Publications by authors named "Jean-Nicolas Tournier"

57 Publications

Investigation of a COVID-19 outbreak on the Charles de Gaulle aircraft carrier, March to April 2020: a retrospective cohort study.

Euro Surveill 2022 May;27(21)

French Armed Forces Center for Epidemiology and Public Health (CESPA), Marseille, France.

BackgroundSARS-CoV-2 emergence was a threat for armed forces. A COVID-19 outbreak occurred on the French aircraft carrier Charles de Gaulle from mid-March to mid-April 2020.AimTo understand how the virus was introduced, circulated then stopped circulation, risk factors for infection and severity, and effectiveness of preventive measures.MethodsWe considered the entire crew as a cohort and collected personal, clinical, biological, and epidemiological data. We performed viral genome sequencing and searched for SARS-CoV-2 in the environment.ResultsThe attack rate was 65% (1,148/1,767); 1,568 (89%) were included. The male:female ratio was 6.9, and median age was 29 years (IQR: 24-36). We examined four clinical profiles: asymptomatic (13.0%), non-specific symptomatic (8.1%), specific symptomatic (76.3%), and severe (i.e. requiring oxygen therapy, 2.6%). Active smoking was not associated with severe COVID-19; age and obesity were risk factors. The instantaneous reproduction rate (R) and viral sequencing suggested several introductions of the virus with 4 of 5 introduced strains from within France, with an acceleration of R when lifting preventive measures. Physical distancing prevented infection (adjusted OR: 0.55; 95% CI: 0.40-0.76). Transmission may have stopped when the proportion of infected personnel was large enough to prevent circulation (65%; 95% CI: 62-68).ConclusionNon-specific clinical pictures of COVID-19 delayed detection of the outbreak. The lack of an isolation ward made it difficult to manage transmission; the outbreak spread until a protective threshold was reached. Physical distancing was effective when applied. Early surveillance with adapted prevention measures should prevent such an outbreak.
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http://dx.doi.org/10.2807/1560-7917.ES.2022.27.21.2100612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9137271PMC
May 2022

Antibodies against Anthrax Toxins: A Long Way from Benchlab to the Bedside.

Toxins (Basel) 2022 02 25;14(3). Epub 2022 Feb 25.

Département Microbiologie et Maladies Infectieuses, Institut de Recherche Biomédicale des Armées, 91220 Brétigny-sur-Orge, France.

Anthrax is an acute disease caused by the bacterium , and is a potential biowarfare/bioterrorist agent. Its pulmonary form, caused by inhalation of the spores, is highly lethal and is mainly related to injury caused by the toxins secretion. Antibodies neutralizing the toxins of are regarded as promising therapeutic drugs, and two are already approved by the Federal Drug Administration. We developed a recombinant human-like humanized antibody, 35PA83 6.20, that binds the protective antigen and that neutralized anthrax toxins in-vivo in White New Zealand rabbits infected with the lethal 9602 strain by intranasal route. Considering these promising results, the preclinical and clinical phase one development was funded and a program was started. Unfortunately, after 5 years, the preclinical development was cancelled due to industrial and scientific issues. This shutdown underlined the difficulty particularly, but not only, for an academic laboratory to proceed to clinical development, despite the drug candidate being promising. Here, we review our strategy and some preliminary results, and we discuss the issues that led to the no-go decision of the pre-clinical development of 35PA83 6.20 mAb. Our review provides general information to the laboratories planning a (pre-)clinical development.
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http://dx.doi.org/10.3390/toxins14030172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8955606PMC
February 2022

[Exploration of vaccine immunogenicity].

Rev Francoph Lab 2022 Mar 4;2022(540):40-52. Epub 2022 Mar 4.

Laboratoire d'innovation : vaccins, Institut Pasteur, 28 rue du Dr-Roux, 75015 Paris, France.

The development of new vaccines has traditionally been a long-term job, although recent experience with the emergence of Covid-19 has caused development and production delays to skyrocket. The fact remains that the development of vaccines in the preclinical phases and in phases 1 and 2 of clinical development is based on the study of the specific immune response of the adaptive immune system.
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http://dx.doi.org/10.1016/S1773-035X(22)00098-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8896448PMC
March 2022

A live measles-vectored COVID-19 vaccine induces strong immunity and protection from SARS-CoV-2 challenge in mice and hamsters.

Nat Commun 2021 11 1;12(1):6277. Epub 2021 Nov 1.

Institut Pasteur, Université de Paris, Innovation Lab: Vaccines, Paris, France.

Several COVID-19 vaccines have now been deployed to tackle the SARS-CoV-2 pandemic, most of them based on messenger RNA or adenovirus vectors.The duration of protection afforded by these vaccines is unknown, as well as their capacity to protect from emerging new variants. To provide sufficient coverage for the world population, additional strategies need to be tested. The live pediatric measles vaccine (MV) is an attractive approach, given its extensive safety and efficacy history, along with its established large-scale manufacturing capacity. We develop an MV-based SARS-CoV-2 vaccine expressing the prefusion-stabilized, membrane-anchored full-length S antigen, which proves to be efficient at eliciting strong Th1-dominant T-cell responses and high neutralizing antibody titers. In both mouse and golden Syrian hamster models, these responses protect the animals from intranasal infectious challenge. Additionally, the elicited antibodies efficiently neutralize in vitro the three currently circulating variants of SARS-CoV-2.
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http://dx.doi.org/10.1038/s41467-021-26506-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560864PMC
November 2021

Biodefence research: what to fund now?

Lancet Infect Dis 2021 11;21(11):1487-1488

École du Val-de-Grâce, Paris, France; Hôpital d'Instruction des Armées Bégin, Service des Maladies Infectieuses et Tropicales, Paris, France.

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http://dx.doi.org/10.1016/S1473-3099(21)00622-8DOI Listing
November 2021

Neutralizing antibody response to SARS-CoV-2 persists 9 months post symptom onset in mild and asymptomatic patients.

Int J Infect Dis 2021 Nov 8;112:8-12. Epub 2021 Sep 8.

Microbiology and Infectious Diseases Department, Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France.

Objective: A better understanding of the immune response against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is critical to predict its dynamics within the general population and its impact on the vaccination strategy. This study assessed the persistence of neutralizing antibody (Nab) activity and SARS-CoV-2 serology in serum samples of mild and asymptomatic patients 9 months post symptom onset (PSO) in a primary care context among immunocompetent adults.

Methods: A longitudinal cohort of crew members (CMs) exposed to coronavirus disease 2019 (COVID-19) during an outbreak of SARS-CoV-2 on the French aircraft carrier 'Charles de Gaulle' in April 2020 was created. CMs infected with COVID-19 and with positive serology at the end of quarantine were tested 9 months PSO. Samples were collected 18 and 280 days PSO. For each patient, both serology and serum viral neutralizing activity were performed.

Results: In total, 86 CMs were analysed. Samples were collected 18 and 280 days PSO. The seroconversion rates were 100% and 93% (82/86) at 18 and 280 days PSO, respectively, and 72.7% of patients exhibited persistent Nab activity at 9 months, regardless of disease severity.

Conclusion: Nab activity persists for up to 9 months following asymptomatic/mild COVID-19 among young adults, regardless of serological results.
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http://dx.doi.org/10.1016/j.ijid.2021.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425675PMC
November 2021

What chikungunya teaches us about COVID-19.

Lancet Infect Dis 2021 08 19;21(8):1070-1071. Epub 2021 May 19.

Ecole du Val-de-Grâce, Paris, France; Institut de Recherche Biomédicale des Armées, Microbiology and Infectious Diseases Department, Brétigny-sur-Orge, France; CNRS UMR-3569, Innovative Vaccine Laboratory, Virology Department, Institut Pasteur, Paris, France.

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http://dx.doi.org/10.1016/S1473-3099(21)00272-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133766PMC
August 2021

Virus Eradication and Synthetic Biology: Changes with SARS-CoV-2?

Viruses 2021 03 28;13(4). Epub 2021 Mar 28.

Microbiology and Infectious Diseases Department, Institut de Recherche Biomédicale des Armées, 91220 Brétigny-sur-Orge, France.

The eradication of infectious diseases has been achieved only once in history, in 1980, with smallpox. Since 1988, significant effort has been made to eliminate poliomyelitis viruses, but eradication is still just out of reach. As the goal of viral disease eradication approaches, the ability to recreate historically eradicated viruses using synthetic biology has the potential to jeopardize the long-term sustainability of eradication. However, the emergence of the severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 pandemic has highlighted our ability to swiftly and resolutely respond to a potential outbreak. This virus has been synthetized faster than any other in the past and is resulting in vaccines before most attenuated candidates reach clinical trials. Here, synthetic biology has the opportunity to demonstrate its truest potential to the public and solidify a footing in the world of vaccines.
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http://dx.doi.org/10.3390/v13040569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066276PMC
March 2021

Ricin Antibodies' Neutralizing Capacity against Different Ricin Isoforms and Cultivars.

Toxins (Basel) 2021 01 29;13(2). Epub 2021 Jan 29.

Paris-Saclay University, CEA, INRAE, Medicines and Healthcare Technologies Department (DMTS), SPI, 91191 Gif-sur-Yvette, France.

Ricin, a highly toxic protein from , is considered a potential biowarfare agent. Despite the many data available, no specific treatment has yet been approved. Due to their ability to provide immediate protection, antibodies (Abs) are an approach of choice. However, their high specificity might compromise their capacity to protect against the different ricin isoforms (D and E) found in the different cultivars. In previous work, we have shown the neutralizing potential of different Abs (43RCA-G1 (anti ricin A-chain) and RB34 and RB37 (anti ricin B-chain)) against ricin D. In this study, we evaluated their protective capacity against both ricin isoforms. We show that: (i) RB34 and RB37 recognize exclusively ricin D, whereas 43RCA-G1 recognizes both isoforms, (ii) their neutralizing capacity in vitro varies depending on the cultivar, and (iii) there is a synergistic effect when combining RB34 and 43RCA-G1. This effect is also demonstrated in vivo in a mouse model of intranasal intoxication with ricin D/E (1:1), where approximately 60% and 40% of mice treated 0 and 6 h after intoxication, respectively, are protected. Our results highlight the importance of evaluating the effectiveness of the Abs against different ricin isoforms to identify the treatment with the broadest spectrum neutralizing effect.
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http://dx.doi.org/10.3390/toxins13020100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911099PMC
January 2021

Differential serological and neutralizing antibody dynamics after an infection by a single SARS-CoV-2 strain.

Infection 2021 Aug 2;49(4):781-783. Epub 2021 Jan 2.

Microbiology and Infectious Diseases Department, Institut de Recherche Biomédicale des Armées (IRBA), 1 place Général Valérie André, 91220, Brétigny sur Orge, France.

Background: We report here the case of two coworkers infected by the same SARS-CoV-2 strain, presenting two different immunological outcomes.

Case: One patient presented a strong IgG anti-receptor-binding domain immune response correlated with a low and rapidly decreasing titer of neutralizing antibodies. The other patient had a similar strong IgG anti-receptor-binding domain immune response but high neutralizing antibody titers.

Discussion And Conclusion: Thus, host individual factors may be the main drivers of the immune response varying with age and clinical severity.
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http://dx.doi.org/10.1007/s15010-020-01556-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776280PMC
August 2021

[COVID-19 and vaccination: a global disruption].

Med Sci (Paris) 2020 Nov 5;36(11):1034-1037. Epub 2020 Nov 5.

Institut de recherche biomédicale des armées (IRBA), Unité biothérapies anti-infectieuses et immunité, 1 place Général Valérie André, 91220 Brétigny-sur-Orge, France - Institut Pasteur, Innovative vaccine laboratory, 75015 Paris, France - École du Val-de-Grâce, 1 place Alphonse Laveran, 75005 Paris, France.

Coronavirus disease (COVID)-19 is an emerging pandemic infection whose significant ability to spread in a naïve population is well established. The first response of states to the COVID-19 outbreak was to impose lock-down and social barrier measures, such as wearing a surgical mask or social distancing. One of the consequences of this pandemic in terms of public health was the suspension or slowdown of infant vaccination campaigns, in almost all countries. The indirect effects of COVID-19 may therefore weigh on mortality from measles and polio in developing countries. In this pandemic chaos, the only hope lies in the rapid development of an effective vaccine against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). However, acceptance of this vaccine has not yet been won, as beyond the many unknowns that will inevitably weigh around such rapid development, skepticism among vaccine hesitants is growing.
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http://dx.doi.org/10.1051/medsci/2020203DOI Listing
November 2020

Natural outbreaks and bioterrorism: How to deal with the two sides of the same coin?

J Glob Health 2020 Dec;10(2):020317

Bacteriology Unit, French Armed Forces Biomedical Research Institute (IRBA), Bretigny sur Orge, France.

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http://dx.doi.org/10.7189/jogh.10.020317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535343PMC
December 2020

Pandemic Legion History More Complex than Previously Thought.

mBio 2020 10 9;11(5). Epub 2020 Oct 9.

Institut de Recherche Biomédicale des Armées (IRBA), Microbiology and Infectious Diseases Department, Brétigny sur Orge, France

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http://dx.doi.org/10.1128/mBio.02377-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547204PMC
October 2020

[A race against the clock: creation of SARS-Cov-2 in the laboratory, a month after its emergence!]

Med Sci (Paris) 2020 Aug-Sep;36(8-9):797-802. Epub 2020 Aug 5.

Institut de recherche biomédicale des armées, Unité Biothérapies anti-infectieuses et immunité, Département Microbiologie et maladies infectieuses, Brétigny-sur-Orge, France - Institut Pasteur, unité génomique virale et vaccination, CNRS UMR 3569, Paris, France - École du Val-de-Grâce, Paris, France.

SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2, which emerged in China at the end of 2019, is responsible for a global health crisis resulting in the confinement of more than 3 billion people worldwide and the sharp decline of the world economy. In this context, a race against the clock is launched in order to develop a treatment to stop the pandemic as soon as possible. A study published in Nature by the Volker Thiel team reports the development of reverse genetics for SARS-CoV-2 allowing them to recreate the virus in just a few weeks. The perspectives of this work are very interesting since it will allow the genetic manipulation of the virus and thus the development of precious tools which will be useful to fight the infection. Even though this approach represents a technological leap that will improve our knowledge of the virus, it also carries the germ of possible misuse and the creation of the virus for malicious purposes. The advantages and disadvantages of recreating SARS-CoV-2 in this pandemic period are discussed in this mini-synthesis.
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http://dx.doi.org/10.1051/medsci/2020124DOI Listing
August 2020

Anthrax Toxin Detection: From in Vivo Studies to Diagnostic Applications.

Microorganisms 2020 Jul 23;8(8). Epub 2020 Jul 23.

Unité Bactériologie Biothérapies Anti-infectieuses et Immunité, Institut de Recherche Biomédicale des Armées (IRBA), 1 place Général Valérie André, 91220 Brétigny sur Orge, France.

Anthrax toxins are produced by throughout infection and shape the physiopathogenesis of the disease. They are produced in low quantities but are highly efficient. They have thus been long ignored, but recent biochemical methods have improved our knowledge in animal models. This article reviews the various methods that have been used and how they could be applied to clinical diagnosis.
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http://dx.doi.org/10.3390/microorganisms8081103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464488PMC
July 2020

Case Report of an Injectional Anthrax in France, 2012.

Microorganisms 2020 Jun 30;8(7). Epub 2020 Jun 30.

CNR-LE Charbon (National Reference Laboratory for Anthrax), Institut de Recherche Biomédicale des Armées, 1 Place Général Valérie André, 91220 Brétigny sur Orge, France.

(1) Background: is a spore-forming, Gram-positive bacterium causing anthrax, a zoonosis affecting mainly livestock. When occasionally infecting humans, provokes three different clinical forms: cutaneous, digestive and inhalational anthrax. More recently, an injectional anthrax form has been described in intravenous drug users. (2) Case presentation: We report here the clinical and microbiological features, as well as the strain phylogenetic analysis, of the only injectional anthrax case observed in France so far. A 27-year-old patient presented a massive dermohypodermatitis with an extensive edema of the right arm, and the development of drug-resistant shocks. After three weeks in an intensive care unit, the patient recovered, but the microbiological identification of was achieved after a long delay. (3) Conclusions: Anthrax diagnostic may be difficult clinically and microbiologically. The phylogenetic analysis of the strain PF1 confirmed its relatedness to the injectional anthrax European outbreak group-II.
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http://dx.doi.org/10.3390/microorganisms8070985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409126PMC
June 2020

Chikungunya vaccine: a single shot for a long protection?

Lancet Infect Dis 2020 10 1;20(10):1111-1112. Epub 2020 Jun 1.

Microbiology and Infectious Diseases Department, Anti-Infectious Biotherapies and Immunity, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge Cedex, France; Ecole du Val-de-Grâce, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(20)30286-3DOI Listing
October 2020

Very Early Blood Diffusion of the Active Lethal and Edema Factors of Bacillus anthracis After Intranasal Infection.

J Infect Dis 2020 02;221(4):660-667

Unité Biothérapies Anti-Infectieuses et Immunité, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France.

Background: Lethal and edema toxins are critical virulence factors of Bacillus anthracis. Few data are available on their presence in the early stage of intranasal infection.

Methods: To investigate the diffusion of edema factor (EF) and lethal factor (LF), we use sensitive quantitative methods to measure their enzymatic activities in mice intranasally challenged with a wild-type B anthracis strain or with an isogenic mutant deficient for the protective antigen.

Results: One hour after mouse challenge, although only 7% of mice presented bacteremia, LF and EF were detected in the blood of 100% and 42% of mice, respectively. Protective antigen facilitated the diffusion of LF and EF into the blood compartment. Toxins played a significant role in the systemic dissemination of B anthracis in the blood, spleen, and liver. A mouse model of intoxination further confirmed that LT and ET could diffuse rapidly in the circulation, independently of bacteria.

Conclusions: In this inhalational model, toxins have disseminated rapidly in the blood, playing a significant and novel role in the early systemic diffusion of bacteria, demonstrating that they may represent a very early target for the diagnosis and the treatment of anthrax.
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http://dx.doi.org/10.1093/infdis/jiz497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996859PMC
February 2020

Cerebrospinal meningitis: lessons learnt from Africa.

Lancet Infect Dis 2019 10;19(10):1056

Institut de recherche biomédicale des armées, Microbiology and Infectious Diseases Department, Brétigny-sur-Orge, France; Institut Pasteur, Viral Genomics and Vaccination Unit, CNRS UMR-3569, Paris, France; French National Reference Center for Anthrax (CNR-LE charbon), Brétigny sur Orge, France. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(19)30479-7DOI Listing
October 2019

Questionable Efficacy of Therapeutic Antibodies in the Treatment of Anthrax.

mSphere 2019 06 19;4(3). Epub 2019 Jun 19.

Institut de Recherche Biomédicale des Armées, Bacteriology, Anti-infectious Biotherapies, and Immunity Unit, Brétigny-sur-Orge, France.

Inhalational anthrax caused by , a spore-forming Gram-positive bacterium, is a highly lethal infection. Antibodies targeting the protective antigen (PA) binding component of the toxins have recently been authorized as an adjunct to antibiotics, although no conclusive evidence demonstrates that anthrax antitoxin therapy has any significant benefit. We discuss here the rational basis of anti-PA development regarding the pathogenesis of the disease. We argue that inductive reasoning may induce therapeutic bias. We identified anthrax animal model analysis as another bias. Further studies are needed to assess the benefit of anti-PA antibodies in the treatment of inhalational anthrax, while a clearer consensus should be established around what evidence should be proven in an anthrax model.
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http://dx.doi.org/10.1128/mSphere.00282-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584371PMC
June 2019

[The eradication of infectious viral diseases endangered by advances in synthetic biology].

Med Sci (Paris) 2019 Feb 18;35(2):181-186. Epub 2019 Feb 18.

Institut de recherche biomédicale des armées, Unité Biothérapies anti-infectieuses et immunité, Département Microbiologie et maladies infectieuses, 1, place général Valérie André, 91220 Brétigny-sur-Orge, France - Institut Pasteur, unité génomique virale et vaccination, CNRS UMR-3569, 25, rue du Docteur Roux, 75015 Paris, France - École du Val-de-Grâce, 74, boulevard de Port-Royal, 75005 Paris, France.

The eradication of infectious diseases is one of the oldest dreams of mankind. It has been materialized only once in History with smallpox in 1980. Considerable efforts are being developed against poliomyelitis viruses since 1988, but the ultimate goal of eradication is not yet achieved. Paradoxically, while the objective of having eradicated these two viral diseases is approaching, synthetic biology multiplies the prowesses of virus "neosynthesis", imperiling at least virtually the durability of these advances. This article emphasizes the potential of a new biology on one side, and the difficult reality of the fight against infections on the other.
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http://dx.doi.org/10.1051/medsci/2019005DOI Listing
February 2019

The threat of bioterrorism.

Lancet Infect Dis 2019 01;19(1):18-19

Infectious Diseases Department, Hôpital d'Instruction des Armées Laveran, Marseille, France.

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http://dx.doi.org/10.1016/S1473-3099(18)30709-6DOI Listing
January 2019

[iNKT cells: potential therapeutic targets to fight anthrax].

Med Sci (Paris) 2017 May 14;33(5):488-490. Epub 2017 Jun 14.

Pathogénie des toxi-infections bactériennes, Institut Pasteur, 28, rue du Docteur Roux, 75724 Paris, France - Unité interactions hôte-agents pathogènes, institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge, France.

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http://dx.doi.org/10.1051/medsci/20173305010DOI Listing
May 2017

Mechanisms of Invariant NKT Cell Activity in Restraining Bacillus anthracis Systemic Dissemination.

J Immunol 2016 10 7;197(8):3225-3232. Epub 2016 Sep 7.

Pathogénie des Toxi-Infections Bactériennes, Département de Microbiologie, Institut Pasteur, 75724 Paris, France.

Exogenous activation of invariant NKT (iNKT) cells by the superagonist α-galactosylceramide (α-GalCer) can protect against cancer, autoimmune diseases, and infections. In the current study, we investigated the effect of α-GalCer against Bacillus anthracis infection, the agent of anthrax. Using an experimental model of s.c. B. anthracis infection (an encapsulated nontoxigenic strain), we show that concomitant administration of α-GalCer delayed B. anthracis systemic dissemination and prolonged mouse survival. Depletion of subcapsular sinus CD169-positive macrophages by clodronate-containing liposome was associated with a lack of iNKT cell activation in the draining lymph nodes (dLNs) and prevented the protective effect of α-GalCer on bacterial dissemination out of the dLNs. Production of IFN-γ triggered chemokine (C-C motif) ligand 3 synthesis and recruitment of neutrophils in the dLNs, leading to the restraint of B. anthracis dissemination. Our data highlight a novel immunological pathway leading to the control of B. anthracis infection, a finding that might lead to improved therapeutics based on iNKT cells.
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http://dx.doi.org/10.4049/jimmunol.1600830DOI Listing
October 2016

In vivo dynamics of active edema and lethal factors during anthrax.

Sci Rep 2016 Mar 21;6:23346. Epub 2016 Mar 21.

Pathogénie des Toxi-Infections Bactériennes, Institut Pasteur, Paris, France.

Lethal and edema toxins are critical virulence factors of Bacillus anthracis. However, little is known about their in vivo dynamics of production during anthrax. In this study, we unraveled for the first time the in vivo kinetics of production of the toxin components EF (edema factor) and LF (lethal factor) during cutaneous infection with a wild-type toxinogenic encapsulated strain in immuno-competent mice. We stratified the asynchronous infection process into defined stages through bioluminescence imaging (BLI), while exploiting sensitive quantitative methods by measuring the enzymatic activity of LF and EF. LF was produced in high amounts, while EF amounts steadily increased during the infectious process. This led to high LF/EF ratios throughout the infection, with variations between 50 to a few thousands. In the bloodstream, the early detection of active LF and EF despite the absence of bacteria suggests that they may exert long distance effects. Infection with a strain deficient in the protective antigen toxin component enabled to address its role in the diffusion of LF and EF within the host. Our data provide a picture of the in vivo complexity of the infectious process.
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http://dx.doi.org/10.1038/srep23346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800402PMC
March 2016

Physical Sequestration of Bacillus anthracis in the Pulmonary Capillaries in Terminal Infection.

J Infect Dis 2016 07 14;214(2):281-7. Epub 2016 Mar 14.

Institut Pasteur, Histopathologie Humaine et Modèles Animaux Pathogénie des Toxi-Infections Bactériennes.

The lung is the terminal target of Bacillus anthracis before death, whatever the route of infection (cutaneous, inhalational, or digestive). During a cutaneous infection in absence of toxins, we observed encapsulated bacteria colonizing the alveolar capillary network, bacteria and hemorrhages in alveolar and bronchiolar spaces, and hypoxic foci in the lung (endothelial cells) and brain (neurons and neuropil). Circulating encapsulated bacteria were as chains of approximately 13 µm in length. Bacteria of such size were immediately trapped within the lung capillary network, but bacteria of shorter length were not. Controlling lung-targeted pathology would be beneficial for anthrax treatment.
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http://dx.doi.org/10.1093/infdis/jiw098DOI Listing
July 2016

Intravital microscopy of the lung: minimizing invasiveness.

J Biophotonics 2016 09 5;9(9):868-78. Epub 2016 Feb 5.

Unité Interactions Hôte-Agents pathogènes, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge cedex, 91223, France.

In vivo microscopy has recently become a gold standard in lung immunology studies involving small animals, largely benefiting from the democratization of multiphoton microscopy allowing for deep tissue imaging. This technology represents currently our only way of exploring the lungs and inferring what happens in human respiratory medicine. The interest of lung in vivo microscopy essentially relies upon its relevance as a study model, fulfilling physiological requirements in comparison with in vitro and ex vivo experiments. However, strategies developed in order to overcome movements of the thorax caused by breathing and heartbeats remain the chief drawback of the technique and a major source of invasiveness. In this context, minimizing invasiveness is an unavoidable prerequisite for any improvement of lung in vivo microscopy. This review puts into perspective the main techniques enabling lung in vivo microscopy, providing pros and cons regarding invasiveness.
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http://dx.doi.org/10.1002/jbio.201500246DOI Listing
September 2016

Crossing of the epithelial barriers by Bacillus anthracis: the Known and the Unknown.

Front Microbiol 2015 9;6:1122. Epub 2015 Oct 9.

Pathogénie des Toxi-Infections Bactériennes, Institut Pasteur , Paris, France ; Unité Interactions Hôte-Agents Pathogènes, Institut de Recherche Biomédicale des Armées , Brétigny-sur-Orge, France ; Ecole du Val-de-Grâce , Paris, France.

Anthrax, caused by Bacillus anthracis, a Gram-positive spore-forming bacterium, is initiated by the entry of spores into the host body. There are three types of human infection: cutaneous, inhalational, and gastrointestinal. For each form, B. anthracis spores need to cross the cutaneous, respiratory or digestive epithelial barriers, respectively, as a first obligate step to establish infection. Anthrax is a toxi-infection: an association of toxemia and rapidly spreading infection progressing to septicemia. The pathogenicity of Bacillus anthracis mainly depends on two toxins and a capsule. The capsule protects bacilli from the immune system, thus promoting systemic dissemination. The toxins alter host cell signaling, thereby paralyzing the immune response of the host and perturbing the endocrine and endothelial systems. In this review, we will mainly focus on the events and mechanisms leading to crossing of the respiratory epithelial barrier, as the majority of studies have addressed inhalational infection. We will discuss the critical gaps of knowledge that need to be addressed to gain a comprehensive view of the initial steps of inhalational anthrax. We will then discuss the few data available on B. anthracis crossing the cutaneous and digestive epithelia.
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http://dx.doi.org/10.3389/fmicb.2015.01122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598578PMC
October 2015
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