Publications by authors named "Jean-Marc Cavaillon"

127 Publications

The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity.

Lancet Respir Med 2021 06 6;9(6):622-642. Epub 2021 May 6.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.
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http://dx.doi.org/10.1016/S2213-2600(21)00218-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102044PMC
June 2021

Once upon a time, inflammation.

J Venom Anim Toxins Incl Trop Dis 2021 Apr 9;27:e20200147. Epub 2021 Apr 9.

French National Research Agency(ANR), Paris, France.

Inflammation has accompanied humans since their first ancestors appeared on Earth. Aulus Cornelius Celsus (25 BC-50 AD), a Roman encyclopedist, offered a still valid statement about inflammation: "", defining the four cardinal signs of inflammation as redness and swelling with heat and pain. While inflammation has long been considered as a morbid phenomenon, John Hunter (18 century) and Elie Metchnikoff (19 century) understood that it was a natural and beneficial event that aims to address a sterile or an infectious insult. Many other famous scientists and some forgotten ones have identified the different cellular and molecular players, and deciphered the different mechanisms of inflammation. This review pays tribute to some of the giants who made major contributions, from Hippocrates to the late 19 and first half of the 20 century. We particularly address the discoveries related to phagocytes, diapedesis, chemotactism, and fever. We also mention the findings of the various inflammatory mediators and the different approaches designed to treat inflammatory disorders.
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http://dx.doi.org/10.1590/1678-9199-JVATITD-2020-0147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040910PMC
April 2021

Bridging animal and clinical research during SARS-CoV-2 pandemic: A new-old challenge.

EBioMedicine 2021 Apr 1;66:103291. Epub 2021 Apr 1.

Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Donaueschingenstrasse 13, 1200, Vienna, Austria. Electronic address:

Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.
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http://dx.doi.org/10.1016/j.ebiom.2021.103291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016444PMC
April 2021

Optimal combination of early biomarkers for infection and sepsis diagnosis in the emergency department: The BIPS study.

J Infect 2021 04 18;82(4):11-21. Epub 2021 Feb 18.

Emergency Department, Pitié-Salpêtrière Hospital, Groupe Hospitalier Sorbonne Université, AP-PH, Paris, France; Sorbonne-Université, GRC-14 BIOSFAST, UMR 1166, Paris France. Electronic address:

Objective: To define the best combination of biomarkers for the diagnosis of infection and sepsis in the emergency room.

Methods: In this prospective study, consecutive patients with a suspicion of infection in the emergency room were included. Eighteen different biomarkers measured in plasma, and twelve biomarkers measured on monocytes, neutrophils, B and T-lymphocytes were studied and the best combinations determined by a gradient tree boosting approach.

Results: Overall, 291 patients were included and analysed, 148 with bacterial infection, and 47 with viral infection. The best biomarker combination which first allowed the diagnosis of bacterial infection, included HLA-DR (human leukocyte antigen DR) on monocytes, MerTk (Myeloid-epithelial-reproductive tyrosine kinase) on neutrophils and plasma metaloproteinase-8 (MMP8) with an area under the curve (AUC) = 0.94 [95% confidence interval (IC95): 0.91;0.97]. Among patients in whom a bacterial infection was excluded, the combination of CD64 expression, and CD24 on neutrophils and CX3CR1 on monocytes ended to an AUC = 0.98 [0.96;1] to define those with a viral infection.

Conclusion: In a convenient cohort of patients admitted with a suspicion of infection, two different combinations of plasma and cell surface biomarkers were performant to identify bacterial and viral infection.
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http://dx.doi.org/10.1016/j.jinf.2021.02.019DOI Listing
April 2021

[Jules Bordet, a man of conviction. Centenary of his Nobel Prize].

Med Sci (Paris) 2020 Aug-Sep;36(8-9):803-809. Epub 2020 Aug 21.

Institute for Interdisciplinary Innovation in healthcare (I3h), Université libre de Bruxelles, Belgique.

Jules Bordet came to the Institut Pasteur soon after his MD graduation at the Université libre de Bruxelles, thanks to a grant from the Belgian government. He joined there the laboratory of Elie Metchnikoff, the father of phagocytes and cellular immunity. Amazingly, he will decipher there some of the key mechanisms of humoral immunity initially discovered by the German school against which his mentor was fighting. He described the mechanisms that govern bacteriolysis and hemolysis, following the action of immune sera. Even if he favored the term alexin coined by Hans Buchner, he is indeed one of the founding fathers of the complement system (term coined by Paul Ehrlich). It is for these works that he was awarded in October 1920 the 1919 Nobel Prize. Back in Belgium, he became the director of Institut Pasteur du Brabant and made another landmark discovery, namely the identification of the bacillus of whooping cough, now named Bordetella pertussis.
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http://dx.doi.org/10.1051/medsci/2020135DOI Listing
October 2020

SARS-CoV-2/COVID-19: Evolving Reality, Global Response, Knowledge Gaps, and Opportunities.

Shock 2020 10;54(4):416-437

Department of Trauma and Orthopaedic Surgery, Cologne-Merheim Medical Center (CMMC), University of Witten/Herdecke, Cologne-Merheim Campus, Cologne, Germany.

Approximately 3 billion people around the world have gone into some form of social separation to mitigate the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The uncontrolled influx of patients in need of emergency care has rapidly brought several national health systems to near-collapse with deadly consequences to those afflicted by Coronavirus Disease 2019 (COVID-19) and other critical diseases associated with COVID-19. Solid scientific evidence regarding SARS-CoV-2/COVID-19 remains scarce; there is an urgent need to expand our understanding of the SARS-CoV-2 pathophysiology to facilitate precise and targeted treatments. The capacity for rapid information dissemination has emerged as a double-edged sword; the existing gap of high-quality data is frequently filled by anecdotal reports, contradictory statements, and misinformation. This review addresses several important aspects unique to the SARS-CoV-2/COVID-19 pandemic highlighting the most relevant knowledge gaps and existing windows-of-opportunity. Specifically, focus is given on SARS-CoV-2 immunopathogenesis in the context of experimental therapies and preclinical evidence and their applicability in supporting efficacious clinical trial planning. The review discusses the existing challenges of SARS-CoV-2 diagnostics and the potential application of translational technology for epidemiological predictions, patient monitoring, and treatment decision-making in COVID-19. Furthermore, solutions for enhancing international strategies in translational research, cooperative networks, and regulatory partnerships are contemplated.
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http://dx.doi.org/10.1097/SHK.0000000000001565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363382PMC
October 2020

Sepsis therapies: learning from 30 years of failure of translational research to propose new leads.

EMBO Mol Med 2020 04 16;12(4):e10128. Epub 2020 Mar 16.

Laboratory of Flow Cytometry and Department of Anesthesiology and Intensive Care Medicine, Centre of Postgraduate Medical Education, Warsaw, Poland.

Sepsis has been identified by the World Health Organization (WHO) as a global health priority. There has been a tremendous effort to decipher underlying mechanisms responsible for organ failure and death, and to develop new treatments. Despite saving thousands of animals over the last three decades in multiple preclinical studies, no new effective drug has emerged that has clearly improved patient outcomes. In the present review, we analyze the reasons for this failure, focusing on the inclusion of inappropriate patients and the use of irrelevant animal models. We advocate against repeating the same mistakes and propose changes to the research paradigm. We discuss the long-term consequences of surviving sepsis and, finally, list some putative approaches-both old and new-that could help save lives and improve survivorship.
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http://dx.doi.org/10.15252/emmm.201810128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136965PMC
April 2020

H3K4me1 Supports Memory-like NK Cells Induced by Systemic Inflammation.

Cell Rep 2019 12;29(12):3933-3945.e3

G5 Chromatine et Infection, Institut Pasteur, Paris, France. Electronic address:

Natural killer (NK) cells are unique players in innate immunity and, as such, an attractive target for immunotherapy. NK cells display immune memory properties in certain models, but the long-term status of NK cells following systemic inflammation is unknown. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memory-like properties, showing increased production of IFNγ upon specific secondary stimulation. The NK cell memory response is detectable for at least 9 weeks and contributes to protection from E. coli infection upon adoptive transfer. Importantly, we reveal a mechanism essential for NK cell memory, whereby an H3K4me1-marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erases the enhancer and abolishes NK cell memory. Thus, NK cell memory develops after endotoxemia in a histone methylation-dependent manner, ensuring a heightened response to secondary stimulation.
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http://dx.doi.org/10.1016/j.celrep.2019.11.043DOI Listing
December 2019

André Boivin: A pioneer in endotoxin research and an amazing visionary during the birth of molecular biology.

Innate Immun 2020 04 1;26(3):165-171. Epub 2019 Nov 1.

Experimental Neuropathology Unit, Institut Pasteur, 28 rue Dr. Roux, 75015, Paris, France.

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http://dx.doi.org/10.1177/1753425919842307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144033PMC
April 2020

Current gaps in sepsis immunology: new opportunities for translational research.

Lancet Infect Dis 2019 12 17;19(12):e422-e436. Epub 2019 Oct 17.

Hospital Universitario Río Hortega, Valladolid, Spain; Group for Biomedical Research in Sepsis, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain; Centro de Investigación Biomedica En Red-Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy. Addressing these gaps should help us to better understand sepsis physiopathology, offering translational opportunities to improve its prevention, diagnosis, and care.
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http://dx.doi.org/10.1016/S1473-3099(19)30567-5DOI Listing
December 2019

100th Anniversary of Jules Bordet's Nobel Prize: Tribute to a Founding Father of Immunology.

Front Immunol 2019 11;10:2114. Epub 2019 Sep 11.

Institute for Interdisciplinary Innovation in Healthcare (I3h), Université Libre de Bruxelles, Brussels, Belgium.

The 100th Anniversary of the Nobel Prize in Physiology or Medicine 1919 awarded to Jules Bordet offers the opportunity to underline the contributions of this Belgian doctor to the blooming of immunology at the end of the nineteenth century at the Institut Pasteur de Paris. It is also the occasion to emphasize his achievements as director of the Institut Pasteur du Brabant and professor at the Université libre de Bruxelles. Both in France and Belgium, he developed a holistic vision of immunology as a science at the crossroads of chemistry, physiology, and microbiology.
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http://dx.doi.org/10.3389/fimmu.2019.02114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749103PMC
October 2020

Duclaux, Chamberland, Roux, Grancher, and Metchnikoff: the five musketeers of Louis Pasteur.

Microbes Infect 2019 Jun - Jul;21(5-6):192-201. Epub 2019 Jun 28.

Centre de Ressources en Information Scientifique, Institut Pasteur, France.

The Institut Pasteur was created thanks to worldwide generosity with the aim to welcome and treat rabies patients, to provide a place for scientific research and to offer new teaching programs in microbiology. Louis Pasteur invited his main collaborators, who had accompanied him during his previous investigations at École Normale Supérieure, to join him in his new institute. They contributed to the principle discoveries of Pasteur, such as the fight against spontaneous generation, the identification of the ferments of putrefaction, the fight against the silk worm disease, the research on wine and beer, and the set-up of the first vaccines against avian cholera, anthrax, swine erysipelas and rabies. There were two scientists, Émile Duclaux and Charles Chamberland, and two medical doctors, Émile Roux, and Joseph Grancher. In addition, two Russian scientists were invited to join the Institute and to head a research laboratory, Élie Metchnikoff and Nikolaï Gamaleïa, the later will finally never join the institute.
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http://dx.doi.org/10.1016/j.micinf.2019.06.006DOI Listing
February 2020

From septicemia to sepsis 3.0 - from Ignaz Semmelweis to Louis Pasteur.

Microbes Infect 2019 Jun - Jul;21(5-6):213-221. Epub 2019 Jun 27.

Experimental Neuropathology Unit, Institut Pasteur, 28 rue Dr. Roux, 75015, Paris, France; Service Hospitalo-Universitaire de Neuropathologie, GHU, France; Paris-Psychiatrie NeuroSciences, Université Paris Descartes, France.

Sepsis remains a contemporary threat, and its frequency remains high amongst an aging population. Its definition has been regularly revisited, but the impact of the translational research studying it remains very modest compared to the results seen after the introduction of hygiene and the use of antibiotics. In the past, the main forms of sepsis were hospital gangrene (also known as nosocomial fever or putrid fever) that affected the wounded, and puerperal fever that affected women shortly after delivery. In 1858, Armand Trousseau stated that these two pathologies were identical. Lucrezia Borgia, who died in 1519, is undoubtedly the most famous woman to die from puerperal fever. The notion of sepsis as a real epidemic was deplored. For decades doctors remained deaf to the recommendations of their clairvoyant colleagues who advocated for the use of hygienic measures. It was as early as 1795 that Alexander Gordon (UK) and later in 1843, Oliver Holmes (USA), called for the use of hygienic practices. In 1847, Ignaz Semmelweis, a Hungarian physician, provided an irrefutable demonstration of the importance of hygiene in the prevention of contamination by the hands of the practitioners. But Ignaz Semmelweis' life was a tragedy, his fight against the medical nomenklatura was a tragedy, and his death was a tragedy! Nowadays, Ignaz Semmelweis is receiving the honor that he deserves, but never received during his life. Carl Mayrhofer, Victor Feltz, and Léon Coze were the first to associate the presence of bacteria with sepsis. These observations were confirmed by Louis Pasteur who, thanks to his prestige, had a great influence on how to undertake measures to prevent infections. He inspired Joseph Lister who reduced mortality associated with surgery, particularly amputation, by utilizing antiseptic methods.
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http://dx.doi.org/10.1016/j.micinf.2019.06.005DOI Listing
February 2020

Duclaux, Chamberland, Roux, Grancher, and Metchnikoff: the five musketeers of Louis Pasteur.

Genes Immun 2019 05 29;20(5):344-356. Epub 2019 Mar 29.

Centre de ressources en information scientifique, Institut Pasteur, Paris, France.

The Institut Pasteur was created, thanks to worldwide generosity with the aim to welcome and treat rabies patients, to provide a place for scientific research and to offer new teaching programs in microbiology. Louis Pasteur invited his main collaborators, who had accompanied him during his previous investigations at École Normale Supérieure, to join him in his new institute. They contributed to the principle discoveries of Pasteur, such as the fight against spontaneous generation, the identification of the ferments of putrefaction, the fight against the silk worm disease, the research on wine and beer, and the set-up of the first vaccines against avian cholera, anthrax, swine erysipelas, and rabies. There were two scientists, Émile Duclaux and Charles Chamberland, and two medical doctors, Émile Roux, and Joseph Grancher. In addition, two Russian scientists were invited to join the Institute and to head a research laboratory, Élie Metchnikoff and Nikolaï Gamaleïa; the later will finally never join the institute.
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http://dx.doi.org/10.1038/s41435-019-0064-1DOI Listing
May 2019

From septicemia to sepsis 3.0-from Ignaz Semmelweis to Louis Pasteur.

Genes Immun 2019 05 22;20(5):371-382. Epub 2019 Mar 22.

Experimental Neuropathology Unit, Institut Pasteur, 28 rue Dr. Roux, 75015, Paris, France.

Sepsis remains a contemporary threat, and its frequency remains high amongst an aging population. Its definition has been regularly revisited, but the impact of the translational research studying it remains very modest compared to the results seen after the introduction of hygiene and the use of antibiotics. In the past, the main forms of sepsis were hospital gangrene (also known as nosocomial fever or putrid fever) that affected the wounded, and puerperal fever that affected women shortly after delivery. In 1858, Armand Trousseau stated that these two pathologies were identical. Lucrezia Borgia, who died in 1519, is undoubtedly the most famous woman to die from puerperal fever. The notion of sepsis as a real epidemic was deplored. For decades doctors remained deaf to the recommendations of their clairvoyant colleagues who advocated for the use of hygienic measures. It was as early as 1795 that Alexander Gordon (UK) and later in 1843, Oliver Holmes (USA), called for the use of hygienic practices. In 1847, Ignaz Semmelweis, a Hungarian physician, provided an irrefutable demonstration of the importance of hygiene in the prevention of contamination by the hands of the practitioners. But Ignaz Semmelweis' life was a tragedy, his fight against the medical nomenklatura was a tragedy, and his death was a tragedy! Nowadays, Ignaz Semmelweis is receiving the honor that he deserves, but never received during his life. Carl Mayrhofer, Victor Feltz, and Léon Coze were the first to associate the presence of bacteria with sepsis. These observations were confirmed by Louis Pasteur who, thanks to his prestige, had a great influence on how to undertake measures to prevent infections. He inspired Joseph Lister who reduced mortality associated with surgery, particularly amputation, by utilizing antiseptic methods.
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http://dx.doi.org/10.1038/s41435-019-0063-2DOI Listing
May 2019

Inner sensors of endotoxin - implications for sepsis research and therapy.

FEMS Microbiol Rev 2019 05;43(3):239-256

Experimental Neuropathology Unit, Institut Pasteur, 28 rue Dr. Roux, 75015 Paris, France.

Despite great efforts and numerous clinical trials, there is still a major need for effective therapies for sepsis. Neutralization or elimination of bacterial toxins remains a promising approach. The understanding of the interaction of the endotoxin (lipopolysaccharide, LPS) of Gram-negative bacteria with its cellular receptor, namely the CD14/TLR4/MD2 complex, was a major breakthrough. Unfortunately, clinical trials for sepsis on the neutralization of LPS or on the inhibition of TLR4 signaling failed whereas those on LPS removal remain controversial. Recent discoveries of another class of LPS receptors localized within the cytoplasm, namely caspase-11 in mice and caspases-4/5 in humans, have renewed interest in the field. These provide new potential targets for intervention in sepsis pathogenesis. Since cytoplasmic recognition of LPS induces non-canonical inflammasome pathway, a potentially harmful host response, it is conceivable to therapeutically target this mechanism. However, a great deal of care should be used in the translation of research on the non-canonical inflammasome inhibition due to multiple inter-species differences. In this review, we summarize the knowledge on endotoxin sensing in sepsis with special focus on the intracellular sensing. We also highlight the murine versus human differences and discuss potential therapeutic approaches addressing the newly discovered pathways.
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http://dx.doi.org/10.1093/femsre/fuz004DOI Listing
May 2019

Immunosuppression is Inappropriately Qualifying the Immune Status of Septic and SIRS Patients.

Shock 2019 09;52(3):307-317

4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.

Immunosuppression is the most commonly used concept to qualify the immune status of patients with either sterile systemic inflammatory response syndrome (SIRS) or sepsis. In this review we attempt to demonstrate that the concept of immunosuppression is an oversimplification of the complex anti-inflammatory response that occurs in patients dealing with a severe sterile or infectious insult. Particularly, the immune status of leukocytes varies greatly depending on the compartment from where they are derived from. Furthermore, although certain functions of immune cells present in the blood stream or in the hematopoietic organs can be significantly diminished, other functions are either unchanged or even enhanced. This juxtaposition illustrates that there is no global defect. The mechanisms called reprogramming or trained innate immunity are probably aimed at preventing a generalized deleterious inflammatory reaction, and work to maintain the defense mechanisms at their due levels.
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http://dx.doi.org/10.1097/SHK.0000000000001266DOI Listing
September 2019

Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis.

Intensive Care Med Exp 2018 Aug 14;6(1):26. Epub 2018 Aug 14.

Xiangya School of Medicine, Central South University, Chagnsha, Hunan, China.

Background: Pre-clinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking.

Objective: To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May 2017. The goal of the conference was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the "Minimum Quality Threshold in Pre-Clinical Sepsis Studies" (MQTiPSS), to enhance translational value of these models.

Methods: A total of 31 experts from 13 countries participated and were divided into 6 thematic working groups (WG): (1) study design, (2) humane modeling, (3) infection types, (4) organ failure/dysfunction, (5) fluid resuscitation, and (6) antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002-2013).

Results: Overall, the participants reached consensus on 29 points; 20 at "recommendation" (R) and 9 at "consideration" (C) strength. This executive summary provides a synopsis of the MQTiPSS consensus (Tables 1, 2, and 3). Detailed commentaries to all Rs and Cs are simultaneously published in three separate full-length papers.

Conclusions: We believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as "best practices" for animal models of sepsis that should be implemented. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.
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http://dx.doi.org/10.1186/s40635-018-0189-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093828PMC
August 2018

Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): An International Expert Consensus Initiative for Improvement of Animal Modeling in Sepsis.

Shock 2018 10;50(4):377-380

Xiangya School of Medicine, Central South University, Chagnsha, Hunan, China.

Preclinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of preclinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on preclinical sepsis modeling was held in Vienna in May, 2017. The goal of the conference was to identify limitations of preclinical sepsis models and to propose a set of guidelines, defined as the "Minimum Quality Threshold in Preclinical Sepsis Studies" (MQTiPSS), to enhance translational value of these models. A total of 31 experts from 13 countries participated and were divided into six thematic Working Groups: Study Design, Humane modeling, Infection types, Organ failure/dysfunction, Fluid resuscitation, and Antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002-2013). Overall, the participants reached consensus on 29 points; 20 at "recommendation" and nine at "consideration" strength. This Executive Summary provides a synopsis of the MQTiPSS consensus. We believe that these recommendations and considerations will serve to bring a level of standardization to preclinical models of sepsis and ultimately improve translation of preclinical findings. These guideline points are proposed as "best practices" for animal models of sepsis that should be implemented. To encourage its wide dissemination, this article is freely accessible on the Intensive Care Medicine Experimental and Infection journal websites. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection, and Intensive Care Medicine Experimental.
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http://dx.doi.org/10.1097/SHK.0000000000001212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133201PMC
October 2018

Part II: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Types of Infections and Organ Dysfunction Endpoints.

Shock 2019 01;51(1):23-32

Boston University School of Medicine, Boston, Massachusetts.

Although the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review has not been done for preclinical models. To address this deficit, a Wiggers-Bernard Conference on preclinical sepsis modeling reviewed the 260 most highly cited papers between 2003 and 2012 using sepsis models to create a series of recommendations. This Part II report provides recommendations for the types of infections and documentation of organ injury in preclinical sepsis models. Concerning the types of infections, the review showed that the cecal ligation and puncture model was used for 44% of the studies while 40% injected endotoxin. Recommendation #8 (numbered sequentially from Part I): endotoxin injection should not be considered as a model of sepsis; live bacteria or fungal strains derived from clinical isolates are more appropriate. Recommendation #9: microorganisms should replicate those typically found in human sepsis. Sepsis-3 states that sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection, but the review of the papers showed limited attempts to document organ dysfunction. Recommendation #10: organ dysfunction definitions should be used in preclinical models. Recommendation #11: not all activities in an organ/system need to be abnormal to verify organ dysfunction. Recommendation #12: organ dysfunction should be measured in an objective manner using reproducible scoring systems. Recommendation #13: not all experiments must measure all parameters of organ dysfunction, but investigators should attempt to fully capture as much information as possible. These recommendations are proposed as "best practices" for animal models of sepsis.
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http://dx.doi.org/10.1097/SHK.0000000000001242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296883PMC
January 2019

Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis.

Infection 2018 Oct;46(5):687-691

Xiangya School of Medicine, Central South University, Chagnsha, Hunan, China.

Purpose: Pre-clinical animal studies precede the majority of clinical trials. While the clinical sepsis definitions and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May, 2017. The conference goal was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the "Minimum Quality Threshold in Pre-Clinical Sepsis Studies" (MQTiPSS), to enhance translational value of these models.

Methods: 31 experts from 13 countries participated and were divided into 6 thematic Working Groups (WG): (1) Study Design, (2) Humane modeling, (3) Infection types, (4) Organ failure/dysfunction, (5) Fluid resuscitation and (6) Antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002-2013).

Results: Overall, the participants reached consensus on 29 points; 20 at "recommendation" (R) and 9 at "consideration" (C) strength. This Executive Summary provides a synopsis of the MQTiPSS consensus (Tables 1, 2 and 3).

Conclusions: We believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as "best practices" that should be implemented for animal sepsis models. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.
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http://dx.doi.org/10.1007/s15010-018-1183-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182493PMC
October 2018

Circulating biomarkers may be unable to detect infection at the early phase of sepsis in ICU patients: the CAPTAIN prospective multicenter cohort study.

Intensive Care Med 2018 07 30;44(7):1061-1070. Epub 2018 Jun 30.

Service de Médecine Intensive et Réanimation, Groupe Hospitalier Paris Saint-Joseph, Paris, France.

Purpose: Sepsis and non-septic systemic inflammatory response syndrome (SIRS) are the same syndromes, differing by their cause, sepsis being secondary to microbial infection. Microbiological tests are not enough to detect infection early. While more than 50 biomarkers have been proposed to detect infection, none have been repeatedly validated.

Aim: To assess the accuracy of circulating biomarkers to discriminate between sepsis and non-septic SIRS.

Methods: The CAPTAIN study was a prospective observational multicenter cohort of 279 ICU patients with hypo- or hyperthermia and criteria of SIRS, included at the time the attending physician considered antimicrobial therapy. Investigators collected blood at inclusion to measure 29 plasma compounds and ten whole blood RNAs, and-for those patients included within working hours-14 leukocyte surface markers. Patients were classified as having sepsis or non-septic SIRS blindly to the biomarkers results. We used the LASSO method as the technique of multivariate analysis, because of the large number of biomarkers.

Results: During the study period, 363 patients with SIRS were screened, 84 having exclusion criteria. Ninety-one patients were classified as having non-septic SIRS and 188 as having sepsis. Eight biomarkers had an area under the receiver operating curve (ROC-AUC) over 0.6 with a 95% confidence interval over 0.5. LASSO regression identified CRP and HLA-DRA mRNA as being repeatedly associated with sepsis, and no model performed better than CRP alone (ROC-AUC 0.76 [0.68-0.84]).

Conclusions: The circulating biomarkers tested were found to discriminate poorly between sepsis and non-septic SIRS, and no combination performed better than CRP alone.
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http://dx.doi.org/10.1007/s00134-018-5228-3DOI Listing
July 2018

Gastro-protective, therapeutic and anti-inflammatory activities of Pistacia lentiscus L. fatty oil against ethanol-induced gastric ulcers in rats.

J Ethnopharmacol 2018 Oct 31;224:273-282. Epub 2018 May 31.

Team "Cytokines and NO Synthases", LBCM (Laboratory of Cellular and Molecular Biology), FSB (Faculty of Biological Science), USTHB (University of Sciences and Technology Houari Boumediene), PB 32 El-Alia, 16111 Algiers, Algeria. Electronic address:

Ethnopharmacological Relevance: Pistacia lentiscus L. (Anacardiaceae) (PL) is a flowering plant that grows in the Mediterranean area. It is traditionally used in the treatment of various skin, respiratory and gastrointestinal disorders AIM OF THE STUDY: In the present study, we investigated the anti-ulcerogenic activity of Pistacia lentiscus fatty oil (PLFO) on ethanol-induced gastric ulcers in Wistar rats MATERIAL AND METHODS: PLFO was orally administered to two experimental groups of rats before or after ethanol induction of gastric ulcer. The lesions of the gastric mucosa were evaluated by macroscopic and histopathological examination. In addition, the amount of nitric oxide (NO) and pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the supernatant from cultures of gastric mucosa explants were assessed. Finally, the mucus production and iNOS (inducible NO synthase) expression were determined by histochemical and immunohistochemical analysis, respectively RESULT: Our results indicated that the PLFO pretreatment or PLFO treatment significantly reduced ulcerated and hemorrhagic areas. Additionally, pretreatment or treatment with PLFO after ethanol-induced ulceration significantly reduced the plasma concentration of NO. Furthermore, a significant decrease of NO, IL-6 and TNF-α levels was observed in explant culture supernatants. iNOS expression was also reduced in the gastric mucosa. In contrast, mucus production by goblet cells was enhanced. Interestingly, histological analysis of the gastric mucosa has indicated that PLFO- pretreated and treated groups displayed normal histology CONCLUSION: Our results demonstrate that PLFO display significant prophylactic and therapeutic effects against gastric ulcers. Importantly, the mechanism underlying PLFO activities might implicate inhibition of inflammatory responses during gastric ulcer.
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http://dx.doi.org/10.1016/j.jep.2018.05.040DOI Listing
October 2018

Specific features of human monocytes activation by monophosphoryl lipid A.

Sci Rep 2018 05 4;8(1):7096. Epub 2018 May 4.

Unit "Cytokines & Inflammation", Institut Pasteur, Paris, France.

We deciphered the mechanisms of production of pro- and anti-inflammatory cytokines by adherent human blood mononuclear cells (PBMC) activated by lipopolysaccharide (LPS) or monophosphoryl lipid A (MPLA). Both LPS and MPLA induced tumor necrosis factor (TNF) production proved to be dependent on the production of interleukin-1β (IL-1β). Of note, MPLA induced IL-1β release in human adherent PBMCs whereas MPLA was previously reported to not induce this cytokine in murine cells. Both LPS and MPLA stimulatory effects were inhibited by Toll-like receptor-4 (TLR4) antagonists. Only monocytes activation by LPS was dependent on CD14. Other differences were noticed between LPS and MPLA. Among the different donors, a strong correlation existed in terms of the levels of TNF induced by different LPSs. In contrast, there was no correlation between the TNF productions induced by LPS and those induced by MPLA. However, there was a strong correlation when IL-6 production was analyzed. Blocking actin polymerization and internalization of the agonists inhibited MPLA induced TNF production while the effect on LPS induced TNF production depended on the donors (i.e. high TNF producers versus low TNF producers). Finally, conventional LPS, tolerized adherent PBMCs to TLR2 agonists, while MPLA primed cells to further challenge with TLR2 agonists.
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http://dx.doi.org/10.1038/s41598-018-25367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935727PMC
May 2018

Historical links between toxinology and immunology.

Pathog Dis 2018 04;76(3)

Unit Cytokines and Inflammation, Institut Pasteur, 28 rue Dr. Roux, 75015 Paris, France.

Research on bacterial toxins is closely linked to the birth of immunology. Our understanding of the interaction of bacterial protein toxins with immune cells has helped to decipher immunopathology, develop preventive and curative treatments for infections, and propose anti-cancer immunotherapies. The link started when Behring and Kitasato demonstrated that serotherapy was effective against 'the strangling angel', namely diphtheria, and its dreadful toxin discovered by Roux and Yersin. The antitoxin treatment helped to save thousands of children. Glenny demonstrated the efficacy of the secondary immune response compared to the primary one. Ramon described anatoxins that allowed the elaboration of effective vaccines and discovered the use of adjuvant to boost the antibody response. Similar approaches were later made for the tetanus toxin. Studying antitoxin antibodies Ehrlich demonstrated, for the first time, the transfer of immunity from mother to newborns. In 1989 Marrack and Kappler coined the concept of 'superantigens' to characterize protein toxins that induce T-lymphocyte proliferation, and cytokine release by both T-lymphocytes and antigen presenting cells. More recently, immunotoxins have been designed to kill cancer cells targeted by either specific antibodies or cytokines. Finally, the action of IgE antibodies against toxins may explain their persistence through evolution despite their side effect in allergy.
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http://dx.doi.org/10.1093/femspd/fty019DOI Listing
April 2018

A Novel Polyaminocarboxylate Compound To Treat Murine Pulmonary Aspergillosis by Interfering with Zinc Metabolism.

Antimicrob Agents Chemother 2018 06 25;62(6). Epub 2018 May 25.

Institut Pasteur, Cytokines & Inflammation Unit, Paris, France

can cause pulmonary aspergillosis in immunocompromised patients and is associated with a high mortality rate due to a lack of reliable treatment options. This opportunistic pathogen requires zinc in order to grow and cause disease. Novel compounds that interfere with fungal zinc metabolism may therefore be of therapeutic interest. We screened chemical libraries containing 59,223 small molecules using a resazurin assay that compared their effects on an wild-type strain grown under zinc-limiting conditions and on a zinc transporter knockout strain grown under zinc-replete conditions to identify compounds affecting zinc metabolism. After a first screen, 116 molecules were selected whose inhibitory effects on fungal growth were further tested by using luminescence assays and hyphal length measurements to confirm their activity, as well as by toxicity assays on HeLa cells and mice. Six compounds were selected following a rescreening, of which two were pyrazolones, two were porphyrins, and two were polyaminocarboxylates. All three groups showed good activity, but only one of the polyaminocarboxylates was able to significantly improve the survival of immunosuppressed mice suffering from pulmonary aspergillosis. This two-tier screening approach led us to the identification of a novel small molecule with fungicidal effects and low murine toxicity that may lead to the development of new treatment options for fungal infections by administration of this compound either as a monotherapy or as part of a combination therapy.
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http://dx.doi.org/10.1128/AAC.02510-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971598PMC
June 2018

Compartment diversity in innate immune reprogramming.

Microbes Infect 2018 03 27;20(3):156-165. Epub 2017 Dec 27.

Cytokines & Inflammation, Institut Pasteur, Paris, France. Electronic address:

Pathogens or endogenous molecules can reprogram innate immunity. This process can take the form of priming or tolerance depending on the activating signal, and favors enhanced resistance to infection and other insults, by modulating inflammation. Similarly to their organ-specific properties, reprogramming of macrophages and NK cells, is also compartmentalized.
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http://dx.doi.org/10.1016/j.micinf.2017.12.008DOI Listing
March 2018

Exotoxins and endotoxins: Inducers of inflammatory cytokines.

Toxicon 2018 Jul 19;149:45-53. Epub 2017 Oct 19.

Unit Cytokines & Inflammation, Institut Pasteur, 28 Rue Dr. Roux, 75015, Paris, France. Electronic address:

Endotoxins and exotoxins are among the most potent bacterial inducers of cytokines. During infectious processes, the production of inflammatory cytokines including tumor necrosis factor (TNF), interleukin-1β (IL-1β), gamma interferon (IFNγ) and chemokines orchestrates the anti-infectious innate immune response. However, an overzealous production, leading up to a cytokine storm, can be deleterious and contributes to mortality consecutive to sepsis or toxic shock syndrome. Endotoxins of Gram-negative bacteria (lipopolysaccharide, LPS) are particularly inflammatory because they generate auto-amplificatory loops after activation of monocytes/macrophages. LPS and numerous pore-forming exotoxins also activate the inflammasome, the molecular platform that allows the release of mature IL-1β and IL-18. Among exotoxins, some behave as superantigens, and as such activate the release of cytokines by T-lymphocytes. In most cases, pre-exposure to exotoxins enhances the cytokine production induced by LPS and its lethality, whereas pre-exposure to endotoxin usually results in tolerance. In this review we recall the various steps, which, from the very early discovery of pyrogenicity induced by bacterial products, ended to the discovery of the endogenous pyrogen. Furthermore, we compare the specific characteristics of endotoxins and exotoxins in their capacity to induce inflammatory cytokines.
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http://dx.doi.org/10.1016/j.toxicon.2017.10.016DOI Listing
July 2018
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