Publications of Laurent Gillet
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See detailA gammaherpesvirus licenses CD8 T cells to protect the host from pneumovirus-induced immunopathologies.
Dourcy, Mickael ULiege; Maquet, Céline ULiege; Dams, Lorène ULiege et al

in Mucosal Immunology (2020)

Human respiratory syncytial virus (RSV) is a pneumovirus that causes severe infections in infants worldwide. Despite intensive research, safe and effective vaccines against RSV have remained elusive. The ... [more ▼]

Human respiratory syncytial virus (RSV) is a pneumovirus that causes severe infections in infants worldwide. Despite intensive research, safe and effective vaccines against RSV have remained elusive. The main reason is that RSV infection of children previously immunized with formalin-inactivated-RSV vaccines has been associated with exacerbated pathology, a phenomenon called RSV vaccine-enhanced respiratory disease. In parallel, despite the high RSV prevalence, only a minor proportion of children develop severe diseases. Interestingly, variation in the immune responses against RSV or following RSV vaccination could be linked with differences of exposure to microbes during childhood. Gammaherpesviruses (γHVs), such as the Epstein–Barr virus, are persistent viruses that deeply influence the immune system of their host and could therefore affect the development of pneumovirus-induced immunopathologies for the long term. Here, we showed that a previous ɣHV infection protects against both pneumovirus vaccine-enhanced disease and pneumovirus primary infection and that CD8 T cells are essential for this protection. These observations shed a new light on the understanding of pneumovirus-induced diseases and open new perspectives for the development of vaccine strategies. [less ▲]

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See detailInitial Step of Virus Entry: Virion Binding to Cell-Surface Glycans.
Koehler, Melanie; Delguste, Martin; Sieben, Christian et al

in Annual review of virology (2020)

Virus infection is an intricate process that requires the concerted action of both viral and host cell components. Entry of viruses into cells is initiated by interactions between viral proteins and cell ... [more ▼]

Virus infection is an intricate process that requires the concerted action of both viral and host cell components. Entry of viruses into cells is initiated by interactions between viral proteins and cell-surface receptors. Various cell-surface glycans function as initial, usually low-affinity attachment factors, providing a first anchor of the virus to the cell surface, and further facilitate high-affinity binding to virus-specific cell-surface receptors, while other glycans function as specific entry receptors themselves. It is now possible to rapidly identify specific glycan receptors using different techniques, define atomic-level structures of virus-glycan complexes, and study these interactions at the single-virion level. This review provides a detailed overview of the role of glycans in viral infection and highlights experimental approaches to study virus-glycan binding along with specific examples. In particular, we highlight the development of the atomic force microscope to investigate interactions with glycans at the single-virion level directly on living mammalian cells, which offers new perspectives to better understand virus-glycan interactions in physiologically relevant conditions. Expected final online publication date for the Annual Review of Virology, Volume 7 is September 29, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. [less ▲]

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See detailIFN-lambda Decreases Murid Herpesvirus-4 Infection of the Olfactory Epithelium but Fails to Prevent Virus Reactivation in the Vaginal Mucosa.
Jacobs, Sophie; Zeippen, Caroline ULiege; Wavreil, Fanny et al

in Viruses (2019), 11(8),

Murid herpesvirus-4 (MuHV-4), a natural gammaherpesvirus of rodents, can infect the mouse through the nasal mucosa, where it targets sustentacular cells and olfactory neurons in the olfactory epithelium ... [more ▼]

Murid herpesvirus-4 (MuHV-4), a natural gammaherpesvirus of rodents, can infect the mouse through the nasal mucosa, where it targets sustentacular cells and olfactory neurons in the olfactory epithelium before it propagates to myeloid cells and then to B cells in lymphoid tissues. After establishment of latency in B cells, viral reactivation occurs in the genital tract in 80% of female mice, which can lead to spontaneous sexual transmission to co-housed males. Interferon-lambda (IFN-lambda) is a key player of the innate immune response at mucosal surfaces and is believed to limit the transmission of numerous viruses by acting on epithelial cells. We used in vivo plasmid-mediated IFN-lambda expression to assess whether IFN-lambda could prophylactically limit MuHV-4 infection in the olfactory and vaginal mucosae. In vitro, IFN-lambda decreased MuHV-4 infection in cells that overexpressed IFN-lambda receptor 1 (IFNLR1). In vivo, prophylactic IFN-lambda expression decreased infection of the olfactory epithelium but did not prevent virus propagation to downstream organs, such as the spleen where the virus establishes latency. In the olfactory epithelium, sustentacular cells readily responded to IFN-lambda. In contrast, olfactory neurons did not respond to IFN-lambda, thus, likely allowing viral entry. In the female genital tract, columnar epithelial cells strongly responded to IFN-lambda, as did most vaginal epithelial cells, although with some variation from mouse to mouse. IFN-lambda expression, however, failed to prevent virus reactivation in the vaginal mucosa. In conclusion, IFN-lambda decreased MuHV-4 replication in the upper respiratory epithelium, likely by protecting the sustentacular epithelial cells, but it did not protect olfactory neurons and failed to block virus reactivation in the genital mucosa. [less ▲]

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See detailOral vaccination with replication-competent adenovirus in mice reveals the dissemination of the viral vaccine beyond the gastrointestinal tract.
Goffin, Emeline ULiege; Javaux, Justine; Destexhe, Eric et al

in Journal of virology (2019)

Since the 1970s, replication-competent human adenoviruses 4 and 7 have been used as oral vaccines to protect US soldiers against the severe respiratory diseases caused by these viruses. These vaccines are ... [more ▼]

Since the 1970s, replication-competent human adenoviruses 4 and 7 have been used as oral vaccines to protect US soldiers against the severe respiratory diseases caused by these viruses. These vaccines are thought to establish a digestive tract infection conferring protection against respiratory challenge through antibodies. The success of these vaccines makes replication-competent adenoviruses attractive candidates for use as oral vaccine vectors. However, the inability of human adenoviruses to replicate efficiently in laboratory animals has hampered the study of such vectors. Here, we used mouse adenovirus type 1 (MAV-1) in mice to study oral replication-competent adenovirus-based vaccines. We showed that MAV-1 oral administration recapitulates the protection against homologous respiratory challenge observed with adenoviruses 4 and 7 vaccines. Moreover, live oral MAV-1 vaccine better protected against a respiratory challenge than inactivated vaccines. This protection was linked not only with the presence of MAV-1-specific antibodies but also with a better recruitment of effector CD8 T cells. However, unexpectedly, we found that such oral replication-competent vaccine systemically spread all over the body. Our results therefore support using MAV-1 to study replication-competent oral adenovirus-based vaccines but also highlight the fact that those vaccines could disseminate widely in the body.IMPORTANCE Replication-competent adenoviruses appear to be promising vectors for the development of oral vaccines in humans. However, study and development of these vaccines suffer from the lack of any reliable animal model. In this study, mouse adenovirus type 1 has been used to develop a small animal model for oral replication-competent adenovirus vaccines. While this model reproduced in mice what is observed with human adenovirus oral vaccines, it also highlighted that oral immunization with such replication-competent vaccine is associated with the systemic spread of the virus. This study is therefore of major importance for the future development of such vaccine platforms and their use in large human populations. [less ▲]

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See detailRecruitment of hepatic macrophages from monocytes is independent of IL-4Ralpha but is associated with ablation of resident macrophages in schistosomiasis.
Rolot, Marion ULiege; Dougall, Annette; Javaux, Justine et al

in European journal of immunology (2019)

Alternatively-activated Mphis (AAMphi) accumulate in hepatic granulomas during schistosomiasis and have been suggested to originate in the bone marrow. What is less understood is how these Mphi responses ... [more ▼]

Alternatively-activated Mphis (AAMphi) accumulate in hepatic granulomas during schistosomiasis and have been suggested to originate in the bone marrow. What is less understood is how these Mphi responses are regulated after S. mansoni infection. Here, we investigated the role of IL-4 receptor alpha-chain (IL-4Ralpha)-signalling in the dynamics of liver Mphi responses. We observed that IL-4Ralpha signalling was dispensable for the recruitment of Ly6C(hi) monocytes and for their conversion into F4/80(hi) CD64(hi) CD11b(hi) Mphi. Moreover, while IL-4Ralpha provided an AAMphi phenotype to liver F4/80(hi) CD64(hi) CD11b(hi) Mphi that was associated with regulation of granuloma formation, it was dispensable for host survival. Resident F4/80(hi) CD64(hi) CD11b(lo) Mphi did not upregulate the AAMphi signature gene Ym1. Rather, resident Mphi nearly disappeared by week 8 after infection and artificial ablation of resident Mphi in CD169(DTR) mice did not affect the response to S. mansoni infection. Interestingly, ablation of CD169(+) cells in naive mice resulted in the accumulation of F4/80(hi) CD64(hi) CD11b(hi) Mphi, which was amplified when ablation occurred during schistosomiasis. Altogether, our results suggest the ablation of resident KCs after S. mansoni infection to be associated with the recruitment and accumulation of F4/80(hi) CD64(hi) CD11b(hi) Mphi with lyz2-dependent IL-4Ralpha contributing to the regulation of granuloma inflammation but being dispensable for host survival. This article is protected by copyright. All rights reserved. [less ▲]

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See detailHelminth-induced IL-4 expands bystander memory CD8+ T cells for early control of viral infection
Rolot, Marion; Dougall, Annette; Chetty, Alisha et al

Conference (2018, August)

Infection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes. Bystander or virtual memory CD8+ T cells (TVM) are non-conventional T cells displaying memory ... [more ▼]

Infection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes. Bystander or virtual memory CD8+ T cells (TVM) are non-conventional T cells displaying memory properties that can be generated through responsiveness to interleukin (IL)-4. However, it is not clear if helminth-induced type 2 immunity functionally affects the TVM compartment. Here, we show that helminths expand CD44hiCD62LhiCXCR3hiCD49dlo TVM cells through direct IL-4 signaling in CD8+ T cells. Importantly, helminth-mediated conditioning of TVM cells provided enhanced control of acute respiratory infection with the murid gammaherpesvirus 4 (MuHV-4). This enhanced control of MuHV-4 infection could further be explained by an increase in antigen-specific CD8+ T cell effector responses in the lung and was directly dependent on IL-4 signaling. These results demonstrate that IL-4 during helminth infection can non-specifically condition CD8+ T cells, leading to a subsequently raised antigen-specific CD8+ T cell activation that enhanced control of viral infection. [less ▲]

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See detailL’infection par un herpèsvirus gamma protège l’hôte du développement de l’asthme allergique
Machiels, Bénédicte ULiege; Gillet, Laurent ULiege

in MS. Medecine Sciences (2018), 34(10), 774-777

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See detailAntiviral effect of the nucleoside analogue cidofovir in the context of sexual transmission of a gammaherpesvirus in mice.
Zeippen, Caroline ULiege; Javaux, Justine ULiege; Snoeck, Robert et al

in Journal of Antimicrobial Chemotherapy (2018)

Objectives: To investigate the efficacy of cidofovir to block gammaherpesvirus replication in the context of sexual transmission. Methods: A luciferase-expressing strain of murid herpesvirus 4 (MuHV-4 ... [more ▼]

Objectives: To investigate the efficacy of cidofovir to block gammaherpesvirus replication in the context of sexual transmission. Methods: A luciferase-expressing strain of murid herpesvirus 4 (MuHV-4) was used to monitor genital virus excretion from infected female BALB/c mice and sexual transmission to naive males. The efficiency of cidofovir to block genital excretion from infected females or replication and host colonization of naive males after sexual contact was tested by treating infected females (either once daily or at a single timepoint), naive males before exposure (either once daily or at a single timepoint) or males 24 h post-exposure. Results: We showed that daily treatment of infected females can reduce MuHV-4 genital shedding by 75%. Similarly, daily preventive treatment of naive males was sufficient to block viral replication and latency establishment in males. In contrast, a single administration of cidofovir to infected females at day 14 post-infection or to naive males 2 to 6 days before contact with MuHV-4-excreting females was not sufficient to significantly reduce viral shedding from females or infection of males, respectively. Interestingly, a single administration of cidofovir to males 24 h after contact with MuHV-4-infected females excreting the virus in the genital tract significantly reduced virus replication in males and seroconversion. Conclusions: Altogether, our results show that cidofovir can significantly reduce gammaherpesvirus replication, excretion and colonization of the naive partner in the context of sexual transmission. Such treatments could therefore be recommended in some specific conditions where gammaherpesvirus infections could be deleterious. [less ▲]

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See detailTopography imaging of herpesvirus in native condition using atomic force microscopy.
Delguste, M.; Koehler, M.; Gillet, Laurent ULiege et al

in Clinical Microbiology and Infection (2018), 24(6), 610-611

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See detailMultivalent binding of herpesvirus to living cells is tightly regulated during infection.
Delguste, Martin; Zeippen, Caroline ULiege; Machiels, Bénédicte ULiege et al

in Science Advances (2018), 4(8), 1273

Viral infection, initiated by the landing of a virion on a cellular surface, is largely defined by the preliminary interactions established between viral particles and their receptors at the cell surface ... [more ▼]

Viral infection, initiated by the landing of a virion on a cellular surface, is largely defined by the preliminary interactions established between viral particles and their receptors at the cell surface. While multiple parallel interactions would allow strong virus attachment, a low number of bonds could be preferred to allow lateral diffusion toward specific receptors and to promote efficient release of progeny virions from the cell surface. However, so far, the molecular mechanisms underlying the regulation of the multivalency in virus attachment to receptors are poorly understood. We introduce a new method to force-probe multivalent attachment directly on living cells, and we show, for the first time, direct evidence of a new mechanism by which a herpesvirus surface glycoprotein acts as a key negative regulator in the first step of herpesvirus binding. Using atomic force microscopy, we probe at the single-virion level the number and the strength of the bonds established with heparan sulfate both on model surfaces and on living cells. Our biophysical results, correlated with other techniques, show that the major envelope glycoprotein functions as a regulator of binding valency during both attachment and release steps, determining the binding, diffusion, and release potential of virions at the cellular surface. [less ▲]

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See detailCorrection to: A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes (Nature Immunology, (2017), 18, 12, (1310-1320), 10.1038/ni.3857)
Machiels, Bénédicte ULiege; Dourcy, Mickael ULiege; Xiao, X. et al

in Nature Immunology (2018), 19(9), 1035

In the version of this article initially published, the accession code for the RNA-seq data set deposited in the NCBI public repository Sequence Read Archive was missing from the ‘Data availability’ ... [more ▼]

In the version of this article initially published, the accession code for the RNA-seq data set deposited in the NCBI public repository Sequence Read Archive was missing from the ‘Data availability’ subsection of the Methods section. The accession code is SRP125477. © 2017, The Author(s). [less ▲]

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See detailHelminth-induced IL-4 expands bystander memory CD8(+) T cells for early control of viral infection.
Rolot, Marion ULiege; Dougall, Annette M.; Chetty, Alisha et al

in Nature Communications (2018), 9(1), 4516

Infection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes. Bystander or virtual memory CD8(+) T cells (TVM) are non-conventional T cells displaying ... [more ▼]

Infection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes. Bystander or virtual memory CD8(+) T cells (TVM) are non-conventional T cells displaying memory properties that can be generated through responsiveness to interleukin (IL)-4. However, it is not clear if helminth-induced type 2 immunity functionally affects the TVM compartment. Here, we show that helminths expand CD44(hi)CD62L(hi)CXCR3(hi)CD49d(lo) TVM cells through direct IL-4 signaling in CD8(+) T cells. Importantly, helminth-mediated conditioning of TVM cells provided enhanced control of acute respiratory infection with the murid gammaherpesvirus 4 (MuHV-4). This enhanced control of MuHV-4 infection could further be explained by an increase in antigen-specific CD8(+) T cell effector responses in the lung and was directly dependent on IL-4 signaling. These results demonstrate that IL-4 during helminth infection can non-specifically condition CD8(+) T cells, leading to a subsequently raised antigen-specific CD8(+) T cell activation that enhances control of viral infection. [less ▲]

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See detailProteomic and functional analyses of the virion transmembrane proteome of cyprinid herpesvirus 3.
Vancsok, Catherine ULiege; Penaranda, Ma Michelle D.; Raj, V. Stalin et al

in Journal of Virology (2017), 91(21),

Virion transmembrane proteins (VTPs) mediate key functions in the herpesvirus infectious cycle. Cyprinid herpesvirus 3 (CyHV-3) is the archetype of fish alloherpesviruses. The present study was devoted to ... [more ▼]

Virion transmembrane proteins (VTPs) mediate key functions in the herpesvirus infectious cycle. Cyprinid herpesvirus 3 (CyHV-3) is the archetype of fish alloherpesviruses. The present study was devoted to CyHV-3 VTPs. Using mass spectrometry approaches, we identified 16 VTPs of the CyHV-3 FL strain. Mutagenesis experiments demonstrated that eight of these proteins are essential for viral growth in vitro (ORF32, ORF59, ORF81, ORF83, ORF99, ORF106, ORF115, and ORF131), and eight are non-essential (ORF25, ORF64, ORF65, ORF108, ORF132, ORF136, ORF148, and ORF149). Among the non-essential proteins, deletion of ORF25, ORF132, ORF136, ORF148, or ORF149 affects viral replication in vitro, and deletion of ORF25, ORF64, ORF108, ORF132, or ORF149 impacts plaque size. Lack of ORF148 or ORF25 causes attenuation in vivo to a minor or major extent, respectively. The safety and efficacy of a virus lacking ORF25 were compared to those of a previously described vaccine candidate deleted for ORF56 and ORF57 (Delta56-57). Using quantitative PCR, we demonstrated that the ORF25 deleted virus infects fish through skin infection and then spreads to internal organs as reported previously for the wild-type parental virus and the Delta56-57 virus. However, compared to the parental wild-type virus, the replication of the ORF25 deleted virus was reduced in intensity and duration to levels similar to those observed for the Delta56-57 virus. Vaccination of fish with a virus lacking ORF25 was safe but had low efficacy at the doses tested. This characterization of the virion transmembrane proteome of CyHV-3 provides a firm basis for further research on alloherpesvirus VTPs.IMPORTANCE Virion transmembrane proteins play key roles in the biology of herpesviruses. Cyprinid herpesvirus 3 (CyHV-3) is the archetype of fish alloherpesviruses and the causative agent of major economic losses in common and koi carp worldwide. In this study of the virion transmembrane proteome of CyHV-3, the major findings were: (i) the FL strain encodes 16 virion transmembrane proteins; (ii) eight of these proteins are essential for viral growth in vitro; (iii) seven of the non-essential proteins affect viral growth in vitro, and two affect virulence in vivo; and (iv) a mutant lacking ORF25 is highly attenuated but induces moderate immune protection. This study represents a major breakthrough in understanding the biology of CyHV-3 and will contribute to the development of prophylactic methods. It also provides a firm basis for the further research on alloherpesvirus virion transmembrane proteins. [less ▲]

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