38 results on '"Mathieu Iampietro"'
Search Results
2. SARS-CoV-2 awakens ancient retroviral genes and the expression of proinflammatory HERV-W envelope protein in COVID-19 patients
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Benjamin Charvet, Joanna Brunel, Justine Pierquin, Mathieu Iampietro, Didier Decimo, Nelly Queruel, Alexandre Lucas, María del Mar Encabo-Berzosa, Izaskun Arenaz, Tania Perez Marmolejo, Arturo Ivan Gonzalez, Armando Castorena Maldonado, Cyrille Mathieu, Patrick Küry, Jose Flores-Rivera, Fernanda Torres-Ruiz, Santiago Avila-Rios, Gonzalo Salgado Montes de Oca, Jon Schoorlemmer, Hervé Perron, and Branka Horvat
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Health sciences ,Virology ,Molecular Genetics ,Science - Abstract
Summary: Patients with COVID-19 may develop abnormal inflammatory response, followed in some cases by severe disease and long-lasting syndromes. We show here that in vitro exposure to SARS-CoV-2 activates the expression of the human endogenous retrovirus (HERV) HERV-W proinflammatory envelope protein (ENV) in peripheral blood mononuclear cells from a subset of healthy donors, in ACE2 receptor and infection-independent manner. Plasma and/or sera of 221 COVID-19 patients from different cohorts, infected with successive SARS-CoV-2 variants including the Omicron, had detectable HERV-W ENV, which correlated with ENV expression in T lymphocytes and peaked with the disease severity. HERV-W ENV was also found in postmortem tissues of lungs, heart, gastrointestinal tract, brain olfactory bulb, and nasal mucosa from COVID-19 patients. Altogether, these results demonstrate that SARS-CoV-2 could induce HERV-W envelope protein expression and suggest its involvement in the immunopathogenesis of certain COVID-19-associated syndromes and thereby its relevance in the development of personalized treatment of patients.
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- 2023
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3. Interplay between RNA viruses and cGAS/STING axis in innate immunity
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Lucia Amurri, Branka Horvat, and Mathieu Iampietro
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cGAS/STING ,RNA virus ,innate immunity ,viral evasion ,host-pathogen interactions ,antiviral strategies ,Microbiology ,QR1-502 - Abstract
While the function of cGAS/STING signalling axis in the innate immune response to DNA viruses is well deciphered, increasing evidence demonstrates its significant contribution in the control of RNA virus infections. After the first evidence of cGAS/STING antagonism by flaviviruses, STING activation has been detected following infection by various enveloped RNA viruses. It has been discovered that numerous viral families have implemented advanced strategies to antagonize STING pathway through their evolutionary path. This review summarizes the characterized cGAS/STING escape strategies to date, together with the proposed mechanisms of STING signalling activation perpetrated by RNA viruses and discusses possible therapeutic approaches. Further studies regarding the interaction between RNA viruses and cGAS/STING-mediated immunity could lead to major discoveries important for the understanding of immunopathogenesis and for the treatment of RNA viral infections.
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- 2023
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4. Nipah virus W protein harnesses nuclear 14-3-3 to inhibit NF-κB-induced proinflammatory response
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François Enchéry, Claire Dumont, Mathieu Iampietro, Rodolphe Pelissier, Noémie Aurine, Louis-Marie Bloyet, Caroline Carbonnelle, Cyrille Mathieu, Chloé Journo, Denis Gerlier, and Branka Horvat
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Biology (General) ,QH301-705.5 - Abstract
In a study using both human cells and the African green monkeys, Enchery et al report that the highly pathogenic bat-borne Nipah virus (NiV), inhibits the NF-κB pathway via its nonstructural W protein. They demonstrate that it exerts this effect by causing nuclear accumulation of the cellular scaffold protein 14-3-3, which sheds light on pathomechanism of NiV infection.
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- 2021
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5. Hamster organotypic modeling of SARS-CoV-2 lung and brainstem infection
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Marion Ferren, Valérie Favède, Didier Decimo, Mathieu Iampietro, Nicole A. P. Lieberman, Jean-Luc Weickert, Rodolphe Pelissier, Magalie Mazelier, Olivier Terrier, Anne Moscona, Matteo Porotto, Alexander L. Greninger, Nadia Messaddeq, Branka Horvat, and Cyrille Mathieu
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Science - Abstract
Here, Ferren et al. isolate Syrian hamster brainstem and lung tissue to establish ex vivo culture systems to study SARS-CoV-2 local viral tropism, immune response and tissue pathology. Further, they provide evidence that these systems can be used for screening of anti-viral compounds.
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- 2021
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6. Hamster organotypic kidney culture model of early-stage SARS-CoV-2 infection highlights a two-step renal susceptibility
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Sophie R Shyfrin, Marion Ferren, Laure Perrin-Cocon, Maxime Espi, Xavier Charmetant, Manon Brailly, Didier Decimo, Mathieu Iampietro, Lola Canus, Branka Horvat, Vincent Lotteau, Pierre-Olivier Vidalain, Olivier Thaunat, and Cyrille Mathieu
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Biochemistry ,QD415-436 - Abstract
Kidney pathology is frequently reported in patients hospitalized with COVID-19, the pandemic disease caused by the Severe acute respiratory coronavirus 2 (SARS-CoV-2). However, due to a lack of suitable study models, the events occurring in the kidney during the earliest stages of infection remain unknown. We have developed hamster organotypic kidney cultures (OKCs) to study the early stages of direct renal infection. OKCs maintained key renal structures in their native three-dimensional arrangement. SARS-CoV-2 productively replicated in hamster OKCs, initially targeting endothelial cells and later disseminating into proximal tubules. We observed a delayed interferon response, markers of necroptosis and pyroptosis, and an early repression of pro-inflammatory cytokines transcription followed by a strong later upregulation. While it remains an open question whether an active replication of SARS-CoV-2 takes place in the kidneys of COVID-19 patients with AKI, our model provides new insights into the kinetics of SARS-CoV-2 kidney infection and can serve as a powerful tool for studying kidney infection by other pathogens and testing the renal toxicity of drugs.
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- 2022
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7. Early Permissiveness of Central Nervous System Cells to Measles Virus Infection Is Determined by Hyperfusogenicity and Interferon Pressure
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Marion Ferren, Alexandre Lalande, Mathieu Iampietro, Lola Canus, Didier Decimo, Denis Gerlier, Matteo Porotto, and Cyrille Mathieu
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measles virus ,central nervous system infection ,hyperfusogenicity ,viral encephalitis ,cell susceptibility ,interferon treatment ,Microbiology ,QR1-502 - Abstract
The cessation of measles virus (MeV) vaccination in more than 40 countries as a consequence of the COVID-19 pandemic is expected to significantly increase deaths due to measles. MeV can infect the central nervous system (CNS) and lead to lethal encephalitis. Substantial part of virus sequences recovered from patients’ brain were mutated in the matrix and/or the fusion protein (F). Mutations of the heptad repeat domain located in the C terminal (HRC) part of the F protein were often observed and were associated to hyperfusogenicity. These mutations promote brain invasion as a hallmark of neuroadaptation. Wild-type F allows entry into the brain, followed by limited spreading compared with the massive invasion observed for hyperfusogenic MeV. Taking advantage of our ex vivo models of hamster organotypic brain cultures, we investigated how the hyperfusogenic mutations in the F HRC domain modulate virus distribution in CNS cells. In this study, we also identified the dependence of neural cells susceptibility on both their activation state and destabilization of the virus F protein. Type I interferon (IFN-I) impaired mainly astrocytes and microglial cells permissiveness contrarily to neurons, opening a new way of consideration on the development of treatments against viral encephalitis.
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- 2023
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8. Measles Virus-Induced Host Immunity and Mechanisms of Viral Evasion
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Lucia Amurri, Olivier Reynard, Denis Gerlier, Branka Horvat, and Mathieu Iampietro
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Measles virus ,innate immunity ,immune evasion ,signaling ,immune amnesia ,sensors ,Microbiology ,QR1-502 - Abstract
The immune system deploys a complex network of cells and signaling pathways to protect host integrity against exogenous threats, including measles virus (MeV). However, throughout its evolutionary path, MeV developed various mechanisms to disrupt and evade immune responses. Despite an available vaccine, MeV remains an important re-emerging pathogen with a continuous increase in prevalence worldwide during the last decade. Considerable knowledge has been accumulated regarding MeV interactions with the innate immune system through two antagonistic aspects: recognition of the virus by cellular sensors and viral ability to inhibit the induction of the interferon cascade. Indeed, while the host could use several innate adaptors to sense MeV infection, the virus is adapted to unsettle defenses by obstructing host cell signaling pathways. Recent works have highlighted a novel aspect of innate immune response directed against MeV unexpectedly involving DNA-related sensing through activation of the cGAS/STING axis, even in the absence of any viral DNA intermediate. In addition, while MeV infection most often causes a mild disease and triggers a lifelong immunity, its tropism for invariant T-cells and memory T and B-cells provokes the elimination of one primary shield and the pre-existing immunity against previously encountered pathogens, known as “immune amnesia”.
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- 2022
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9. Activation of cGAS/STING pathway upon paramyxovirus infection
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Mathieu Iampietro, Claire Dumont, Cyrille Mathieu, Julia Spanier, Jonathan Robert, Aude Charpenay, Sébastien Dupichaud, Kévin P. Dhondt, Noémie Aurine, Rodolphe Pelissier, Marion Ferren, Stéphane Mély, Denis Gerlier, Ulrich Kalinke, and Branka Horvat
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immune system ,molecular biology ,Virology ,Science - Abstract
Summary: During inflammatory diseases, cancer, and infection, the cGAS/STING pathway is known to recognize foreign or self-DNA in the cytosol and activate an innate immune response. Here, we report that negative-strand RNA paramyxoviruses, Nipah virus (NiV), and measles virus (MeV), can also trigger the cGAS/STING axis. Although mice deficient for MyD88, TRIF, and MAVS still moderately control NiV infection when compared with wild-type mice, additional STING deficiency resulted in 100% lethality, suggesting synergistic roles of these pathways in host protection. Moreover, deletion of cGAS or STING resulted in decreased type I interferon production with enhanced paramyxoviral infection in both human and murine cells. Finally, the phosphorylation and ubiquitination of STING, observed during viral infections, confirmed the activation of cGAS/STING pathway by NiV and MeV. Our data suggest that cGAS/STING activation is critical in controlling paramyxovirus infection and possibly represents attractive targets to develop countermeasures against severe disease induced by these pathogens.
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- 2021
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10. Ebola virus-mediated T-lymphocyte depletion is the result of an abortive infection.
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Patrick Younan, Rodrigo I Santos, Palaniappan Ramanathan, Mathieu Iampietro, Andrew Nishida, Mukta Dutta, Tatiana Ammosova, Michelle Meyer, Michael G Katze, Vsevolod L Popov, Sergei Nekhai, and Alexander Bukreyev
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Ebola virus (EBOV) infections are characterized by a pronounced lymphopenia that is highly correlative with fatalities. However, the mechanisms leading to T-cell depletion remain largely unknown. Here, we demonstrate that both viral mRNAs and antigens are detectable in CD4+ T cells despite the absence of productive infection. A protein phosphatase 1 inhibitor, 1E7-03, and siRNA-mediated suppression of viral antigens were used to demonstrate de novo synthesis of viral RNAs and antigens in CD4+ T cells, respectively. Cell-to-cell fusion of permissive Huh7 cells with non-permissive Jurkat T cells impaired productive EBOV infection suggesting the presence of a cellular restriction factor. We determined that viral transcription is partially impaired in the fusion T cells. Lastly, we demonstrate that exposure of T cells to EBOV resulted in autophagy through activation of ER-stress related pathways. These data indicate that exposure of T cells to EBOV results in an abortive infection, which likely contributes to the lymphopenia observed during EBOV infections.
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- 2019
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11. Recent advances in the understanding of Nipah virus immunopathogenesis and anti-viral approaches [version 1; peer review: 3 approved]
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Rodolphe Pelissier, Mathieu Iampietro, and Branka Horvat
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Medicine ,Science - Abstract
Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus that emerged at the end of last century as a human pathogen capable of causing severe acute respiratory infection and encephalitis. Although NiV provokes serious diseases in numerous mammalian species, the infection seems to be asymptomatic in NiV natural hosts, the fruit bats, which provide a continuous virus source for further outbreaks. Consecutive human-to-human transmission has been frequently observed during outbreaks in Bangladesh and India. NiV was shown to interfere with the innate immune response and interferon type I signaling, restraining the anti-viral response and permitting viral spread. Studies of adaptive immunity in infected patients and animal models have suggested an unbalanced immune response during NiV infection. Here, we summarize some of the recent studies of NiV pathogenesis and NiV-induced modulation of both innate and adaptive immune responses, as well as the development of novel prophylactic and therapeutic approaches, necessary to control this highly lethal emerging infection.
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- 2019
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12. Disabling of lymphocyte immune response by Ebola virus.
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Patrick Younan, Mathieu Iampietro, and Alexander Bukreyev
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Published
- 2018
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13. Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm
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Patrick Younan, Mathieu Iampietro, Andrew Nishida, Palaniappan Ramanathan, Rodrigo I. Santos, Mukta Dutta, Ndongala Michel Lubaki, Richard A. Koup, Michael G. Katze, and Alexander Bukreyev
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cytokine storm ,T lymphocytes ,transcriptome ,cytokines ,Ebola virus ,viral pathogenesis ,Microbiology ,QR1-502 - Abstract
ABSTRACT Ebola virus (EBOV) disease (EVD) results from an exacerbated immunological response that is highlighted by a burst in the production of inflammatory mediators known as a “cytokine storm.” Previous reports have suggested that nonspecific activation of T lymphocytes may play a central role in this phenomenon. T-cell immunoglobulin and mucin domain-containing protein 1 (Tim-1) has recently been shown to interact with virion-associated phosphatidylserine to promote infection. Here, we demonstrate the central role of Tim-1 in EBOV pathogenesis, as Tim-1−/− mice exhibited increased survival rates and reduced disease severity; surprisingly, only a limited decrease in viremia was detected. Tim-1−/− mice exhibited a modified inflammatory response as evidenced by changes in serum cytokines and activation of T helper subsets. A series of in vitro assays based on the Tim-1 expression profile on T cells demonstrated that despite the apparent absence of detectable viral replication in T lymphocytes, EBOV directly binds to isolated T lymphocytes in a phosphatidylserine–Tim-1-dependent manner. Exposure to EBOV resulted in the rapid development of a CD4Hi CD3Low population, non-antigen-specific activation, and cytokine production. Transcriptome and Western blot analysis of EBOV-stimulated CD4+ T cells confirmed the induction of the Tim-1 signaling pathway. Furthermore, comparative analysis of transcriptome data and cytokine/chemokine analysis of supernatants highlight the similarities associated with EBOV-stimulated T cells and the onset of a cytokine storm. Flow cytometry revealed virtually exclusive binding and activation of central memory CD4+ T cells. These findings provide evidence for the role of Tim-1 in the induction of a cytokine storm phenomenon and the pathogenesis of EVD. IMPORTANCE Ebola virus infection is characterized by a massive release of inflammatory mediators, which has come to be known as a cytokine storm. The severity of the cytokine storm is consistently linked with fatal disease outcome. Previous findings have demonstrated that specific T-cell subsets are key contributors to the onset of a cytokine storm. In this study, we investigated the role of Tim-1, a T-cell-receptor-independent trigger of T-cell activation. We first demonstrated that Tim-1-knockout (KO) mice survive lethal Ebola virus challenge. We then used a series of in vitro assays to demonstrate that Ebola virus directly binds primary T cells in a Tim-1–phosphatidylserine-dependent manner. We noted that binding induces a cytokine storm-like phenomenon and that blocking Tim-1–phosphatidylserine interactions reduces viral binding, T-cell activation, and cytokine production. These findings highlight a previously unknown role of Tim-1 in the development of a cytokine storm and “immune paralysis.”
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- 2017
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14. Ebola virus glycoprotein directly triggers T lymphocyte death despite of the lack of infection.
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Mathieu Iampietro, Patrick Younan, Andrew Nishida, Mukta Dutta, Ndongala Michel Lubaki, Rodrigo I Santos, Richard A Koup, Michael G Katze, and Alexander Bukreyev
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Fatal outcomes of Ebola virus (EBOV) infections are typically preceded by a 'sepsis-like' syndrome and lymphopenia despite T cells being resistant to Ebola infection. The mechanisms that lead to T lymphocytes death remain largely unknown; however, the degree of lymphopenia is highly correlative with fatalities. Here we investigated whether the addition of EBOV or its envelope glycoprotein (GP) to isolated primary human CD4+ T cells induced cell death. We observed a significant decrease in cell viability in a GP-dependent manner, which is suggestive of a direct role of GP in T cell death. Using immunoprecipitation assays and flow cytometry, we demonstrate that EBOV directly binds to CD4+ T cells through interaction of GP with TLR4. Transcriptome analysis revealed that the addition of EBOV to CD4+ T cells results in the significant upregulation of pathways associated with interferon signaling, pattern recognition receptors and intracellular activation of NFκB signaling pathway. Both transcriptome analysis and specific inhibitors allowed identification of apoptosis and necrosis as mechanisms associated with the observed T cell death following exposure to EBOV. The addition of the TLR4 inhibitor CLI-095 significantly reduced CD4+ T cell death induced by GP. EBOV stimulation of primary CD4+ T cells resulted in a significant increase in secreted TNFα; inhibition of TNFα-mediated signaling events significantly reduced T cell death while inhibitors of both necrosis and apoptosis similarly reduced EBOV-induced T cell death. Lastly, we show that stimulation with EBOV or GP augments monocyte maturation as determined by an overall increase in expression levels of markers of differentiation. Subsequently, the increased rates of cellular differentiation resulted in higher rates of infection further contributing to T cell death. These results demonstrate that GP directly subverts the host's immune response by increasing the susceptibility of monocytes to EBOV infection and triggering lymphopenia through direct and indirect mechanisms.
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- 2017
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15. The Ebola Interferon Inhibiting Domains Attenuate and Dysregulate Cell-Mediated Immune Responses.
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Ndongala Michel Lubaki, Patrick Younan, Rodrigo I Santos, Michelle Meyer, Mathieu Iampietro, Richard A Koup, and Alexander Bukreyev
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Ebola virus (EBOV) infections are characterized by deficient T-lymphocyte responses, T-lymphocyte apoptosis and lymphopenia. We previously showed that disabling of interferon-inhibiting domains (IIDs) in the VP24 and VP35 proteins effectively unblocks maturation of dendritic cells (DCs) and increases the secretion of cytokines and chemokines. Here, we investigated the role of IIDs in adaptive and innate cell-mediated responses using recombinant viruses carrying point mutations, which disabled IIDs in VP24 (EBOV/VP24m), VP35 (EBOV/VP35m) or both (EBOV/VP35m/VP24m). Peripheral blood mononuclear cells (PBMCs) from cytomegalovirus (CMV)-seropositive donors were inoculated with the panel of viruses and stimulated with CMV pp65 peptides. Disabling of the VP35 IID resulted in increased proliferation and higher percentages of CD4+ T cells secreting IFNγ and/or TNFα. To address the role of aberrant DC maturation in the IID-mediated suppression of T cell responses, CMV-stimulated DCs were infected with the panel of viruses and co-cultured with autologous T-lymphocytes. Infection with EBOV/VP35m infection resulted in a significant increase, as compared to wt EBOV, in proliferating CD4+ cells secreting IFNγ, TNFα and IL-2. Experiments with expanded CMV-specific T cells demonstrated their increased activation following co-cultivation with CMV-pulsed DCs pre-infected with EBOV/VP24m, EBOV/VP35m and EBOV/VP35m/VP24m, as compared to wt EBOV. Both IIDs were found to block phosphorylation of TCR complex-associated adaptors and downstream signaling molecules. Next, we examined the effects of IIDs on the function of B cells in infected PBMC. Infection with EBOV/VP35m and EBOV/VP35m/VP24m resulted in significant increases in the percentages of phenotypically distinct B-cell subsets and plasma cells, as compared to wt EBOV, suggesting inhibition of B cell function and differentiation by VP35 IID. Finally, infection with EBOV/VP35m increased activation of NK cells, as compared to wt EBOV. These results demonstrate a global suppression of cell-mediated responses by EBOV IIDs and identify the role of DCs in suppression of T-cell responses.
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- 2016
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16. SARS-CoV-2 induces human endogenous retrovirus type W envelope protein expression in blood lymphocytes and in tissues of COVID-19 patients
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Benjamin Charvet, Joanna Brunel, Justine Pierquin, Mathieu Iampietro, Didier Decimo, Nelly Queruel, Alexandre Lucas, María del Mar Encabo-Berzosa, Izaskun Arenaz, Tania Perez Marmolejo, Francina Valezka Bolaños Morales, Arturo Ivan Gonzalez Gonzalez, Armando Castorena Maldonado, César Luna Rivero, Cyrille Mathieu, Patrick Küry, Jose Flores-Rivera, Santiago Avila Rios, Gonzalo Salgado Montes de Oca, Jon Schoorlemmer, Branka Horvat, Hervé Perron, GeNeuro Innovation [Lyon], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto Aragonés de Ciencias de la Salud [Zaragoza] (IACS), Instituto Nacional de Enfermedades Respiratorias [México, Mexico], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], and National Institute of Neurology and Neurosurgery
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[SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases ,viruses - Abstract
Patients with COVID-19 may develop abnormal inflammatory response and lymphopenia, followed in some cases by delayed-onset syndromes, often long-lasting after the initial SARS-CoV-2 infection. As viral infections may activate human endogenous retroviral elements (HERV), we studied the effect of SARS-CoV-2 on HERV-W and HERV-K envelope (ENV) expression, known to be involved in immunological and neurological pathogenesis of human diseases. Our results have showed that the exposure to SARS-CoV-2 virus activates early HERV-W and K transcription but only HERV-W ENV protein expression, in an infection- and ACE2-independent way within peripheral blood mononuclear cell cultures from one-third of healthy donors. Moreover, HERV-W ENV protein was significantly increased in serum and plasma of COVID-19 patients, correlating with its expression in CD3+ lymphocytes and with disease severity. Finally, HERV-W ENV was found expressed in post-mortem tissues of lungs, heart, brain olfactory bulb and nasal mucosa from acute COVID-19 patients in cell-types relevant for COVID-19-associated pathogenesis within affected organs, but different from those expressing of SARS-CoV-2 antigens. Altogether, the present study revealed that SARS-CoV-2 can induce HERV-W ENV expression in cells from individuals with symptomatic and severe COVID-19. Our data suggest that HERV-W ENV is likely to be involved in pathogenic features underlying symptoms of acute and post-acute COVID. It highlights the importance to further understand patients’ genetic susceptibility to HERV-W activation and the relevance of this pathogenic element as a prognostic marker and a therapeutic target in COVID-19 associated syndromes.Graphical abstract
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- 2022
17. Measles Virus-Induced Host Immunity and Mechanisms of Viral Evasion
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Olivier Reynard, Branka Horvat, Mathieu Iampietro, Lucia Amurri, and Denis Gerlier
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Infectious Diseases ,Virology - Abstract
The immune system deploys a complex network of cells and signaling pathways to protect host integrity against exogenous threats, including measles virus (MeV). However, throughout its evolutionary path, MeV developed various mechanisms to disrupt and evade immune responses. Despite an available vaccine, MeV remains an important re-emerging pathogen with a continuous increase in prevalence worldwide during the last decade. Considerable knowledge has been accumulated regarding MeV interactions with the innate immune system through two antagonistic aspects: recognition of the virus by cellular sensors and viral ability to inhibit the induction of the interferon cascade. Indeed, while the host could use several innate adaptors to sense MeV infection, the virus is adapted to unsettle defenses by obstructing host cell signaling pathways. Recent works have highlighted a novel aspect of innate immune response directed against MeV unexpectedly involving DNA-related sensing through activation of the cGAS/STING axis, even in the absence of any viral DNA intermediate. In addition, while MeV infection most often causes a mild disease and triggers a lifelong immunity, its tropism for invariant T-cells and memory T and B-cells provokes the elimination of one primary shield and the pre-existing immunity against previously encountered pathogens, known as “immune amnesia”.
- Published
- 2022
18. [The cGAS/STING signaling pathway controls infections by measles and Nipah viruses]
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Mathieu, Iampietro, Lucia, Amurri, and Branka, Horvat
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Nipah Virus ,Humans ,Nucleotidyltransferases ,Measles ,Signal Transduction - Published
- 2022
19. Control of Nipah Virus Infection in Mice by the Host Adaptors Mitochondrial Antiviral Signaling Protein (MAVS) and Myeloid Differentiation Primary Response 88 (MyD88)
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Hervé Raoul, Audrey Vallve, Claire Dumont, Rodolphe Pelissier, Kévin P. Dhondt, Mathieu Iampietro, Julia Spanier, Branka Horvat, Noémie Aurine, Ulrich Kalinke, and TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
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0301 basic medicine ,mice ,Mice, Transgenic ,Nipah virus ,Biology ,Mitochondrion ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Interferon ,TLR ,medicine ,Animals ,Immunology and Allergy ,Receptor ,TRIF ,innate immunity ,Adaptor Proteins, Signal Transducing ,Mitochondrial antiviral-signaling protein ,Henipavirus Infections ,Mice, Knockout ,Innate immune system ,Toll-Like Receptors ,Nipah Virus ,interferon ,Interferon-beta ,MAVS ,MyD88 ,Virology ,In vitro ,030104 developmental biology ,Infectious Diseases ,Gene Expression Regulation ,Interferon Type I ,Myeloid Differentiation Factor 88 ,DEAD Box Protein 58 ,Signal transduction ,030215 immunology ,medicine.drug - Abstract
Interferon (IFN) type I plays a critical role in the protection of mice from lethal Nipah virus (NiV) infection, but mechanisms responsible for IFN-I induction remain unknown. In the current study, we demonstrated the critical role of the mitochondrial antiviral signaling protein signaling pathway in IFN-I production and NiV replication in murine embryonic fibroblasts in vitro, and the redundant but essential roles of both mitochondrial antiviral signaling protein and myeloid differentiation primary response 88 adaptors, but not toll/interleukin-1 receptor/resistance [TIR] domain–containing adaptor–inducing IFN-β (TRIF), in the control of NiV infection in mice. These results reveal potential novel targets for antiviral intervention and help in understanding NiV immunopathogenesis.
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- 2019
20. Organotypic modeling of SARS-CoV-2 lung and brainstem infection
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Mathieu Iampietro, Jean-Luc Weickert, Matteo Porotto, Anne Moscona, Rodolphe Pelissier, Didier Decimo, Nicole A P Lieberman, Magalie Mazelier, Branka Horvat, Cyrille Mathieu, Nadia Messaddeq, Alexander L. Greninger, Valérie Favede, Olivier Terrier, Marion Ferren, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Washington [Seattle], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Columbia University Medical Center (CUMC), Columbia University [New York], University of the Study of Campania Luigi Vanvitelli, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0303 health sciences ,Programmed cell death ,Innate immune system ,Lung ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,030306 microbiology ,business.industry ,[SDV]Life Sciences [q-bio] ,Virus ,3. Good health ,Pathogenesis ,03 medical and health sciences ,medicine.anatomical_structure ,Interferon ,Immunology ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Medicine ,Brainstem ,business ,Tropism ,030304 developmental biology ,medicine.drug - Abstract
SARS-CoV-2 has caused a global pandemic of Covid-19 since its emergence in December 2019. The infection causes a severe acute respiratory syndrome and may also lead to central nervous system infection and neurological sequelae. We developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer the unique opportunity to study the early steps of the pathogenesis and screening of antivirals. Using these models, we validated the early tropism of the virus in the lung and demonstrated that SARS-CoV2 can infect brainstem and cerebellum, mainly by targeting granular neurons. Viral infection induced specific interferon and innate immune responses with patterns specific to each organ along with apoptotic, necroptotic, and pyroptotic cell death. Overall, our data illustrate the potential of rapidly modeling complex tissue level interactions of viral infection in a newly emerged virus.
- Published
- 2021
21. SARS-CoV-2 induces transcription of human endogenous retrovirus RNA followed by type W envelope protein expression in human lymphoid cells
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Magalie Mazelier, Pierquin J, Didier Decimo, Mathieu Iampietro, Branka Horvat, Brunel J, Charvet B, Mougari S, Queruel N, Perron H, Matthieu C, GeNeuro Innovation [Lyon], Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mathieu, Cyrille, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and ANR-21-CO15-0007,COVERI,Activation immunopathologique de la protéine rétrovirale endogène HERV-W par SRAS-CoV-2 chez les patients COVID-19(2021)
- Subjects
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Transcription (biology) ,Human endogenous retrovirus ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,viruses ,embryonic structures ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,RNA ,Biology ,Protein expression ,3. Good health ,Cell biology - Abstract
Patients with COVID-19 may develop abnormal inflammatory response and lymphopenia, followed in some cases by delayed-onset syndromes, often long-lasting after resolution of the initial SARS-CoV-2 infection. As viral infections may activate human endogenous retroviral elements (HERV), we studied the effect of SARS-CoV-2 on HERV-W and HERV-K envelope (ENV) expression, known to be involved in immunological and neurological pathogenesis of human diseases. We demonstrate here that an initial exposure to SARS-CoV-2 virus activates early HERV-W and K transcription in peripheral blood mononuclear cell (PBMC) cultures from healthy donors. Within a week of primary PBMC culture, only HERV-W ENV protein expression was detected in lymphoid cells of some donors, although SARS-CoV-2 infection of PBMC was not observed. HERV activation was reproduced with UV-inactivated virus and with a recombinant spike protein. Interestingly, exposure to SARS-CoV-2 protein induced a significant production of interleukin 6 in PBMC, independently from detectable HERV expression. Altogether, these results show that SARS-CoV-2 viral protein could induce HERV-W ENV expression in lymphocytes from some individuals, underlying the importance to further address the implicated molecular pathways, to understand patients‘ genetic susceptibility associated to the activation of HERV-W and its possible relevance for targeting therapeutic intervention in COVID-19 associated syndromes.
- Published
- 2021
22. Activation of cGAS/STING pathway upon paramyxovirus infection
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Cyrille Mathieu, Marion Ferren, Branka Horvat, Julia Spanier, Aude Charpenay, Mathieu Iampietro, Claire Dumont, Sébastien Dupichaud, Noémie Aurine, Rodolphe Pelissier, Stéphane Mély, Kévin P. Dhondt, Denis Gerlier, Ulrich Kalinke, Jonathan Robert, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre for Experimental and Clinical Infection Research [Hanover] (TWINCORE), Laboratoire P4 - Jean Mérieux, Centre Européen de Virologie/Immunologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Mathieu, Cyrille, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and ANR-18-CE11-0014,NiPah-C,Structure et fonctions de la protéine C du virus Nipah(2018)
- Subjects
Science ,Biology ,Article ,Measles virus ,03 medical and health sciences ,0302 clinical medicine ,Ubiquitin ,Virology ,molecular biology ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,0303 health sciences ,Innate immune system ,RNA ,biology.organism_classification ,eye diseases ,3. Good health ,Sting ,Cytosol ,immune system ,TRIF ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,biology.protein ,Phosphorylation ,030217 neurology & neurosurgery - Abstract
Summary During inflammatory diseases, cancer, and infection, the cGAS/STING pathway is known to recognize foreign or self-DNA in the cytosol and activate an innate immune response. Here, we report that negative-strand RNA paramyxoviruses, Nipah virus (NiV), and measles virus (MeV), can also trigger the cGAS/STING axis. Although mice deficient for MyD88, TRIF, and MAVS still moderately control NiV infection when compared with wild-type mice, additional STING deficiency resulted in 100% lethality, suggesting synergistic roles of these pathways in host protection. Moreover, deletion of cGAS or STING resulted in decreased type I interferon production with enhanced paramyxoviral infection in both human and murine cells. Finally, the phosphorylation and ubiquitination of STING, observed during viral infections, confirmed the activation of cGAS/STING pathway by NiV and MeV. Our data suggest that cGAS/STING activation is critical in controlling paramyxovirus infection and possibly represents attractive targets to develop countermeasures against severe disease induced by these pathogens., Graphical abstract, Highlights • RNA sensors are insufficient for the effective control of paramyxovirus infection • STING adaptor protein is involved in controlling Nipah virus infection in mice • cGAS/STING axis is primordial for optimal production of IFN-I against NiV and MeV • STING protein can be activated during infections by RNA viruses, Immune system; Molecular biology; Virology
- Published
- 2021
23. Quercetin Blocks Ebola Virus Infection by Counteracting the VP24 Interferon-Inhibitory Function
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Simona Distinto, Mathieu Iampietro, Enzo Tramontano, Angela Corona, Branka Horvat, Elisa Fanunza, Marina Quartu, and Elias Maccioni
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Viral protein ,Virulence ,Biology ,medicine.disease_cause ,Antiviral Agents ,Viral Proteins ,03 medical and health sciences ,Interferon ,medicine ,Humans ,Pharmacology (medical) ,IC50 ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Ebola virus ,030306 microbiology ,Drug discovery ,Hemorrhagic Fever, Ebola ,Ebolavirus ,Virology ,Infectious Diseases ,Mechanism of action ,Drug development ,Quercetin ,Interferons ,medicine.symptom ,medicine.drug - Abstract
Ebola virus (EBOV) is among the most devastating pathogens causing fatal hemorrhagic fever in humans. The epidemics from 2013 to 2016 resulted in more than 11,000 deaths, and another outbreak is currently ongoing. Since there is no FDA-approved drug so far to fight EBOV infection, there is an urgent need to focus on drug discovery. Considering the tight correlation between the high EBOV virulence and its ability to suppress the type I interferon (IFN-I) system, identifying molecules targeting viral protein VP24, one of the main virulence determinants blocking the IFN response, is a promising novel anti-EBOV therapy approach. Hence, in the effort to find novel EBOV inhibitors, a screening of a small set of flavonoids was performed; it showed that quercetin and wogonin can suppress the VP24 effect on IFN-I signaling inhibition. The mechanism of action of the most active compound, quercetin, showing a half-maximal inhibitory concentration (IC(50)) of 7.4 μM, was characterized to significantly restore the IFN-I signaling cascade, blocked by VP24, by directly interfering with the VP24 binding to karyopherin-α and thus restoring P-STAT1 nuclear transport and IFN gene transcription. Quercetin significantly blocked viral infection, specifically targeting EBOV VP24 anti-IFN-I function. Overall, quercetin is the first identified inhibitor of the EBOV VP24 anti-IFN function, representing a molecule interacting with a viral binding site that is very promising for further drug development aiming to block EBOV infection at the early steps.
- Published
- 2020
24. Ebola Virus Shed Glycoprotein Triggers Differentiation, Infection, and Death of Monocytes Through Toll-Like Receptor 4 Activation
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Ndongala Michel Lubaki, Mathieu Iampietro, Alexander Bukreyev, and Rodrigo I. Santos
- Subjects
0301 basic medicine ,Programmed cell death ,THP-1 Cells ,viruses ,030106 microbiology ,Supplement Articles ,Biology ,medicine.disease_cause ,Monocytes ,Pathogenesis ,03 medical and health sciences ,Immune system ,Viral Envelope Proteins ,medicine ,Humans ,Immunology and Allergy ,Ebola Vaccines ,Receptor ,Glycoproteins ,chemistry.chemical_classification ,Toll-like receptor ,Ebola virus ,Cell Death ,Ebola vaccine ,virus diseases ,Cell Differentiation ,Hemorrhagic Fever, Ebola ,Ebolavirus ,Virology ,Toll-Like Receptor 4 ,030104 developmental biology ,Infectious Diseases ,chemistry ,Host-Pathogen Interactions ,Glycoprotein - Abstract
A better understanding of the mechanisms used by Ebola virus to disable the host immune system and spread the infection are of great importance for development of new therapeutic strategies. We demonstrate that treatment of monocytic cells with Ebola virus shed glycoprotein (GP) promotes their differentiation resulting in increased infection and cell death. The effects were inhibited by blocking Toll-like receptor 4 pathway. In addition, high levels of shed GP were detected in supernatants of cells treated with Ebola vaccines. This study highlights the role of shed GP in Ebola pathogenesis and also in adverse effects associated with Ebola vaccines.
- Published
- 2018
25. Ebola virus-mediated T-lymphocyte depletion is the result of an abortive infection
- Author
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Alexander Bukreyev, Mathieu Iampietro, Andrew Nishida, Michael G. Katze, Rodrigo I. Santos, Mukta Dutta, Palaniappan Ramanathan, Vsevolod L. Popov, Tatiana Ammosova, Sergei Nekhai, Michelle Meyer, and Patrick Younan
- Subjects
CD4-Positive T-Lymphocytes ,Indoles ,Physiology ,viruses ,medicine.disease_cause ,Virus Replication ,Jurkat cells ,Biochemistry ,Cell Fusion ,White Blood Cells ,Guide RNA ,Jurkat Cells ,Spectrum Analysis Techniques ,Animal Cells ,Immune Physiology ,Protein Phosphatase 1 ,Chlorocebus aethiops ,Medicine and Health Sciences ,Urea ,Post-Translational Modification ,Phosphorylation ,RNA, Small Interfering ,Biology (General) ,Antigens, Viral ,Staining ,0303 health sciences ,Cell fusion ,Immune System Proteins ,Cell Death ,T Cells ,030302 biochemistry & molecular biology ,Cell Staining ,Flow Cytometry ,Ebolavirus ,Endoplasmic Reticulum Stress ,3. Good health ,Nucleic acids ,Spectrophotometry ,Cell Processes ,Host-Pathogen Interactions ,RNA, Viral ,RNA Interference ,Cytophotometry ,Antibody ,Cellular Types ,Research Article ,Cell Physiology ,QH301-705.5 ,Immune Cells ,Autophagic Cell Death ,Immunology ,Biology ,Research and Analysis Methods ,Microbiology ,Antibodies ,Cell Line ,03 medical and health sciences ,Viral Proteins ,Antigen ,Virology ,Lymphopenia ,Genetics ,medicine ,Autophagy ,Animals ,Humans ,Molecular Biology ,Vero Cells ,030304 developmental biology ,Ebola virus ,Blood Cells ,Biology and Life Sciences ,Proteins ,T lymphocyte ,Cell Biology ,Hemorrhagic Fever, Ebola ,RC581-607 ,HEK293 Cells ,Cell culture ,Specimen Preparation and Treatment ,Vero cell ,biology.protein ,RNA ,Parasitology ,Immunologic diseases. Allergy ,Transcription Factors - Abstract
Ebola virus (EBOV) infections are characterized by a pronounced lymphopenia that is highly correlative with fatalities. However, the mechanisms leading to T-cell depletion remain largely unknown. Here, we demonstrate that both viral mRNAs and antigens are detectable in CD4+ T cells despite the absence of productive infection. A protein phosphatase 1 inhibitor, 1E7-03, and siRNA-mediated suppression of viral antigens were used to demonstrate de novo synthesis of viral RNAs and antigens in CD4+ T cells, respectively. Cell-to-cell fusion of permissive Huh7 cells with non-permissive Jurkat T cells impaired productive EBOV infection suggesting the presence of a cellular restriction factor. We determined that viral transcription is partially impaired in the fusion T cells. Lastly, we demonstrate that exposure of T cells to EBOV resulted in autophagy through activation of ER-stress related pathways. These data indicate that exposure of T cells to EBOV results in an abortive infection, which likely contributes to the lymphopenia observed during EBOV infections., Author summary Lymphopenia is a common characteristic of the disease caused by EBOV. We determined that despite the apparent lack of productive infection, EBOV is capable of entering T cells and producing both viral RNAs and proteins. Furthermore, we demonstrate that EBOV causes an abortive infection in T cells due to the presence of a cellular restriction factor. The abortive infection was associated with cell death following ER-stress induced autophagy. Collectively, these findings suggest that abortive infection in T cells is likely to contribute to lymphopenia during Ebola virus disease, which is uniformly linked with the severity of the disease. All EBOV vaccine candidates utilize GP as the sole antigen inducing a protective antibody response and in some clinical trials were shown to induce adverse side effects. The present study suggests that these effects can be associated with GP, which may lead to abortive infection of the vaccine construct in T cells contributing to the inflammatory response to the vaccines.
- Published
- 2019
26. Recent advances in the understanding of Nipah virus immunopathogenesis and anti-viral approaches
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Mathieu Iampietro, Branka Horvat, and Rodolphe Pelissier
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0301 basic medicine ,India ,Human pathogen ,Review ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Animals ,Humans ,030212 general & internal medicine ,General Pharmacology, Toxicology and Pharmaceutics ,innate immunity ,Henipavirus Infections ,Bangladesh ,Innate immune system ,contra-measures ,General Immunology and Microbiology ,Transmission (medicine) ,pathogenesis ,Nipah Virus ,General Medicine ,Articles ,adaptive immunity ,medicine.disease ,Acquired immune system ,Virology ,animal models ,Immunity, Innate ,3. Good health ,030104 developmental biology ,Encephalitis ,Interferon type I ,medicine.drug - Abstract
Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus that emerged at the end of last century as a human pathogen capable of causing severe acute respiratory infection and encephalitis. Although NiV provokes serious diseases in numerous mammalian species, the infection seems to be asymptomatic in NiV natural hosts, the fruit bats, which provide a continuous virus source for further outbreaks. Consecutive human-to-human transmission has been frequently observed during outbreaks in Bangladesh and India. NiV was shown to interfere with the innate immune response and interferon type I signaling, restraining the anti-viral response and permitting viral spread. Studies of adaptive immunity in infected patients and animal models have suggested an unbalanced immune response during NiV infection. Here, we summarize some of the recent studies of NiV pathogenesis and NiV-induced modulation of both innate and adaptive immune responses, as well as the development of novel prophylactic and therapeutic approaches, necessary to control this highly lethal emerging infection.
- Published
- 2019
27. Antibody-Mediated Protective Mechanisms Induced by a Trivalent Parainfluenza Virus-Vectored Ebolavirus Vaccine
- Author
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J. Brian Kimble, Alexander Bukreyev, Marcus M. Karim, Galit Alter, Bronwyn M. Gunn, Mathieu Iampietro, Michelle Meyer, Delphine C. Malherbe, Kai Huang, Khaled S. Mohamed, Yuri I. Wolf, Philipp A. Ilinykh, Pavlo Gilchuk, James E. Crowe, Werner Braun, and Surendra S. Negi
- Subjects
medicine.drug_class ,Immunology ,Genetic Vectors ,Guinea Pigs ,medicine.disease_cause ,Monoclonal antibody ,Antibodies, Viral ,Microbiology ,Epitope ,Cell Line ,03 medical and health sciences ,Epitopes ,Antigen ,Viral Envelope Proteins ,Virology ,Vaccines and Antiviral Agents ,medicine ,Animals ,Ebola Vaccines ,030304 developmental biology ,Glycoproteins ,Ebolavirus ,0303 health sciences ,Ebola virus ,biology ,030306 microbiology ,Polyvalent Vaccine ,Ferrets ,Antibodies, Monoclonal ,Viral Vaccines ,Hemorrhagic Fever, Ebola ,Antibodies, Neutralizing ,Parainfluenza Virus 3, Human ,Drug Combinations ,Immunization ,Insect Science ,biology.protein ,Female ,Antibody - Abstract
Ebolaviruses Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) cause human disease with high case fatality rates. Experimental monovalent vaccines, which all utilize the sole envelope glycoprotein (GP), do not protect against heterologous ebolaviruses. Human parainfluenza virus type 3-vectored vaccines offer benefits, including needle-free administration and induction of mucosal responses in the respiratory tract. Multiple approaches were taken to induce broad protection against the three ebolaviruses. While GP consensus-based antigens failed to elicit neutralizing antibodies, polyvalent vaccine immunization induced neutralizing responses to all three ebolaviruses and protected animals from death and disease caused by EBOV, SUDV, and BDBV. As immunization with a cocktail of antigenically related antigens can skew the responses and change the epitope hierarchy, we performed comparative analysis of antibody repertoire and Fc-mediated protective mechanisms in animals immunized with monovalent versus polyvalent vaccines. Compared to sera from guinea pigs receiving the monovalent vaccines, sera from guinea pigs receiving the trivalent vaccine bound and neutralized EBOV and SUDV at equivalent levels and BDBV at only a slightly reduced level. Peptide microarrays revealed a preponderance of binding to amino acids 389 to 403, 397 to 415, and 477 to 493, representing three linear epitopes in the mucin-like domain known to induce a protective antibody response. Competition binding assays with monoclonal antibodies isolated from human ebolavirus infection survivors demonstrated that the immune sera block the binding of antibodies specific for the GP glycan cap, the GP1-GP2 interface, the mucin-like domain, and the membrane-proximal external region. Thus, administration of a cocktail of three ebolavirus vaccines induces a desirable broad antibody response, without skewing of the response toward preferential recognition of a single virus. IMPORTANCE The symptoms of the disease caused by the ebolaviruses Ebola, Bundibugyo, and Sudan are similar, and their areas of endemicity overlap. However, because of the limited antigenic relatedness of the ebolavirus glycoprotein (GP) used in all candidate vaccines against these viruses, they protect only against homologous and not against heterologous ebolaviruses. Therefore, a broadly specific pan-ebolavirus vaccine is required, and this might be achieved by administration of a cocktail of vaccines. The effects of cocktail administration of ebolavirus vaccines on the antibody repertoire remain unknown. Here, an in-depth analysis of the antibody responses to administration of a cocktail of human parainfluenza virus type 3-vectored vaccines against individual ebolaviruses was performed, which included analysis of binding to GP, neutralization of individual ebolaviruses, epitope specificity, Fc-mediated functions, and protection against the three ebolaviruses. The results demonstrated potent and balanced responses against individual ebolaviruses and no significant reduction of the responses compared to that induced by individual vaccines.
- Published
- 2018
28. Role of Transmembrane Protein 16F in the Incorporation of Phosphatidylserine Into Budding Ebola Virus Virions
- Author
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Palaniappan Ramanathan, Vsevolod L. Popov, Rodrigo I. Santos, Patrick Younan, Mathieu Iampietro, and Alexander Bukreyev
- Subjects
0301 basic medicine ,Infectivity ,Budding ,Phospholipid scramblase ,Ebola virus ,Chemistry ,viruses ,Phosphatidylserine ,medicine.disease_cause ,Cell biology ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Infectious Diseases ,Viral envelope ,Tissue tropism ,medicine ,Immunology and Allergy ,Erratum ,Integral membrane protein - Abstract
Viral apoptotic mimicry, which is defined by exposure of phosphatidylserine (PtdSer) into the outer leaflet of budding enveloped viruses, increases viral tropism, infectivity and promotes immune evasion. Here, we report that the calcium (Ca2+)-dependent scramblase, transmembrane protein 16F (TMEM16F), is responsible for the incorporation of PtdSer into virion membranes during Ebola virus infection. Infection of Huh7 cells with Ebola virus resulted in a pronounced increase in plasma membrane-associated PtdSer, which was demonstrated to be dependent on TMEM16F function. Analysis of virions using imaging flow cytometry revealed that short hairpin RNA-mediated down-regulation of TMEM16F function directly reduced virion-associated PtdSer. Taken together, these studies demonstrate that TMEM16F is a central cellular factor in the exposure of PtdSer in the outer leaflet of viral membranes.
- Published
- 2018
29. Disruption of Phosphatidylserine Synthesis or Trafficking Reduces Infectivity of Ebola Virus
- Author
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Patrick Younan, Rodrigo I. Santos, Palaniappan Ramanathan, Vsevolod L. Popov, Alexander Bukreyev, and Mathieu Iampietro
- Subjects
0301 basic medicine ,viruses ,CDPdiacylglycerol-Serine O-Phosphatidyltransferase ,Supplement Articles ,Phosphatidylserines ,medicine.disease_cause ,Virus Replication ,Cell membrane ,03 medical and health sciences ,chemistry.chemical_compound ,Chlorocebus aethiops ,medicine ,Immunology and Allergy ,Animals ,Vero Cells ,Virus Release ,Infectivity ,Ebola virus ,030102 biochemistry & molecular biology ,Chemistry ,Virion ,Biological Transport ,Phosphatidylserine ,Viral membrane ,Ebolavirus ,Cell biology ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Viral replication ,Tissue tropism - Abstract
The outer leaflet of the viral membrane of Ebola virus (EBOV) virions is enriched with phosphatidylserine (PtdSer), which is thought to play a central role in viral tropism, entry, and virus-associated immune evasion. We investigated the effects of inhibiting synthesis and/or export of PtdSer to the cell surface of infected cells on viral infectivity. Knockdown of both PtdSer synthase enzymes, PTDSS1 and PTDSS2, effectively decreased viral production. Decreased PtdSer expression resulted in an accumulation of virions at the plasma membrane and adjacent of intracellular organelles, suggesting that virion budding is impaired. The addition of inhibitors that block normal cellular trafficking of PtdSer to the plasma membrane resulted in a similar accumulation of virions and reduced viral replication. These findings demonstrate that plasma membrane-associated PtdSer is required for efficient EBOV budding, increasing EBOV infectivity, and could constitute a potential therapeutic target for the development of future countermeasures against EBOV.
- Published
- 2018
30. Inhibition of Interleukin-2 Gene Expression by Human Herpesvirus 6B U54 Tegument Protein
- Author
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Louis Flamand, Mathieu Iampietro, Guillaume Morissette, and Annie Gravel
- Subjects
Interleukin 2 ,Herpesvirus 6, Human ,viruses ,medicine.medical_treatment ,Immunology ,Plasma protein binding ,Biology ,Microbiology ,Cell Line ,Viral Proteins ,Immune system ,Virology ,Gene expression ,medicine ,Humans ,Immune Evasion ,NFATC Transcription Factors ,Growth factor ,virus diseases ,NFAT ,Viral tegument ,biochemical phenomena, metabolism, and nutrition ,Phosphoric Monoester Hydrolases ,Virus-Cell Interactions ,Cell biology ,Insect Science ,Host-Pathogen Interactions ,Interleukin-2 ,Protein Binding ,medicine.drug - Abstract
Human herpesvirus 6B (HHV-6B) is a ubiquitous pathogen causing lifelong infections in approximately 95% of humans worldwide. To persist within its host, HHV-6B has developed several immune evasion mechanisms, such as latency, during which minimal proteins are expressed, and the ability to disturb innate and adaptive immune responses. The primary cellular targets of HHV-6B are CD4 + T cells. Previous studies by Flamand et al. (L. Flamand, J. Gosselin, I. Stefanescu, D. Ablashi, and J. Menezes, Blood 85:1263–1271, 1995) reported on the capacity of HHV-6A as well as UV-irradiated HHV-6A to inhibit interleukin-2 (IL-2) synthesis in CD4 + lymphocytes, suggesting that viral structural components could be responsible for this effect. In the present study, we identified the HHV-6B U54 tegument protein (U54) as being capable of inhibiting IL-2 expression. U54 binds the calcineurin (CaN) phosphatase enzyme, causing improper dephosphorylation and nuclear translocation of NFAT (nuclear factor of activated T cells) proteins, resulting in suboptimal IL-2 gene transcription. The U54 GISIT motif (amino acids 293 to 297), analogous to the NFAT PXIXIT motif, contributed to the inhibition of NFAT activation. IMPORTANCE Human herpesvirus 6A (HHV-6A) and HHV-6B are associated with an increasing number of pathologies. These viruses have developed strategies to avoid the immune response allowing them to persist in the host. Several studies have illustrated mechanisms by which HHV-6A and HHV-6B are able to disrupt host defenses (reviewed in L. Dagna, J. C. Pritchett, and P. Lusso, Future Virol. 8:273–287, 2013, doi:10.2217/fvl.13.7). Previous work informed us that HHV-6A is able to suppress synthesis of interleukin-2 (IL-2), a key immune growth factor essential for adequate T lymphocyte proliferation and expansion. We obtained evidence that HHV-6B also inhibits IL-2 gene expression and identified the mechanisms by which it does so. Our work led us to the identification of U54, a virion-associated tegument protein, as being responsible for suppression of IL-2. Consequently, we have identified HHV-6B U54 protein as playing a role in immune evasion. These results further contribute to our understanding of HHV-6 interactions with its human host and the efforts deployed to ensure its long-term persistence.
- Published
- 2014
31. Inhibition of Breast Cancer Cell Proliferation through Disturbance of the Calcineurin/NFAT Pathway by Human Herpesvirus 6B U54 Tegument Protein
- Author
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Mathieu Iampietro, Annie Gravel, and Louis Flamand
- Subjects
Herpesvirus 6, Human ,T cell ,Immunology ,Biology ,Microbiology ,Viral Proteins ,NFAT Pathway ,Virology ,medicine ,Humans ,Cell Proliferation ,NFATC Transcription Factors ,Cell growth ,Calcineurin ,NFAT ,Virus-Cell Interactions ,medicine.anatomical_structure ,Insect Science ,Host-Pathogen Interactions ,Cancer cell ,MCF-7 Cells ,Cancer research ,Female ,Signal transduction ,Signal Transduction - Abstract
Nuclear factor of activated T cell (NFAT) proteins are key regulators involved in multiple physiological mechanisms, such as immune response and cell growth. The capacity of selective calcineurin/NFAT inhibitors to decrease NFAT-dependent cancer cell progression, particularly in breast cancer, has already been demonstrated. In this study, we report a role for the human herpesvirus 6B (HHV-6B) U54 tegument protein in inhibiting MCF-7 breast cancer cell proliferation by inhibiting NFAT activation.
- Published
- 2014
32. Ebola virus glycoprotein directly triggers T lymphocyte death despite of the lack of infection
- Author
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Richard A. Koup, Patrick Younan, Mathieu Iampietro, Andrew Nishida, Mukta Dutta, Ndongala Michel Lubaki, Michael G. Katze, Rodrigo I. Santos, and Alexander Bukreyev
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Cellular differentiation ,Apoptosis ,Monocytes ,White Blood Cells ,Spectrum Analysis Techniques ,Viral Envelope Proteins ,Cell Signaling ,Interferon ,Animal Cells ,Medicine and Health Sciences ,Cytotoxic T cell ,Membrane Receptor Signaling ,lcsh:QH301-705.5 ,Cells, Cultured ,Cell Death ,T Cells ,Cell Differentiation ,Ebolavirus ,Flow Cytometry ,Immune Receptor Signaling ,3. Good health ,medicine.anatomical_structure ,Cell Processes ,Spectrophotometry ,Host-Pathogen Interactions ,Cytophotometry ,Cellular Types ,medicine.drug ,Protein Binding ,Research Article ,Signal Transduction ,lcsh:Immunologic diseases. Allergy ,Programmed cell death ,T cell ,Immune Cells ,030106 microbiology ,Immunology ,Biology ,Research and Analysis Methods ,Microbiology ,Necrotic Cell Death ,03 medical and health sciences ,Immune system ,Virology ,Genetics ,medicine ,Humans ,Molecular Biology ,Blood Cells ,Biology and Life Sciences ,T lymphocyte ,Cell Biology ,Hemorrhagic Fever, Ebola ,Toll-Like Receptor 4 ,030104 developmental biology ,lcsh:Biology (General) ,Parasitology ,lcsh:RC581-607 ,Developmental Biology - Abstract
Fatal outcomes of Ebola virus (EBOV) infections are typically preceded by a ‘sepsis-like’ syndrome and lymphopenia despite T cells being resistant to Ebola infection. The mechanisms that lead to T lymphocytes death remain largely unknown; however, the degree of lymphopenia is highly correlative with fatalities. Here we investigated whether the addition of EBOV or its envelope glycoprotein (GP) to isolated primary human CD4+ T cells induced cell death. We observed a significant decrease in cell viability in a GP-dependent manner, which is suggestive of a direct role of GP in T cell death. Using immunoprecipitation assays and flow cytometry, we demonstrate that EBOV directly binds to CD4+ T cells through interaction of GP with TLR4. Transcriptome analysis revealed that the addition of EBOV to CD4+ T cells results in the significant upregulation of pathways associated with interferon signaling, pattern recognition receptors and intracellular activation of NFκB signaling pathway. Both transcriptome analysis and specific inhibitors allowed identification of apoptosis and necrosis as mechanisms associated with the observed T cell death following exposure to EBOV. The addition of the TLR4 inhibitor CLI-095 significantly reduced CD4+ T cell death induced by GP. EBOV stimulation of primary CD4+ T cells resulted in a significant increase in secreted TNFα; inhibition of TNFα-mediated signaling events significantly reduced T cell death while inhibitors of both necrosis and apoptosis similarly reduced EBOV-induced T cell death. Lastly, we show that stimulation with EBOV or GP augments monocyte maturation as determined by an overall increase in expression levels of markers of differentiation. Subsequently, the increased rates of cellular differentiation resulted in higher rates of infection further contributing to T cell death. These results demonstrate that GP directly subverts the host’s immune response by increasing the susceptibility of monocytes to EBOV infection and triggering lymphopenia through direct and indirect mechanisms., Author summary The latest outbreak of Ebola virus (EBOV) in West Africa resulted in more than 28,000 human infections including more than 11,000 deaths thus highlighting the necessity for the development of countermeasures. Monocytes and dendritic cells are among the primary targets of EBOV infection; infection of these critical antigen presenting cells contributes to the immune deficiency observed in Ebola virus disease (EVD). In contrast, lymphocytes are resistant to EBOV infection; however, in fatal EVD, pronounced lymphopenia is uniformly observed. Here we report that T lymphocyte cell death in the absence of detectable infection was observed in an EBOV glycoprotein (GP)-dependent manner. Using transcriptome analysis of EBOV-stimulated CD4+ T cells we show upregulation of both toll-like receptor 4 (TLR4) and cell death associated pathways. Furthermore, we demonstrate that EBOV increases susceptibility of monocytes to infection by promoting cellular differentiation. Both EBOV-induced monocyte differentiation and cell death of T lymphocytes result from a direct interaction between GP and TLR4. Blocking of TLR4 signaling significantly reduced both EBOV-induced T cell death and infection of monocytes. These data contribute to understanding of the ‘immune paralysis’ during EBOV infections and provide evidence for the development of targeted therapies for the treatment of EVD.
- Published
- 2017
33. Human herpesvirus 6B immediate-early I protein contains functional HLA-A*02, HLA-A*03, and HLA-B*07 class I restricted CD8+T-cell epitopes
- Author
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Mathieu Iampietro, Annie Gravel, Matthieu Rousseau, Isabelle Dubuc, Richard J. O'Reilly, Aisha Hasan, Louis Flamand, and Guillaume Morissette
- Subjects
viruses ,medicine.medical_treatment ,Immunology ,virus diseases ,Immunotherapy ,Human leukocyte antigen ,Biology ,Virology ,Epitope ,HLA-B ,HLA-A ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Pathogen ,CD8 - Abstract
Human herpesvirus 6B (HHV-6B) is a ubiquitous pathogen with frequent reactivation observed in immunocompromised patients such as BM transplant (BMT) recipients. Adoptive immunotherapy is a promising therapeutic avenue for the treatment of opportunistic infections, including herpesviruses. While T-cell immunotherapy can successfully control CMV and EBV reactivations in BMT recipients, such therapy is not available for HHV-6 infections, in part due to a lack of identified protective CD8(+) T-cell epitopes. Our goal was to identify CD8(+) T-cell viral epitopes derived from the HHV-6B immediate-early protein I and presented by common human leukocyte Ag (HLA) class I alleles including HLA-A*02, HLA-A*03, and HLA-B*07. These epitopes were functionally tested for their ability to induce CD8(+) T-cell expansion and kill HHV-6-infected autologous cells. Cross-reactivity of specific HHV-6B-expanded T cells against HHV-6A-infected cells was also confirmed for a conserved epitope presented by HLA-A*02 molecule. Our findings will help push forward the field of adoptive immunotherapy for the treatment and/or the prevention of HHV-6 reactivation in BMT recipients.
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- 2014
34. Disabling of lymphocyte immune response by Ebola virus
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Alexander Bukreyev, Patrick Younan, and Mathieu Iampietro
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RNA viruses ,0301 basic medicine ,Physiology ,Lymphocyte ,Pathology and Laboratory Medicine ,medicine.disease_cause ,Immune Receptors ,Biochemistry ,Pearls ,White Blood Cells ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Lymphocytes ,Immune Response ,Toll-like Receptors ,lcsh:QH301-705.5 ,Innate Immune System ,Immune System Proteins ,T Cells ,Ebolavirus ,medicine.anatomical_structure ,Medical Microbiology ,Filoviruses ,Viral Pathogens ,Viruses ,Cytokines ,Cellular Types ,Pathogens ,Ebola Virus ,Signal Transduction ,lcsh:Immunologic diseases. Allergy ,Immune Cells ,030106 microbiology ,Immunology ,Microbiology ,03 medical and health sciences ,Signs and Symptoms ,Immune system ,Diagnostic Medicine ,Lymphopenia ,Virology ,Genetics ,medicine ,Humans ,Microbial Pathogens ,Molecular Biology ,Blood Cells ,Ebola virus ,Hemorrhagic Fever Viruses ,Extramural ,business.industry ,T-cell receptor ,Organisms ,Biology and Life Sciences ,Proteins ,Cell Biology ,Molecular Development ,Hemorrhagic Fever, Ebola ,T Cell Receptors ,030104 developmental biology ,lcsh:Biology (General) ,Immune System ,Parasitology ,Interferons ,lcsh:RC581-607 ,business ,Developmental Biology - Published
- 2018
35. Human herpesvirus 6B immediate-early I protein contains functional HLA-A*02, HLA-A*03, and HLA-B*07 class I restricted CD8(+) T-cell epitopes
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Mathieu, Iampietro, Guillaume, Morissette, Annie, Gravel, Isabelle, Dubuc, Matthieu, Rousseau, Aisha, Hasan, Richard J, O'Reilly, and Louis, Flamand
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Adult ,Male ,Immunity, Cellular ,Adolescent ,Herpesvirus 6, Human ,Epitopes, T-Lymphocyte ,Roseolovirus Infections ,Mice, Transgenic ,CD8-Positive T-Lymphocytes ,HLA-A3 Antigen ,Middle Aged ,Adoptive Transfer ,Immediate-Early Proteins ,HLA-B7 Antigen ,Mice ,HLA-A2 Antigen ,Animals ,Humans ,Female ,Cell Proliferation - Abstract
Human herpesvirus 6B (HHV-6B) is a ubiquitous pathogen with frequent reactivation observed in immunocompromised patients such as BM transplant (BMT) recipients. Adoptive immunotherapy is a promising therapeutic avenue for the treatment of opportunistic infections, including herpesviruses. While T-cell immunotherapy can successfully control CMV and EBV reactivations in BMT recipients, such therapy is not available for HHV-6 infections, in part due to a lack of identified protective CD8(+) T-cell epitopes. Our goal was to identify CD8(+) T-cell viral epitopes derived from the HHV-6B immediate-early protein I and presented by common human leukocyte Ag (HLA) class I alleles including HLA-A*02, HLA-A*03, and HLA-B*07. These epitopes were functionally tested for their ability to induce CD8(+) T-cell expansion and kill HHV-6-infected autologous cells. Cross-reactivity of specific HHV-6B-expanded T cells against HHV-6A-infected cells was also confirmed for a conserved epitope presented by HLA-A*02 molecule. Our findings will help push forward the field of adoptive immunotherapy for the treatment and/or the prevention of HHV-6 reactivation in BMT recipients.
- Published
- 2014
36. Involvement of Angiopoietin-like 4 in Matrix Remodeling during Chondrogenic Differentiation of Mesenchymal Stem Cells
- Author
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David Guérit, Danièle Noël, Marc Mathieu, Mathieu Iampietro, Paul Chuchana, Farida Djouad, Christian Jorgensen, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Recherche du Centre Hospitalier Universitaire de Québec, Histological procedures and immunohistological analyses were performed using the facilities at the 'Réseau d'Histologie Expérimentale de Montpellier' and the 'Plate-forme Régionale d'Imagerie du Languedoc Roussillon'. We thank Gilles Carnac for help in setting up the hypoxia experiment.*This work was supported by the Inserm Institute, the University of Montpellier I, and the European Community's seventh framework program (FP7/2007-2013) for the collaborative project: 'ADIPOA: Adipose-derived stromal cells for osteoarthritis treatment.', European Project: 241719,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,ADIPOA(2010), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hennaut, Odile, and ADIPOSE DERIVED STROMAL CELLS FOR OSTEOARTHRITIS - ADIPOA - - EC:FP7:HEALTH2010-01-01 - 2014-06-30 - 241719 - VALID
- Subjects
Cellular differentiation ,[SDV]Life Sciences [q-bio] ,Type II collagen ,Integrin ,Biology ,Matrix metalloproteinase ,Biochemistry ,MESH: Angiopoietins / metabolism ,Cartilage / cytology ,Cartilage / metabolism ,Cartilage / physiology ,Cell Differentiation ,Cells, Cultured ,Chondrocytes / cytology ,Chondrogenesis ,Collagen Type II / genetics ,Collagen Type II / metabolism ,Gene Expression Regulation, Developmental ,Humans ,Mesenchymal Stem Cells / cytology ,RNA Interference ,Transforming Growth Factor beta / metabolism ,Up-Regulation ,Extracellular matrix ,Chondrocytes ,Transforming Growth Factor beta ,Angiopoietin-Like Protein 4 ,Transforming Growth Factor Beta (TGFbeta) ,Aggrecans ,Collagen Type II ,Molecular Biology ,Aggrecan ,Extracellular Matrix Proteins ,Matrix Metalloproteinase (MMP) ,Tissue Engineering ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Transforming growth factor beta ,Molecular biology ,Cell biology ,[SDV] Life Sciences [q-bio] ,Cartilage ,biology.protein ,Angiopoietins - Abstract
International audience; Background:Due to their ability to differentiate into chondrocytes, mesenchymal stem cells (MSCs) are candidates forcartilage repair.Results:During chondrogenic differentiation of MSCs, angiopoietin-like 4 (ANGPTL4) triggers degradation and reducedsynthesis of the cartilage matrix.Conclusion:ANGPTL4 promotes cartilage matrix remodeling.Significance:In the perspective of MSC-based cartilage engineering, inhibiting ANGPTL4 expression or action could help tostabilize cartilage formation.Mesenchymal stem cells (MSCs) are considered for cartilage engineering given their ability to differentiate into chondrocytes. Chondrogenic differentiation of MSCs is currently triggered by micromass culture in the presence of a member of the TGF-β superfamily. However, the main constituents of the cartilaginous matrix, aggrecan and type II collagen, are degraded at the end of the differentiation process through induction of matrix metallopeptidase (MMP)13. We hypothesized that MSCs undergoing chondrogenic differentiation produce an intermediate cytokine that triggers this matrix remodeling. Analysis of transcriptomic data identified angiopoietin-like 4 (ANGPTL4) as one of the most strongly up-regulated gene encoding a secreted factor during TGF-β-induced chondrogenesis. To gain insight into the role of ANGPTL4 during chondrogenesis, we used recombinant ANGPTL4 as well as a RNA interference approach. Addition of exogenous ANGPTL4 during the course of TGF-β-induced differentiation reduced the mRNA levels of aggrecan and type II collagen, although it increased those of MMP1 and MMP13. Accordingly, deposition of aggrecan and total collagens was diminished, whereas release of MMP1 and MMP13 was increased. Conversely, transfection of MSCs with an siRNA targeting ANGPTL4 prior to induction of chondrogenesis increased expression of type II collagen and aggrecan, whereas it repressed that of MMP1, MMP3, and MMP13. A neutralizing antibody against integrin αVβ5, a known receptor for ANGPTL4, mimicked some of the effects observed after siRNA-mediated ANGPTL4 silencing. Our data provide evidence that ANGPTL4 promotes cartilage matrix remodeling by inhibiting expression of its two key components and by up-regulating the level of certain MMPs.
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- 2014
37. Angiopoietin-like 4 promotes terminal chondrogenic differentiation
- Author
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Marc Mathieu, Mathieu Iampietro, Christian Jorgensen, Danièle Noël, and Paul Chuchana
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Angiopoietin ,Terminal (electronics) ,Rheumatology ,Chemistry ,Biomedical Engineering ,Orthopedics and Sports Medicine ,Chondrogenesis ,Cell biology - Published
- 2012
- Full Text
- View/download PDF
38. High Pathogenicity of Nipah Virus from Pteropus lylei Fruit Bats, Cambodia
- Author
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Julien Fouret, Olivier Reynard, Marion Ferren, Cyrille Mathieu, Claire Dumont, Maria Gaudino, Viktor E. Volchkov, Marie Claude Georges-Courbot, Catherine Legras-Lachuer, Branka Horvat, Noémie Aurine, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Viroscan3D SAS [Lyon, France], Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], This work was supported by LABEX ECOFECT (ANR-11-LABX-0048) of Lyon University, within the program Investissements d'Avenir (ANR-11-IDEX-0007) operated by the French National Research Agency, ANR-18-CE11-0014-02, Aviesan Sino-French Agreement on Nipah Virus Study, and the International Division of the Pasteur Institut in Paris (Actions Concertées Inter-Pasteurienne). J.F. was supported by the doctoral fellowship CIFRE-Défense operated by the Direction Générale de l’Armement., We thank Jean-Marc Reynes and Pasteur Institut staff for providing us with the NiV Cambodia isolate and Doris Preininger, Anton Weissenbacher, and Tiergarten Schönbrunn for P. giganteus bat sampling. We thank Amelia Charlotte Coggon for English proofreading of the manuscript, and we also thank François Enchéry, Kévin Dhondt, Mathieu Iampietro, Sylvain Baize, and Géraldine Gourru-Lesimple for help initiating and finalizing this work., ANR-11-LABX-0048,ECOFECT,Dynamiques eco-évolutives des maladies infectieuses(2011), ANR-11-IDEX-0007,Avenir L.S.E.,PROJET AVENIR LYON SAINT-ETIENNE(2012), Mathieu, Cyrille, Dynamiques eco-évolutives des maladies infectieuses - - ECOFECT2011 - ANR-11-LABX-0048 - LABX - VALID, PROJET AVENIR LYON SAINT-ETIENNE - - Avenir L.S.E.2011 - ANR-11-IDEX-0007 - IDEX - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Structure et fonctions de la protéine C du virus Nipah - - NiPah-C2018 - ANR-18-CE11-0014 - AAPG2018 - VALID, Immunobiologie des infections virales – Immunobiology of Viral Infections (IbIV), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control (Virpath), Bases moléculaires de la pathogénicité virale – Molecular Basis of Viral Pathogenicity (BMPV), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), This work was supported by LABEX ECOFECT (ANR-11-LABX-0048) of Lyon University, within the program Investissements d’Avenir (ANR-11-IDEX-0007) operated by the French National Research Agency, ANR-18-CE11-0014-02, Aviesan Sino-French Agreement on Nipah Virus Study, and the International Division of the Institut Pasteur in Paris (Actions Concertées Inter-Pasteurienne). J.F. was supported by the doctoral fellowship CIFRE-Défense operated by the Direction Générale de l’Armement., ANR-11-IDEX-0007,Avenir L.S.E.,PROJET AVENIR LYON SAINT-ETIENNE(2011), ANR-18-CE11-0014,NiPah-C,Structure et fonctions de la protéine C du virus Nipah(2018), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)
- Subjects
Permissiveness ,Epidemiology ,lcsh:Medicine ,Nipah virus ,Pteropus lylei ,Pteropus bats ,0302 clinical medicine ,Chiroptera ,Genotype ,pathogenicity ,030212 general & internal medicine ,Phylogeny ,CSUR381 ,Henipavirus Infections ,[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,fruit bats ,Phylogenetic tree ,biology ,sequencing ,High Pathogenicity of Nipah Virus from Pteropus lylei Fruit Bats, Cambodia ,phosphoprotein ,3. Good health ,Infectious Diseases ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,RNA, Viral ,Cambodia ,Henipavirus ,Microbiology (medical) ,henipavirus ,spillover ,030231 tropical medicine ,Genome, Viral ,Real-Time Polymerase Chain Reaction ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,Phylogenetics ,Animals ,Humans ,lcsh:RC109-216 ,viruses ,emerging infection ,Whole genome sequencing ,Whole Genome Sequencing ,Research ,phylogenetic analysis ,animal model ,lcsh:R ,Outbreak ,biology.organism_classification ,Virology ,zoonoses ,hamster ,NiV-Malaysia genotype - Abstract
International audience; We conducted an in-depth characterization of the Nipah virus (NiV) isolate previously obtained from a Pteropus lylei bat in Cambodia in 2003 (CSUR381). We performed full-genome sequencing and phylogenetic analyses and confirmed CSUR381 is part of the NiV-Malaysia genotype. In vitro studies revealed similar cell permissiveness and replication of CSUR381 (compared with 2 other NiV isolates) in both bat and human cell lines. Sequence alignments indicated conservation of the ephrin-B2 and ephrin-B3 receptor binding sites, the glycosylation site on the G attachment protein, as well as the editing site in phosphoprotein, suggesting production of nonstructural proteins V and W, known to counteract the host innate immunity. In the hamster animal model, CSUR381 induced lethal infections. Altogether, these data suggest that the Cambodia bat-derived NiV isolate has high pathogenic potential and, thus, provide insight for further studies and better risk assessment for future NiV outbreaks in Southeast Asia.
- Published
- 2020
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