL-4Ralpha-responsive hematopoietic cells, including T cells and macrophages in schistosomiasis. In this study, we examined the role of IL-4Ralpha responsiveness by nonhematopoietic smooth muscle cells during experimental acute murine schistosomiasis. Comparative Schistosoma mansoni infection studies with smooth muscle cell-specific IL-4Ralpha-deficient (SM-MHC(cre)IL-4Ralpha(-/flox)) mice, heterozygous control (IL-4Ralpha(-/flox)) mice, and global IL-4Ralpha-deficient (IL-4Ralpha(-/-)) mice were conducted. S. mansoni-infected SM-MHC(cre)IL-4Ralpha(-/flox) mice showed increased weight loss and earlier mortalities compared with IL-4Ralpha(-/flox) mice, despite comparable T(H)2/type 2 immune responses. In contrast to highly susceptible IL-4Ralpha-deficient mice, increased susceptibility in SM-MHC(cre)IL-4Ralpha(-/flox) mice was not accompanied by intestinal tissue damage and subsequent sepsis. However, both susceptible mutant mouse strains failed to efficiently expel eggs, demonstrated by egg reduction in the feces compared with control mice. Reduced egg expulsion was accompanied by impaired IL-4/IL-13-mediated hypercontractile intestinal responses, which was present in the more resistant control mice. Together, we conclude that IL-4Ralpha responsiveness by smooth muscle cells and subsequent IL-4- and IL-13-mediated hypercontractility are required for host protection during acute schistosomiasis to efficiently expel S. mansoni eggs and to prevent premature mortality. [less ▲]

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See detailIL-4Ralpha-independent expression of mannose receptor and Ym1 by macrophages depends on their IL-10 responsiveness.
Dewals, Benjamin G ULg; Marillier, Reece G; Hoving, Jennifer C et al

in PLoS Neglected Tropical Diseases (2010), 4(5), 689

IL-4Ralpha-dependent responses are essential for granuloma formation and host survival during acute schistosomiasis. Previously, we demonstrated that mice deficient for macrophage-specific IL-4Ralpha ... [more ▼]

IL-4Ralpha-dependent responses are essential for granuloma formation and host survival during acute schistosomiasis. Previously, we demonstrated that mice deficient for macrophage-specific IL-4Ralpha (LysM(cre)Il4ra(-/lox)) developed increased hepatotoxicity and gut inflammation; whereas inflammation was restricted to the liver of mice lacking T cell-specific IL-4Ralpha expression (iLck(cre)Il4ra(-/lox)). In the study presented here we further investigated their role in liver granulomatous inflammation. Frequencies and numbers of macrophage, lymphocyte or granulocyte populations, as well as Th1/Th2 cytokine responses were similar in Schistosoma mansoni-infected LysM(cre)Il4ra(-/lox) liver granulomas, when compared to Il4ra(-/lox) control mice. In contrast, a shift to Th1 responses with high IFN-gamma and low IL-4, IL-10 and IL-13 was observed in the severely disrupted granulomas of iLck(cre)Il4ra(-/lox) and Il4ra(-/-) mice. As expected, alternative macrophage activation was reduced in both LysM(cre)Il4ra(-/lox) and iLck(cre)Il4ra(-/lox) granulomas with low arginase 1 and heightened nitric oxide synthase RNA expression in granuloma macrophages of both mouse strains. Interestingly, a discrete subpopulation of SSC(high)CD11b+I-A/I-E(high)CD204+ macrophages retained expression of mannose receptor (MMR) and Ym1 in LysM(cre)Il4ra(-/lox) but not in iLck(cre)Il4ra(-/lox) granulomas. While aaMphi were in close proximity to the parasite eggs in Il4ra(-/lox) control mice, MMR+Ym1+ macrophages in LysM(cre)Il4ra(-/lox) mice were restricted to the periphery of the granuloma, indicating that they might have different functions. In vivo IL-10 neutralisation resulted in the disappearance of MMR+Ym1+ macrophages in LysM(cre)Il4ra(-/lox) mice. Together, these results show that IL-4Ralpha-responsive T cells are essential to drive alternative macrophage activation and to control granulomatous inflammation in the liver. The data further suggest that in the absence of macrophage-specific IL-4Ralpha signalling, IL-10 is able to drive mannose receptor- and Ym1-positive macrophages, associated with control of hepatic granulomatous inflammation. [less ▲]

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See detailControl of Schistosoma mansoni egg-induced inflammation by IL-4-responsive CD4+CD25−CD103+Foxp3− cells is IL-10-dependent
Dewals, Benjamin G ULg; Hoving, Jennifer C.; Horsnell, William G.C. et al

in European Journal of Immunology (2010), 40

Host protection to helminth infection requires IL-4Rα signalling and the establishment of finely regulated Th2 responses. In the present study, the role of IL-4Rα-responsive T cells in Schistosoma mansoni ... [more ▼]

Host protection to helminth infection requires IL-4Rα signalling and the establishment of finely regulated Th2 responses. In the present study, the role of IL-4Rα-responsive T cells in Schistosoma mansoni egg-induced inflammation was investigated. Egg-induced inflammation in IL-4Rα-responsive BALB/c mice was accompanied with Th2-biased responses, whereas T cell-specific IL-4R-deficient BALB/c mice (iLckcreIl4ra−/lox) developed Th1-biased responses with heightened inflammation. The proportion of Foxp3+ Tregs in the draining lymph node of control mice did not correlate with the control of inflammation and was reduced in comparison to T cell-specific IL-4R-deficient mice. This was due to IL-4-mediated inhibition of CD4+Foxp3+ Tregs conversion, demonstrated in adoptively transferred Rag2−/− mice. Interestingly, reduced footpad swelling in Il4ra−/lox mice was associated with the induction of IL-4 and IL-10-secreting CD4+CD25−CD103+Foxp3− cells, confirmed in S. mansoni infection studies. Transfer of IL-4Rα-responsive CD4+CD25−CD103+ cells, but not CD4+CD25high or CD4+CD25−CD103− cells, controlled inflammation in iLckcreIl4ra−/lox mice. It finally turned out that the control of inflammation depended on IL-10, as transferred CD4+CD25−CD103+ cells from IL-10-deficient mice were not able to effectively downregulate inflammation. Together, these results demonstrate that IL-4 signalling in T cells inhibits Foxp3+ Tregs in vivo and promotes CD4+CD25−CD103+Foxp3− cells that control S. mansoni egg-induced inflammation via IL-10. [less ▲]

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See detailBovine herpesvirus 4 ORF73 is dispensable for viral growth in vitro but is essential for viral persistence in vivo.
Thirion, M.; Machiels, Bénédicte ULg; Farnir, Frédéric ULg et al

in Journal of General Virology (The) (2010), 91(10), 2574-84

ORF73 orthologues encoded by different rhadinoviruses have been studied extensively. These studies revealed that the ORF73 expression product (pORF73) is a multifunctional protein essential for latency ... [more ▼]

ORF73 orthologues encoded by different rhadinoviruses have been studied extensively. These studies revealed that the ORF73 expression product (pORF73) is a multifunctional protein essential for latency that enables episome tethering to mitotic chromosomes and modulates cellular pathways implicated in growth and survival of latently infected cells. Comparison of pORF73 orthologues encoded by rhadinoviruses reveals important variations in amino acid sequence length and composition. Bovine herpesvirus 4 (BoHV-4) encodes by far the shortest ORF73 orthologue with a size equivalent to only 22% of the largest orthologues. The present study focused on determining if BoHV 4 ORF73 is a bona fide gene and investigating whether it is essential for latency as established for larger ORF73 orthologues. Our results demonstrate that BoHV-4 ORF73 is transcribed as immediate-early bicistronic mRNA together with ORF71. Using a BoHV-4 bacterial artificial chromosome clone, we produced a strain deleted for ORF73 and a revertant strain. Deletion of BoHV-4 ORF73 did not affect the capacity of the virus to replicate in vitro, but it prevented latent infection in vivo using a rabbit model. Interestingly, the strain deleted for ORF73 induced an anti-BoHV-4 humoral immune response comparable to that elicited by wild-type and revertant recombinants. Together, these results demonstrate that despite its relatively small size, BoHV-4 ORF73 is a functional homologue of larger rhadinovirus ORF73 orthologues, and highlight the potential of ORF73 deletion for the development of BoHV-4 as a vector in vaccinology. [less ▲]

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See detailEx vivo bioluminescent detection of alcelaphine herpesvirus 1 infection during malignant catarrhal fever induced in rabbits
Dewals, Benjamin G ULg; Myster, Françoise ULg; Massart, François et al

Poster (2009, December 11)

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. The lesions observed are very similar to those described in natural host species. Recently, we demonstrated that WD-MCF induced by AlHV-1 in rabbits is associated with the proliferation of CD8+ cells supporting a latent type of infection. In the present study, we investigated whether the virus could be detected ex vivo in the tissues of rabbits developing WD-MCF. Taking advantage of the recent cloning of the AlHV-1 genome as a bacterial artificial chromosome (BAC), we produced a recombinant plasmid encoding a firefly luciferase (LUC) expression cassette inserted in a non-coding region of the AlHV-1 genome. In vitro, the reconstituted AlHV-1 LUC strain replicated comparably to the parental strain in permissive cells and was able to induce a bioluminescent signal. In vivo, rabbits infected with the AlHV-1 LUC strain developed WD-MCF similarly to the parental wild-type strain with hyperthermia, increased CD8/CD4 ratio and viral genomic charge over time in PBMC and in lymph nodes at time of death. To identify the presence of AlHV-1 infection ex vivo, various organs of infected rabbits developing WD-MCF were analysed by bioluminescent imaging. Luciferase activity could be detected macroscopically at the time of death in most of analyzed organs including lung, popliteal and mesenteric lymph nodes, spleen, liver, kidney and appendix. Infectious virus could be isolated following co-cultures of lymph node and permissive cells, and the isolated virus retained the ability to induce a bioluminescent signal. In conclusion, we produced an AlHV-1 LUC recombinant and we were able to detect the AlHV-1 infection ex vivo in many organs at the time of death. [less ▲]

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