Brigitte Gicquel

Institut Pasteur, Lutetia Parisorum, Île-de-France, France

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Publications (253)1197.68 Total impact

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    ABSTRACT: Identifying those Mycobacterium tuberculosis latent-infected individuals most at risk of developing active tuberculosis (TB) using routine clinical and laboratory tests remains a huge challenge in TB control efforts. We conducted a prospective longitudinal study of clinical and laboratory markers associated with the risk of developing active TB in contacts with latent M. tuberculosis infection.HIV-negative household contacts (n=296) of pulmonary TB patients underwent monitoring of clinical features, full blood cell counts, tuberculin skin text (TST) and chest radiography performed regularly during 18 months of follow-up. Paired statistical tests, a Kaplan-Meier analysis and Cox proportional hazard modelling were performed on variables between contacts progressing or not progressing to active TB.The appearance of TB disease symptoms in contacts was significantly associated with an elevated peripheral percentage of blood monocytes (adjusted hazard ratio (aHR) 6.25, 95% CI 1.63-23.95; p<0.01), a ≥14 mm TST response (aHR 5.72, 95% CI 1.22-26.80; p=0.03) and an increased monocyte:lymphocyte ratio (aHR 4.97, 95% CI 1.3-18.99; p=0.03). Among contacts having TST ≥14 mm, a strong association with risk of progression to TB was found with an elevated blood monocyte percentage (aHR 8.46, 95% CI 1.74-41.22; p<0.01).Elevated percentage of peripheral blood monocytes plus an elevated TST response are potential biomarkers for identifying contacts of TB patients at highest risk of developing active TB. Copyright ©ERS 2015.
    European Respiratory Journal 08/2015; DOI:10.1183/13993003.00263-2015 · 7.13 Impact Factor
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    ABSTRACT: The immune system needs safeguards that prevent collateral tissue damage mediated by the immune system while enabling an effective response against a pathogen. The purinergic pathway is one such mechanism, and finely modulates inflammation by sensing nucleotides in the environment. Extracellular adenosine triphosphate (ATP) is considered to be a danger signal leading to a pro-inflammatory response, whereas adenosine is immunosuppressive. CD73, also called ecto-5' -nucleotidase, occupies a strategic position in this pathway, as it is the main enzyme responsible for the generation of adenosine from ATP. Here, we explore the role of CD73 during tuberculosis, a disease characterized by an immune response that is harmful to the host and unable to eradicate Mycobacterium tuberculosis. Using CD73 knock-out (KO) mice, we found that CD73 regulates the response to M. tuberculosis infection in vitro and in vivo. Mycobacterium-infected murine macrophages derived from CD73 KO mice secrete more KC, TNF-α and IL-6, and release less VEGF upon ATP stimulation than those derived from wild-type (WT) mice. In vivo, CD73 limits the early influx of neutrophils to the lungs without affecting bacterial growth and dissemination. Collectively, our results support the view that CD73 fine-tunes anti-mycobacterial immune responses. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Infection and immunity 07/2015; 83(9). DOI:10.1128/IAI.00418-15 · 4.16 Impact Factor
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    ABSTRACT: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (TB) constitute a major public health concern. To determine the timing of pncA mutations that confer pyrazinamide (PZA) resistance in relation to mutations conferring resistance to isoniazid (INH) and rifampicin (RMP). Isolates from two major urban centres-Paris (101 strains) and Shanghai (171 strains)-were investigated for the association of pncA mutations with resistance to drugs other than PZA. The proportion of pncA mutations found in INH-monoresistant strains was not increased. pncA mutations associated with PZA resistance were found almost exclusively in MDR-TB strains, underlining the importance of determining PZA resistance when treating MDR- or XDR-TB.
    The International Journal of Tuberculosis and Lung Disease 06/2015; 19(6). DOI:10.5588/ijtld.14.0768 · 2.76 Impact Factor
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    ABSTRACT: The optimal coordination of the transcriptional response of host cells to infection is essential for establishing appropriate immunological outcomes. In this context, the role of microRNAs (miRNAs) - important epigenetic regulators of gene expression - in regulating mammalian immune systems is increasingly well recognised. However, the expression dynamics of miRNAs, and that of their isoforms, in response to infection remains largely unexplored. Here, we characterized the genome-wide miRNA transcriptional responses of human dendritic cells, over time, to various mycobacteria differing in their virulence as well as to other bacteria outside the genus Mycobacterium, using small RNA-sequencing. We detected the presence of a core temporal response to infection, shared across bacteria, comprising 49 miRNAs, highlighting a set of miRNAs that may play an essential role in the regulation of basic cellular responses to stress. Despite such broadly shared expression dynamics, we identified specific elements of variation in the miRNA response to infection across bacteria, including a virulence-dependent induction of the miR-132/212 family in response to mycobacterial infections. We also found that infection has a strong impact on both the relative abundance of the miRNA hairpin arms and the expression dynamics of miRNA isoforms. That we observed broadly consistent changes in relative arm expression and isomiR distribution across bacteria suggests that this additional, internal layer of variability in miRNA responses represents an additional source of subtle miRNA-mediated regulation upon infection. Collectively, this study increases our understanding of the dynamism and role of miRNAs in response to bacterial infection, revealing novel features of their internal variability and identifying candidate miRNAs that may contribute to differences in the pathogenicity of mycobacterial infections.
    PLoS Genetics 03/2015; 11(3):e1005064. DOI:10.1371/journal.pgen.1005064 · 8.17 Impact Factor
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    ABSTRACT: Safety of individuals at risk of immune suppression is an important concern for live vaccines. The new-generation tuberculosis vaccine candidate MTBVAC, a genetically engineered doubly attenuated Mycobacterium tuberculosis mutant with deletions in phoP and fadD26 virulence genes has demonstrated comparable safety in different relevant animal models and superior protection in mice as compared to the only currently licensed tuberculosis vaccine Mycobacterium bovis BCG. Here we describe the construction of a highly attenuated MTBVAC-based live vaccine by an additional gene inactivation generated in erp of MTBVAC. The gene product of erp is an exported repeated protein (Erp), a virulence factor described to be involved in intracellular replication of M. tuberculosis. The resultant strain, MTBVAC erp(-), was tested in severe combined immunodeficiency (SCID) mouse model showing to be severely attenuated when compared to BCG and MTBVAC. Experiments conducted in immunocompetent mice revealed that the hyper-attenuated profile observed with MTBVAC erp(-) strain did not compromise its protective efficacy profile in comparison with BCG. These results postulate MTBVAC erp(-) as a potential tuberculosis vaccine candidate for use in high-risk populations of immune suppression (e.g., due to HIV infection), where the use of BCG is not recommended.
    Vaccine 07/2014; 32(40). DOI:10.1016/j.vaccine.2014.07.047 · 3.49 Impact Factor
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    ABSTRACT: Granulomas are the hallmark of Mycobacterium tuberculosis infection. As the host fails to control the bacteria, the center of the granuloma exhibits necrosis resulting from the dying of infected macrophages. The release of the intracellular pool of nucleotides into the surrounding medium may modulate the response of newly infected macrophages, although this has never been investigated. Here, we show that extracellular adenosine triphosphate (ATP) indirectly modulates the expression of 272 genes in human macrophages infected with M. tuberculosis and that it induces their alternative activation. ATP is rapidly hydrolyzed by the ecto-ATPase CD39 into adenosine monophosphate (AMP), and it is AMP that regulates the macrophage response through the adenosine A2A receptor. Our findings reveal a previously unrecognized role for the purinergic pathway in the host response to M. tuberculosis. Dampening inflammation through signaling via the adenosine A2A receptor may limit tissue damage but may also favor bacterial immune escape.
    The Journal of Infectious Diseases 03/2014; 210(5). DOI:10.1093/infdis/jiu135 · 5.78 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are critical regulators of gene expression and their role in a wide variety of biological processes, including host antimicrobial defense, is increasingly well described. Consistent with their diverse functional effects, miRNA expression is highly context-dependent and shows marked changes upon cellular activation. However, the genetic control of miRNA expression in response to external stimuli and the impact of such perturbations on miRNA-mediated regulatory networks at the population level remain to be determined. Here we assessed changes in miRNA expression upon Mycobacterium tuberculosis infection and mapped expression quantitative trait loci (eQTL) in dendritic cells from a panel of healthy individuals. Genome-wide expression profiling revealed that ~40% of miRNAs are differentially expressed upon infection. We find that the expression of 3% of miRNAs is controlled by proximate genetic factors, which are enriched in a promoter-specific histone modification associated with active transcription. Notably, we identify two infection-specific response eQTLs, for miR-326 and miR-1260, providing an initial assessment of the impact of genotype-environment interactions on miRNA molecular phenotypes. Furthermore, we show that infection coincides with a marked remodeling of the genome-wide relationships between miRNA and mRNA expression levels. This observation, supplemented by experimental data using the model of miR-29a, sheds light on the role of a set of miRNAs in cellular responses to infection. Collectively, this study increases our understanding of the genetic architecture of miRNA expression in response to infection, and highlights the wide-reaching impact of altering miRNA expression on the transcriptional landscape of a cell.
    Genome Research 01/2014; 24(5). DOI:10.1101/gr.161471.113 · 13.85 Impact Factor
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    Ludovic Tailleux · Brigitte Gicquel · Olivier Neyrolles
    Medecine sciences: M/S 10/2013; 19(6-7):658-60. DOI:10.1051/medsci/20031967658 · 0.52 Impact Factor
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    ABSTRACT: The development of a new tuberculosis vaccine is an urgent need due to the failure of the current vaccine, BCG, to protect against the respiratory form of the disease. MTBVAC is an attenuated Mycobacterium tuberculosis vaccine candidate genetically engineered to fulfil the Geneva consensus requirements to enter human clinical trials. We selected a M. tuberculosis clinical isolate to generate two independent deletions without antibiotic-resistance markers in the genes phoP, coding for a transcription factor key for the regulation of M. tuberculosis virulence, and fadD26, essential for the synthesis of the complex lipids phthiocerol dimycocerosates (DIM), one of the major mycobacterial virulence factors. The resultant strain MTBVAC exhibits safety and biodistribution profiles similar to BCG and confers superior protection in preclinical studies. These features have enabled MTBVAC to be the first live attenuated M. tuberculosis vaccine to enter clinical evaluation.
    Vaccine 08/2013; 31(42). DOI:10.1016/j.vaccine.2013.07.051 · 3.49 Impact Factor
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    ABSTRACT: The majority of Mycobacterium tuberculosis (Mtb) infections remain asymptomatic with only up to 10% progressing to clinical tuberculosis. However, the constituents of the effective “protective immunity” against tuberculosis responsible for containing most infections remain unknown. Evaluating gene transcriptional profiles in tuberculosis clinical cohorts is one approach to understanding the spectrum of tuberculosis progression. It is clear that apoptosis plays a role in the control of tuberculosis but the utility of apoptosis-related genes as surrogate markers of protection against tuberculosis has not been well investigated. To characterize potential surrogate markers that could discriminate different phases of the clinical tuberculosis spectrum, we investigated gene expression of several TNF-alpha dependent apoptotic genes (TNFR1, TNFR2, FLICE, FLIPs) by real-time RT-PCR of peripheral blood cells from cohorts of individuals with active tuberculosis or potential exposure to tuberculosis. Newly diagnosed tuberculosis patients (n = 23), their close household contacts (n = 80), and community controls (n = 46) were tested at intervals over a period of up to two years. Latent infection or previous Mtb contact was assessed by ELISPOT and TST and complete blood counts were performed during the follow up. Results showed significant upregulation of FLIPs expression by infected individuals regardless of clinical status at entry to the study. A higher percentage of lymphocytes was found in the infected household contacts that remained healthy. In contrast, in individuals with active TB, a significant upregulation of TNFR2 expression, a significantly higher percentage of monocytes and a significantly decreased lymphocyte count were seen, compared to subjects that remained healthy. Moreover, the household contacts who subsequently developed signs of TB also had a significantly high number of monocytes. These data suggest tuberculosis may be associated with decreased T-cell survival (perhaps due to apoptosis) while inhibition of apoptosis in monocytes could lead to a relative increase in these cells: a situation predicted to favour Mtb.
    PLoS ONE 04/2013; 8(4):e61154. DOI:10.1371/journal.pone.0061154 · 3.23 Impact Factor
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    Article: zumla
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    ABSTRACT: The majority of Mycobacterium tuberculosis (Mtb) infections remain asymptomatic with only up to 10% progressing to clinical tuberculosis. However, the constituents of the effective "protective immunity" against tuberculosis responsible for containing most infections remain unknown. Evaluating gene transcriptional profiles in tuberculosis clinical cohorts is one approach to understanding the spectrum of tuberculosis progression. It is clear that apoptosis plays a role in the control of tuberculosis but the utility of apoptosis-related genes as surrogate markers of protection against tuberculosis has not been well investigated. To characterize potential surrogate markers that could discriminate different phases of the clinical tuberculosis spectrum, we investigated gene expression of several TNF-alpha dependent apoptotic genes (TNFR1, TNFR2, FLICE, FLIPs) by real-time RT-PCR of peripheral blood cells from cohorts of individuals with active tuberculosis or potential exposure to tuberculosis. Newly diagnosed tuberculosis patients (n = 23), their close household contacts (n = 80), and community controls (n = 46) were tested at intervals over a period of up to two years. Latent infection or previous Mtb contact was assessed by ELISPOT and TST and complete blood counts were performed during the follow up. Results showed significant upregulation of FLIPs expression by infected individuals regardless of clinical status at entry to the study. A higher percentage of lymphocytes was found in the infected household contacts that remained healthy. In contrast, in individuals with active TB, a significant upregulation of TNFR2 expression, a significantly higher percentage of monocytes and a significantly decreased lymphocyte count were seen, compared to subjects that remained healthy. Moreover, the household contacts who subsequently developed signs of TB also had a significantly high number of monocytes. These data suggest tuberculosis may be associated with decreased T-cell survival (perhaps due to apoptosis) while inhibition of apoptosis in monocytes could lead to a relative increase in these cells: a situation predicted to favour Mtb.
    PLoS ONE 04/2013; 12(8):e61154. DOI:10.1371/journal.pone.0061154. · 3.23 Impact Factor
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    Charles C Wang · Bingdong Zhu · Xionglin Fan · Brigitte Gicquel · Ying Zhang
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    ABSTRACT: Tuberculosis is both highly prevalent across the world and eludes our attempts to control it. The current BCG vaccine has unreliable protection against adult pulmonary tuberculosis. As a result, tuberculosis vaccine development has been an ongoing area of research for several decades. Only recently have research efforts resulted in the development of several vaccine candidates that are further along in clinical trials. The majority of the barriers surrounding tuberculosis vaccine development are related to the lack of defined biomarkers for tuberculosis protective immunity and the lack of understanding of the complex interactions between the host and pathogen in the human immune system. As a result, testing various antigens discovered through molecular biology techniques have been only with surrogates of protection and do not accurately predict protective immunity. This review will address new discoveries in latency antigens and new next generation candidate vaccines that promise the possibility of sterile eradication. Also discussed are the potentially important roles of systems biology and vaccinomics in shortening development of an efficacious tuberculosis vaccine through utilization of high throughput technology, computer modeling, and integrative approaches.
    Respirology 01/2013; 18(3). DOI:10.1111/resp.12052 · 3.50 Impact Factor
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    ABSTRACT: Mycobacterium tuberculosis has the remarkable capacity to survive within the hostile environment of the macrophage, and to resist potent antibacterial molecules such as reactive oxygen species (ROS). Thus, understanding mycobacterial resistance mechanisms against ROS may contribute to the development of new anti-tuberculosis therapies. Here we identified genes involved in such mechanisms by screening a high-density transposon mutant library, and we show that several of them are involved in the intracellular lifestyle of the pathogen. Many of these genes were found to play a part in cell envelope functions, further strengthening the important role of the mycobacterial cell envelope in protection against aggressions such as the ones caused by ROS inside host cells.
    PLoS ONE 01/2013; 8(1):e53486. DOI:10.1371/journal.pone.0053486 · 3.23 Impact Factor
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    ABSTRACT: BACKGROUND: Tuberculosis (TB) is a major cause of childhood morbidity and mortality in developing countries. One of the main difficulties is obtaining adequate specimens for bacteriological confirmation of the disease in children.The aim of this study is to evaluate the adequacy of fine-needle aspiration (FNA) for the diagnosis of TB. METHODS: In a prospective study conducted at the paediatric hospital in Bangui in 2007--2009, we used fine-needle aspiration to obtain samples for diagnosis of TB from 131 children aged 0--17 years with persistent lymphadenitis. RESULTS: Fine-needle aspiration provided samples that could be used for bacteriological confirmation of TB. Ziehl-Neelsen staining for acid-fast bacilli was positive in 42.7% of samples, and culture identified TB in 67.2% of cases. Of 75 samples that were stain-negative, 49 (65.3%) were culture-positive, while 12 stain-positive samples remained culture-negative. Ten of the 12 stain-positive, culture-negative samples were from patients who had received previous antimicrobial therapy. With regard to phenotypic drug susceptibility, 81/88 strains (91.1%) were fully susceptible to isoniazid, rifampicin, ethambutol and streptomycin, six (6.8%) were resistant to one drug, and one multidrug-resistant strain was found. CONCLUSIONS: Fine-needle aspiration is simple, cost-effective and non-invasive and can be performed by trained staff. Combined with rapid molecular diagnostic tests, fine-needle aspirates could improve the diagnosis of TB and provide valuable information for appropriate treatment and drug resistance.
    BMC Pediatrics 12/2012; 12(1):191. DOI:10.1186/1471-2431-12-191 · 1.92 Impact Factor

Publication Stats

14k Citations
1,197.68 Total Impact Points

Institutions

  • 1989–2015
    • Institut Pasteur
      • Department of Immunology
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Fudan University
      • Institutes of Biomedical Sciences
      Shanghai, Shanghai Shi, China
  • 2008–2011
    • Federal University of Minas Gerais
      • Faculdade de Medicina
      Belo Horizonte, Estado de Minas Gerais, Brazil
    • Center for Molecular Genetics
      Gif, Île-de-France, France
  • 2001–2010
    • The Pasteur Institute of Madagascar
      Tananarive, Analamanga, Madagascar
  • 2009
    • University of Hull
      • Department of Biological Sciences
      Kingston upon Hull, England, United Kingdom
  • 2007
    • Massey University
      • Institute of Veterinary, Animal and Biomedical Sciences
      Palmerston North City, Manawatu-Wanganui, New Zealand
    • Imperial College London
      • Centre for Molecular Microbiology and Infection
      London, ENG, United Kingdom
  • 1992–2007
    • French National Centre for Scientific Research
      • Institute of Pharmacology and Structural Biology
      Lutetia Parisorum, Île-de-France, France
  • 2001–2006
    • University of Zaragoza
      • Department of Microbiology, Preventive Medicine and Public Health
      Caesaraugusta, Aragon, Spain
  • 2003
    • Ecole normale supérieure de Cachan
      Cachon, Île-de-France, France
    • Colorado State University
      Fort Collins, Colorado, United States
    • Comenius University in Bratislava
      • Department of Biochemistry
      Presburg, Bratislavský, Slovakia
  • 2002
    • Paul Sabatier University - Toulouse III
      • Institut de Pharmacologie et Biologie Structurale - UMR 5089 - IPBS
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 1999
    • Texas A&M University System Health Science Center
      • Department of Medical Microbiology and Immunology
      Bryan, Texas, United States
  • 1993
    • Institut Pasteur de Tunis
      Tunis-Ville, Tūnis, Tunisia