Etude des cellules NK au cours des infections par le virus du Chikungunya et le virus de la Dengue

Les virus du Chikungunya (CHIKV) et de la dengue (DENV) sont deux virus émergents qui sévissent dans les régions tropicales et subtropicales du monde entier et qui sont transmis par les moustiques du genre Aedes. Ces dernières années, leur transmission a surtout progressé dans les zones urbaines et périurbaines touchant des millions d individus et faisant de ces deux pathogènes des sujets majeurs de préoccupation pour la santé publique. Le Chikungunya et la Dengue sont des infections dites aiguës entrainant une mise en place rapide de la réponse immunitaire innée qui joue un rôle majeur dans le contrôle et l évolution de la maladie. Les cellules Natural Killer (NK) représentent une population cellulaire clé de la réponse innée et jouent un rôle crucial dans les mécanismes de défense mis en place. A travers une étude ex vivo et in vitro, nous nous sommes intéressées à la caractérisation des cellules NK à travers (i) une étude phénotypique et fonctionnelle des cellules NK chez des patients infectés en phase aiguë par le CHIKV, DENV-2 ou par les deux virus et (ii) à la caractérisation des interactions entre les cellules NK et les cellules cibles infectées par le virus. L ensemble de ces données contribue à mieux identifier l implication des cellules NK dans le contrôle des infections par le CHIKV et DENV-2 permettant ainsi de mieux comprendre les mécanismes à l origine des dérèglements de la réponse immunitaire. Au cours des dernières épidémies, plusieurs cas de patients coinfectés par les deux virus ont été répertoriés. De plus, l expansion géographique des moustiques Aedes pourrait amener à une augmentation du nombre de cas de coinfections sans que les mécanismes sous jacents aux coinfections ne soient étudiés. Afin de pouvoir réponse à certaines questions concernant ce phénomène, nous avons mis en place un modèle expérimental de coinfection par CHIKV et DENV-2 chez le macaque Rhésus.Chikungunya (CHIKV) and Dengue (DENV) virus are both re-emerging viruses transmitted by Aedes mosquitoes and responsible of widespread outbreaks in tropical and subtropical country. Recently, transmission of both viruses had emerged in urban and peri-urban area infecting millions of persons. Chikungunya and Dengue are both acute infections where innate immunity rapidly takes place and play a crucial role in the control and in the evolution of the disease. Natural Killer cells (NK) represent one of the major cellular population of innate immunity and play a crucial role in defense mechanism. By way of ex vivo and in vitro studies, we characterized NK cells by (i) a phenotypic and functional study of NK cells in CHIKV, DENV-2 infected patients or CHIKV/DENV-2 co-infected patients and (ii) characterization of NK cells interactions with infected target cells. During last outbreaks, several cases of co-infected patients were reported. Moreover, geographic spread of Aedes mosquitoes could increase number of coinfection cases without underlying mechanisms being explored. In order to respond to certain questions regarding coinfections, we realized a co-infected CHIKV and DENV-2 experimental model in Rhesus macaques.Together, these data will contribute to better identify NK cells implication in the control of CHIKV and DENV-2 infections allowing a better comprehension of mechanisms that causes immune system disorder.PARIS-JUSSIEU-Bib.électronique (751059901) / SudocSudocFranceF

Unconventional Repertoire Profile Is Imprinted during Acute Chikungunya Infection for Natural Killer Cells Polarization toward Cytotoxicity

Chikungunya virus (CHIKV) is a worldwide emerging pathogen. In humans it causes a syndrome characterized by high fever, polyarthritis, and in some cases lethal encephalitis. Growing evidence indicates that the innate immune response plays a role in controlling CHIKV infection. We show here that CHIKV induces major but transient modifications in NK-cell phenotype and function soon after the onset of acute infection. We report a transient clonal expansion of NK cells that coexpress CD94/NKG2C and inhibitory receptors for HLA-C1 alleles and are correlated with the viral load. Functional tests reveal cytolytic capacity driven by NK cells in the absence of exogenous signals and severely impaired IFN-γ production. Collectively these data provide insight into the role of this unique subset of NK cells in controlling CHIKV infection by subset-specific expansion in response to acute infection, followed by a contraction phase after viral clearance

Quantitative proteomic analysis of the influence of lignin on biofuel production by Clostridium acetobutylicum ATCC 824

Background: Clostridium acetobutylicum has been a focus of research because of its ability to produce high-value compounds that can be used as biofuels. Lignocellulose is a promising feedstock, but the lignin–cellulose–hemicellulose biomass complex requires chemical pre-treatment to yield fermentable saccharides, including cellulose-derived cellobiose, prior to bioproduction of acetone–butanol–ethanol (ABE) and hydrogen. Fermentation capability is limited by lignin and thus process optimization requires knowledge of lignin inhibition. The effects of lignin on cellular metabolism were evaluated for C. acetobutylicum grown on medium containing either cellobiose only or cellobiose plus lignin. Microscopy, gas chromatography and 8-plex iTRAQ-based quantitative proteomic technologies were applied to interrogate the effect of lignin on cellular morphology, fermentation and the proteome. Results: Our results demonstrate that C. acetobutylicum has reduced performance for solvent production when lignin is present in the medium. Medium supplemented with 1 g L−1 of lignin led to delay and decreased solvents production (ethanol; 0.47 g L−1 for cellobiose and 0.27 g L−1 for cellobiose plus lignin and butanol; 0.13 g L−1 for cellobiose and 0.04 g L−1 for cellobiose plus lignin) at 20 and 48 h, respectively, resulting in the accumulation of acetic acid and butyric acid. Of 583 identified proteins (FDR < 1 %), 328 proteins were quantified with at least two unique peptides. Up- or down-regulation of protein expression was determined by comparison of exponential and stationary phases of cellobiose in the presence and absence of lignin. Of relevance, glycolysis and fermentative pathways were mostly down-regulated, during exponential and stationary growth phases in presence of lignin. Moreover, proteins involved in DNA repair, transcription/translation and GTP/ATP-dependent activities were also significantly affected and these changes were associated with altered cell morphology. Conclusions: This is the first comprehensive analysis of the cellular responses of C. acetobutylicum to lignin at metabolic and physiological levels. These data will enable targeted metabolic engineering strategies to optimize biofuel production from biomass by overcoming limitations imposed by the presence of lignin

Etude des cellules NK au cours des infections par le virus du Chikungunya et le virus de la Dengue

Chikungunya (CHIKV) and Dengue (DENV) virus are both re-emerging viruses transmitted by Aedes mosquitoes and responsible of widespread outbreaks in tropical and subtropical country. Recently, transmission of both viruses had emerged in urban and peri-urban area infecting millions of persons. Chikungunya and Dengue are both acute infections where innate immunity rapidly takes place and play a crucial role in the control and in the evolution of the disease. Natural Killer cells (NK) represent one of the major cellular population of innate immunity and play a crucial role in defense mechanism. By way of ex vivo and in vitro studies, we characterized NK cells by (i) a phenotypic and functional study of NK cells in CHIKV, DENV-2 infected patients or CHIKV/DENV-2 co-infected patients and (ii) characterization of NK cells interactions with infected target cells. During last outbreaks, several cases of co-infected patients were reported. Moreover, geographic spread of Aedes mosquitoes could increase number of coinfection cases without underlying mechanisms being explored. In order to respond to certain questions regarding coinfections, we realized a co-infected CHIKV and DENV-2 experimental model in Rhesus macaques.Together, these data will contribute to better identify NK cells implication in the control of CHIKV and DENV-2 infections allowing a better comprehension of mechanisms that causes immune system disorder.Les virus du Chikungunya (CHIKV) et de la dengue (DENV) sont deux virus émergents qui sévissent dans les régions tropicales et subtropicales du monde entier et qui sont transmis par les moustiques du genre Aedes. Ces dernières années, leur transmission a surtout progressé dans les zones urbaines et périurbaines touchant des millions d’individus et faisant de ces deux pathogènes des sujets majeurs de préoccupation pour la santé publique. Le Chikungunya et la Dengue sont des infections dites aiguës entrainant une mise en place rapide de la réponse immunitaire innée qui joue un rôle majeur dans le contrôle et l’évolution de la maladie. Les cellules Natural Killer (NK) représentent une population cellulaire clé de la réponse innée et jouent un rôle crucial dans les mécanismes de défense mis en place. A travers une étude ex vivo et in vitro, nous nous sommes intéressées à la caractérisation des cellules NK à travers (i) une étude phénotypique et fonctionnelle des cellules NK chez des patients infectés en phase aiguë par le CHIKV, DENV-2 ou par les deux virus et (ii) à la caractérisation des interactions entre les cellules NK et les cellules cibles infectées par le virus. L’ensemble de ces données contribue à mieux identifier l’implication des cellules NK dans le contrôle des infections par le CHIKV et DENV-2 permettant ainsi de mieux comprendre les mécanismes à l’origine des dérèglements de la réponse immunitaire. Au cours des dernières épidémies, plusieurs cas de patients coinfectés par les deux virus ont été répertoriés. De plus, l’expansion géographique des moustiques Aedes pourrait amener à une augmentation du nombre de cas de coinfections sans que les mécanismes sous jacents aux coinfections ne soient étudiés. Afin de pouvoir réponse à certaines questions concernant ce phénomène, nous avons mis en place un modèle expérimental de coinfection par CHIKV et DENV-2 chez le macaque Rhésus

Implication of Natural Killer cells in Chikungunya and Dengue infections

Les virus du Chikungunya (CHIKV) et de la dengue (DENV) sont deux virus émergents qui sévissent dans les régions tropicales et subtropicales du monde entier et qui sont transmis par les moustiques du genre Aedes. Ces dernières années, leur transmission a surtout progressé dans les zones urbaines et périurbaines touchant des millions d’individus et faisant de ces deux pathogènes des sujets majeurs de préoccupation pour la santé publique. Le Chikungunya et la Dengue sont des infections dites aiguës entrainant une mise en place rapide de la réponse immunitaire innée qui joue un rôle majeur dans le contrôle et l’évolution de la maladie. Les cellules Natural Killer (NK) représentent une population cellulaire clé de la réponse innée et jouent un rôle crucial dans les mécanismes de défense mis en place. A travers une étude ex vivo et in vitro, nous nous sommes intéressées à la caractérisation des cellules NK à travers (i) une étude phénotypique et fonctionnelle des cellules NK chez des patients infectés en phase aiguë par le CHIKV, DENV-2 ou par les deux virus et (ii) à la caractérisation des interactions entre les cellules NK et les cellules cibles infectées par le virus. L’ensemble de ces données contribue à mieux identifier l’implication des cellules NK dans le contrôle des infections par le CHIKV et DENV-2 permettant ainsi de mieux comprendre les mécanismes à l’origine des dérèglements de la réponse immunitaire. Au cours des dernières épidémies, plusieurs cas de patients coinfectés par les deux virus ont été répertoriés. De plus, l’expansion géographique des moustiques Aedes pourrait amener à une augmentation du nombre de cas de coinfections sans que les mécanismes sous jacents aux coinfections ne soient étudiés. Afin de pouvoir réponse à certaines questions concernant ce phénomène, nous avons mis en place un modèle expérimental de coinfection par CHIKV et DENV-2 chez le macaque Rhésus.Chikungunya (CHIKV) and Dengue (DENV) virus are both re-emerging viruses transmitted by Aedes mosquitoes and responsible of widespread outbreaks in tropical and subtropical country. Recently, transmission of both viruses had emerged in urban and peri-urban area infecting millions of persons. Chikungunya and Dengue are both acute infections where innate immunity rapidly takes place and play a crucial role in the control and in the evolution of the disease. Natural Killer cells (NK) represent one of the major cellular population of innate immunity and play a crucial role in defense mechanism. By way of ex vivo and in vitro studies, we characterized NK cells by (i) a phenotypic and functional study of NK cells in CHIKV, DENV-2 infected patients or CHIKV/DENV-2 co-infected patients and (ii) characterization of NK cells interactions with infected target cells. During last outbreaks, several cases of co-infected patients were reported. Moreover, geographic spread of Aedes mosquitoes could increase number of coinfection cases without underlying mechanisms being explored. In order to respond to certain questions regarding coinfections, we realized a co-infected CHIKV and DENV-2 experimental model in Rhesus macaques.Together, these data will contribute to better identify NK cells implication in the control of CHIKV and DENV-2 infections allowing a better comprehension of mechanisms that causes immune system disorder

Editorial: Infectious Agent-Induced Chronic Immune Activation: Causes, Phenotypes, and Consequences

International audiencePersistent immune activation and dysfunction induced by infectious agents may contribute to long term comorbid conditions in individuals exposed to these pathogens. Even during successful antimicrobial treatment, increased levels of inflammation and immune cell activation and inappropriate immune cell migration and retention in tissue sites may contribute to tissue damage and end organ disease (e.g., atherosclerosis or liver or kidney damage). Understanding why some populations infected with a pathogen are able to regulate their immune responses and limit their inflammatory consequences, while other individuals may have exacerbated and persistent immune responses even during suppressive therapy, may provide insights for development of complementary immune-modulatory therapies that may reduce inflammation and morbidity and mortality in these groups. The Research Topic highlights some of these issues.Any infection induces the activation of the human immune system via various mechanisms. The problem is that although some forms of this immune activation are beneficial for the eradication of the microbial agent, others may be toxic, not only in the short term but also in the long term. It is therefore important to understand these pathogenic pathways, inasmuch as they may persist even under efficient antimicrobial therapy

Control of Acute Arboviral Infection by Natural Killer Cells

The recent explosive pandemic of chikungunya virus (CHIKV) followed by Zika (ZIKV) virus infections occurring throughout many countries represents the most unexpected arrival of arthropod-borne viral diseases in the past 20 years. Transmitted through the bite of Aedes mosquitoes, the clinical picture associated with these acute arbovirus infections, including Dengue (DENV), CHIKV and ZIKV, ranges from classical febrile illness to life-threatening disease. Whereas ZIKV and CHIKV-mediated infections have previously been recognized as relatively benign diseases, in contrast to Dengue fever, recent epidemic events have brought waves of increased morbidity and mortality leading to a serious public health problem. Although the host immune response plays a crucial role in controlling infections, it may also promote viral spread and immunopathology. Here, we review recent developments in our understanding of the immune response, with an emphasis on the early antiviral immune response mediated by natural killer cells and emphasize their Janus-faced effects in the control of arbovirus infection and pathogenesis. Improving our understanding knowledge on of the mechanisms that control viral infection is crucial in the current race against the globalization of arbovirus epidemics

Control of acute dengue virus infection by natural killer cells

International audienceDengue fever is the most important arthropod-borne viral disease worldwide, affecting 50–100 million individuals annually. The clinical picture associated with acute dengue virus (DENV) infections ranges from classical febrile illness to life-threatening disease.The innate immunity is the first line of defense in the control of viral replication. This review will examine the particular role of natural killer (NK) cells in DENV infection. Over recent years, our understanding of the interplay between NK cells and viral pathogenesis has improved significantly. NK cells express an array of inhibitory and activating receptors that enable them to detect infected targets while sparing normal cells, and to recruit adaptive immune cells. To date, the exact mechanism by which NK cells may contribute to the control of DENV infection remains elusive. Importantly, DENV has acquired mechanisms to evade NK cell responses, further underlining the relevance of these cells in pathophysiology. Hence, understanding how NK cells affect the outcome of DENV infection could benefit the management of this acute disease

Interests of the Non-Human Primate Models for HIV Cure Research

International audienceNon-human primate (NHP) models are important for vaccine development and also contribute to HIV cure research. Although none of the animal models are perfect, NHPs enable the exploration of important questions about tissue viral reservoirs and the development of intervention strategies. In this review, we describe recent advances in the use of these models for HIV cure research and highlight the progress that has been made as well as limitations using these models. The main NHP models used are (i) the macaque, in which simian immunodeficiency virus (SIVmac) infection displays similar replication profiles as to HIV in humans, and (ii) the macaque infected by a recombinant virus (SHIV) consisting of SIVmac expressing the HIV envelope gene serving for studies analyzing the impact of anti-HIV Env broadly neutralizing antibodies. Lessons for HIV cure that can be learned from studying the natural host of SIV are also presented here. An overview of the most promising and less well explored HIV cure strategies tested in NHP models will be given