Publications by authors named "Catherine Fitting"

51 Publications

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

Surfactant-secreted phospholipase A interplay and respiratory outcome in preterm neonates.

Am J Physiol Lung Cell Mol Physiol 2020 07 13;319(1):L95-L104. Epub 2020 May 13.

Cystic fibrosis and Bronchial diseases team-INSERM U938, Institut Pasteur, Paris, France.

Secreted phospholipase A hydrolyzes surfactant phospholipids and is crucial for the inflammatory cascade; preterm neonates are treated with exogenous surfactant, but the interaction between surfactant and phospholipase is unknown. We hypothesize that this interplay is complex and the enzyme plays a relevant role in neonates needing surfactant replacement. We aimed to: ) identify phospholipases A isoforms expressed in preterm lung; ) study the enzyme role on surfactant retreatment and function and the effect of exogenous surfactant on the enzyme system; and ) verify whether phospholipase A is linked to respiratory outcomes. In bronchoalveolar lavages of preterm neonates, we measured enzyme activity (alone or with inhibitors), enzyme subtypes, surfactant protein-A, and inflammatory mediators. Surfactant function and phospholipid profile were also tested. Urea ratio was used to obtain epithelial lining fluid concentrations. Follow-up data were prospectively collected. Subtype-IIA is the main phospholipase isoform in preterm lung, although subtype-IB may be significantly expressed. Neonates needing surfactant retreatment have higher enzyme activity ( = 0.021) and inflammatory mediators ( always ≤ 0.001) and lower amounts of phospholipids ( always < 0.05). Enzyme activity was inversely correlated to surfactant adsorption (ρ = -0.6; = 0.008; adjusted = 0.009), total phospholipids (ρ = -0.475; = 0.05), and phosphatidylcholine (ρ = -0.622; = 0.017). Exogenous surfactant significantly reduced global phospholipase activity ( < 0.001) and subtype-IIA ( = 0.005) and increased dioleoylphosphatidylglycerol ( < 0.001) and surfactant adsorption ( < 0.001). Enzyme activity correlated with duration of ventilation (ρ = 0.679, = 0.005; adjusted = 0.04) and respiratory morbidity score at 12 mo postnatal age (τ = 0.349, = 0.037; adjusted = 0.043) but was not associated with mortality, bronchopulmonary dysplasia, or other long-term respiratory outcomes.
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http://dx.doi.org/10.1152/ajplung.00462.2019DOI Listing
July 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

Genetic deficiency of NOD2 confers resistance to invasive aspergillosis.

Nat Commun 2018 07 6;9(1):2636. Epub 2018 Jul 6.

Department of Experimental Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Geert Grooteplein zuid 8, 6525GA, Nijmegen, The Netherlands.

Invasive aspergillosis (IA) is a severe infection that can occur in severely immunocompromised patients. Efficient immune recognition of Aspergillus is crucial to protect against infection, and previous studies suggested a role for NOD2 in this process. However, thorough investigation of the impact of NOD2 on susceptibility to aspergillosis is lacking. Common genetic variations in NOD2 has been associated with Crohn's disease and here we investigated the influence of these  genetic variations on the anti-Aspergillus host response. A NOD2 polymorphism reduced the risk of IA after hematopoietic stem-cell transplantation. Mechanistically, absence of NOD2 in monocytes and macrophages increases phagocytosis leading to enhanced fungal killing, conversely, NOD2 activation reduces the antifungal potential of these cells. Crucially, Nod2 deficiency results in resistance to Aspergillus infection in an in vivo model of pulmonary aspergillosis. Collectively, our data demonstrate that genetic deficiency of NOD2 plays a protective role during Aspergillus infection.
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http://dx.doi.org/10.1038/s41467-018-04912-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035256PMC
July 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

The Absence of NOD1 Enhances Killing of Through Modulation of Dectin-1 Expression.

Front Immunol 2017 13;8:1777. Epub 2017 Dec 13.

Laboratory for Experimental Internal Medicine, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.

One of the major life-threatening infections for which severely immunocompromised patients are at risk is invasive aspergillosis (IA). Despite the current treatment options, the increasing antifungal resistance and poor outcome highlight the need for novel therapeutic strategies to improve outcome of patients with IA. In the current study, we investigated whether and how the intracellular pattern recognition receptor NOD1 is involved in host defense against . When exploring the role of NOD1 in an experimental mouse model, we found that mice were protected against IA and demonstrated reduced fungal outgrowth in the lungs. We found that macrophages derived from bone marrow of mice were more efficiently inducing reactive oxygen species and cytokines in response to . Most strikingly, these cells were highly potent in killing compared with wild-type cells. In line, human macrophages in which NOD1 was silenced demonstrated augmented killing and NOD1 stimulation decreased fungal killing. The differentially altered killing capacity of NOD1 silencing versus NOD1 activation was associated with alterations in dectin-1 expression, with activation of NOD1 reducing dectin-1 expression. Furthermore, we were able to demonstrate that mice have elevated dectin-1 expression in the lung and bone marrow, and silencing of gene expression in human macrophages increases dectin-1 expression. The enhanced dectin-1 expression may be the mechanism of enhanced fungal killing of cells and human cells in which NOD1 was silenced, since blockade of dectin-1 reversed the augmented killing in these cells. Collectively, our data demonstrate that NOD1 receptor plays an inhibitory role in the host defense against . This provides a rationale to develop novel immunotherapeutic strategies for treatment of aspergillosis that target the NOD1 receptor, to enhance the efficiency of host immune cells to clear the infection by increasing fungal killing and cytokine responses.
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http://dx.doi.org/10.3389/fimmu.2017.01777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733348PMC
December 2017

Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation.

Immunity 2017 02;46(2):261-272

Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France. Electronic address:

Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease.
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http://dx.doi.org/10.1016/j.immuni.2017.01.006DOI Listing
February 2017

Local Microenvironment Controls the Compartmentalization of NK Cell Responses during Systemic Inflammation in Mice.

J Immunol 2016 09 12;197(6):2444-54. Epub 2016 Aug 12.

Unité Cytokines & Inflammation, Département Infection et Epidémiologie, Institut Pasteur, 75015 Paris, France; and

Systemic inflammatory response syndrome is a whole-body reaction to a triggering insult that often results in life-threatening illness. Contributing to the development of this inflammatory cascade are numerous cellular partners, among which NK cells were shown to play a key role. Accumulating evidence points to organ-specific properties of systemic inflammation and NK cells. However, little is known about compartment-specific activation of NK cells during systemic inflammatory response syndrome or the relative contribution of NK cell-intrinsic properties and microenvironmental cues. In this study, we undertook a sequential characterization of NK responses in the spleen, lungs, bone marrow, peritoneum, and blood using a mouse model of endotoxemia. We report that, despite similar systemic dynamics of NK cell responses, expression of activation markers (CD69 and CD25) and effector molecules (IFN-γ, granzyme B, and IL-10) display organ-specific thresholds of maximum activation. Using adoptive transfers of spleen and lung NK cells, we found that these cells have the capacity to quickly adapt to a new environment and adjust their response levels to that of resident NK cells. This functional adaptation occurs without significant alterations in phenotype and independently of subpopulation-specific trafficking. Thus, using a dynamic in vivo-transfer system, to our knowledge our study is the first to report the compartmentalization of NK cells responses during systemic inflammation and to show that NK cell-intrinsic properties and microenvironmental cues are involved in this process, in a sequential manner.
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http://dx.doi.org/10.4049/jimmunol.1601040DOI Listing
September 2016

Reducing hypoxia and inflammation during invasive pulmonary aspergillosis by targeting the Interleukin-1 receptor.

Sci Rep 2016 05 24;6:26490. Epub 2016 May 24.

Unité de recherche Cytokines &Inflammation, Institut Pasteur, Paris.

Hypoxia as a result of pulmonary tissue damage due to unresolved inflammation during invasive pulmonary aspergillosis (IPA) is associated with a poor outcome. Aspergillus fumigatus can exploit the hypoxic microenvironment in the lung, but the inflammatory response required for fungal clearance can become severely disregulated as a result of hypoxia. Since severe inflammation can be detrimental to the host, we investigated whether targeting the interleukin IL-1 pathway could reduce inflammation and tissue hypoxia, improving the outcome of IPA. The interplay between hypoxia and inflammation was investigated by in vivo imaging of hypoxia and measurement of cytokines in the lungs in a model of corticosteroid immunocompromised and in Cxcr2 deficient mice. Severe hypoxia was observed following Aspergillus infection in both models and correlated with development of pulmonary inflammation and expression of hypoxia specific transcripts. Treatment with IL-1 receptor antagonist reduced hypoxia and slightly, but significantly reduced mortality in immunosuppressed mice, but was unable to reduce hypoxia in Cxcr2(-/-) mice. Our data provides evidence that the inflammatory response during invasive pulmonary aspergillosis, and in particular the IL-1 axis, drives the development of hypoxia. Targeting the inflammatory IL-1 response could be used as a potential immunomodulatory therapy to improve the outcome of aspergillosis.
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http://dx.doi.org/10.1038/srep26490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877709PMC
May 2016

Cathepsin B-Deficient Mice Resolve Leishmania major Inflammation Faster in a T Cell-Dependent Manner.

PLoS Negl Trop Dis 2016 05 16;10(5):e0004716. Epub 2016 May 16.

Institut Pasteur, Département Infection et Epidémiologie, Unité Cytokines & Inflammation, Paris, France.

A critical role for intracellular TLR9 has been described in recognition and host resistance to Leishmania parasites. As TLR9 requires endolysosomal proteolytic cleavage to achieve signaling functionality, we investigated the contribution of different proteases like asparagine endopeptidase (AEP) or cysteine protease cathepsins B (CatB), L (CatL) and S (CatS) to host resistance during Leishmania major (L. major) infection in C57BL/6 (WT) mice and whether they would impact on TLR9 signaling. Unlike TLR9-/-, which are more susceptible to infection, AEP-/-, CatL-/- and CatS-/- mice are as resistant to L. major infection as WT mice, suggesting that these proteases are not individually involved in TLR9 processing. Interestingly, we observed that CatB-/- mice resolve L. major lesions significantly faster than WT mice, however we did not find evidence for an involvement of CatB on either TLR9-dependent or independent cytokine responses of dendritic cells and macrophages or in the innate immune response to L. major infection. We also found no difference in antigen presenting capacity. We observed a more precocious development of T helper 1 responses accompanied by a faster decline of inflammation, resulting in resolution of footpad inflammation, reduced IFNγ levels and decreased parasite burden. Adoptive transfer experiments into alymphoid RAG2-/-γc-/- mice allowed us to identify CD3+ T cells as responsible for the immune advantage of CatB-/- mice towards L. major. In vitro data confirmed the T cell intrinsic differences between CatB-/- mice and WT. Our study brings forth a yet unappreciated role for CatB in regulating T cell responses during L. major infection.
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http://dx.doi.org/10.1371/journal.pntd.0004716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868322PMC
May 2016

Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes.

Mol Med 2016 04 31;21(1):1002-1010. Epub 2016 Mar 31.

Department of Immunology, Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.

Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutralizing single proinflammatory mediators have failed to improve survival in sepsis and aseptic systemic inflammatory response syndromes. This failure could be explained by the widespread gene expression dysregulation known as "genomic storm" in these patients. A multifunctional polyspecific therapeutic agent might be needed to thwart the effects of this storm. Licensed pooled intravenous immunoglobulin preparations seemed to be a promising candidate, but they have also failed in their present form to prevent sepsis-related death. We report here the protective effect of a single dose of intravenous immunoglobulin preparations with additionally enhanced polyspecificity in three models of sepsis and aseptic systemic inflammation. The modification of the pooled immunoglobulin G molecules by exposure to ferrous ions resulted in their newly acquired ability to bind some proinflammatory molecules, complement components and endogenous "danger" signals. The improved survival in endotoxemia was associated with serum levels of proinflammatory cytokines, diminished complement consumption and normalization of the coagulation time. We suggest that intravenous immunoglobulin preparations with additionally enhanced polyspecificity have a clinical potential in sepsis and related systemic inflammatory syndromes.
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http://dx.doi.org/10.2119/molmed.2014.00224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982479PMC
April 2016

Bacterial translocation and plasma cytokines during transcatheter and open-heart aortic valve implantation.

Shock 2015 Jan;43(1):62-7

*Physiology Department, Cochin Academic Hospital, Paris Descartes University, Sorbonne Cite; †Cytokines & Inflammation Unit, Department of Infections and Epidemiology, Pasteur Institute; and ‡Cardiac Surgery Department, Paris Saint-Joseph Hospital, Paris Descartes University, Paris; §Cardiac Surgery Department, Marie-Lannelongue Hospital, Le Plessis-Robinson; and ∥Critical Care Unit, Melun General Hospital, Melun, France.

Objective: To determine whether the good safety profile of transarterial aortic valve implantation (TAVI) is related to lower levels of systemic bacterial translocation and systemic inflammation compared with open-heart surgery.

Background: Transcatheter aortic valve implantation via the transfemoral approach is increasingly used in very high-risk patients with aortic stenosis. The outcomes seem similar to those after open-heart aortic valve replacement (OHAVR).

Methods: Each of 26 consecutive high-risk patients (EuroSCORE >20% for risk of operative death) who underwent TAVI (cases) was matched to the first low-risk patient treated next in our department using elective OHAVR without coronary artery bypass (control subjects). We collected severity, outcome, and echocardiography indicators before and after surgery; complications; proinflammatory cytokine levels; and markers for microbial translocation.

Results: Despite greater illness severity, the TAVI patients had significantly lower vasopressor agent requirements, lower delirium rates, shorter hospital stays, and better hemodynamic findings compared with OHAVR patients. Vascular complications were more common after TAVI than after OHAVR (12, with seven requiring interventional therapy vs. 0, P = 0.006). Patients who underwent TAVI had lower blood transfusion requirements. Two TAVI patients died: one from iliac artery injury and the other from intracardiac prosthesis migration. Patients who underwent TAVI had lower plasma levels of endotoxin and bacterial peptidoglycan, as well as lower proinflammatory cytokine levels, suggesting less gastrointestinal bacterial translocation compared with OHAVR.

Conclusions: Compared with OHAVR, TAVI was associated with decreases in bacterial translocation and inflammation. These differences may explain the lower delirium rate and better hemodynamic stability observed, despite the greater disease severity in TAVI patients.
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http://dx.doi.org/10.1097/SHK.0000000000000262DOI Listing
January 2015

Low titers of serum antibodies inhibiting hemagglutination predict fatal fulminant influenza A(H1N1) 2009 infection.

Am J Respir Crit Care Med 2014 May;189(10):1240-9

1 Laboratory of Immunity and Infection, UPMC Univ Paris 06, UMR-S945, Paris, France.

Rationale: The biology of fatal pandemic influenza infection remains undefined.

Objectives: To characterize the virologic and immune parameters associated with severity or death in patients who required mechanical ventilation for A(H1N1) 2009 pneumonia of various degrees of severity during the two waves of the 2009-2011 pandemic in Paris, France.

Methods: This multicenter study included 34 unvaccinated patients with very severe or fatal confirmed influenza A(H1N1) infections. It analyzed plasma A(H1N1) 2009 reverse-transcriptase polymerase chain reaction, hemagglutinin 222G viral mutation, and humoral and cellular immune responses to the virus, assessed in hemagglutination inhibition (HI), microneutralization, ELISA, lymphoproliferative, ELISpot IFN-γ, and cytokine and chemokine assays.

Measurements And Main Results: The patients' median age was 35 years. Influenza A(H1N1) 2009 viremia was detected in 4 of 34 cases, and a 222G hemagglutinin mutation in 7 of 17 cases, all of them with sequential organ failure assessment greater than or equal to 8. HI antibodies were detectable in 19 of 26 survivors and undetectable in all six fatal fulminant cases. ELISA and microneutralization titers were concordant. B-cell immunophenotyping and plasma levels of immunoglobulin classes did not differ between patients who survived and died. After immune complex dissociation, influenza ELISA serology became strongly positive in the bronchoalveolar lavage of the two fatal cases tested. H1N1-specific T-cell responses in lymphoproliferative and IFN-γ assays were detectable in survivors' peripheral blood, and lymphoproliferative assays were negative in the three fatal cases tested. Plasma levels of IL-6 and IL-10 were high in fatal cases and correlated with severity. Finally, a negative HI serology 4 days after the onset of influenza symptoms predicted death from fulminant influenza (P = 0.04).

Conclusions: Early negative A(H1N1) 2009 HI serology can predict death from influenza. This negative serology in fatal cases in young adults reflects the trapping of anti-H1N1 antibodies in immune complexes in the lungs, associated with poor specific helper T-cell response. Clinical trial registered with www.clinicaltrials.gov (NCT 01089400).
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http://dx.doi.org/10.1164/rccm.201311-2071OCDOI Listing
May 2014

Protective or deleterious role of scavenger receptors SR-A and CD36 on host resistance to Staphylococcus aureus depends on the site of infection.

PLoS One 2014 31;9(1):e87927. Epub 2014 Jan 31.

Institut Pasteur, Cytokines & Inflammation, Département Infection et Epidemiologie, Paris, France.

Staphylococcus aureus is a major human opportunistic pathogen responsible for a broad spectrum of infections ranging from benign skin infection to more severe life threatening disorders (e.g. pneumonia, sepsis), particularly in intensive care patients. Scavenger receptors (SR-A and CD36) are known to be involved in S. aureus recognition by immune cells in addition to MARCO, TLR2, NOD2 and α5β1 integrin. In the present study, we further deciphered the contribution of SR-A and CD36 scavenger receptors in the control of infection of mice by S. aureus. Using double SR-A/CD36 knockout mice (S/C-KO) and S. aureus strain HG001, a clinically relevant non-mutagenized strain, we showed that the absence of these two scavenger receptors was protective in peritoneal infection. In contrast, the deletion of these two receptors was detrimental in pulmonary infection following intranasal instillation. For pulmonary infection, susceptible mice (S/C-KO) had more colony-forming units (CFU) in their broncho-alveolar lavages fluids, associated with increased recruitment of macrophages and neutrophils. For peritoneal infection, susceptible mice (wild-type) had more CFU in their blood, but recruited less macrophages and neutrophils in the peritoneal cavity than resistant mice. Exacerbated cytokine levels were often observed in the susceptible mice in the infected compartment as well as in the plasma. The exception was the enhanced compartmentalized expression of IL-1β for the resistant mice (S/C-KO) after peritoneal infection. A similar mirrored susceptibility to S. aureus infection was also observed for MARCO and TLR2. Marco and tlr2 -/- mice were more resistant to peritoneal infection but more susceptible to pulmonary infection than wild type mice. In conclusion, our results show that innate immune receptors can play distinct and opposite roles depending on the site of infection. Their presence is protective for local pulmonary infection, whereas it becomes detrimental in the peritoneal infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087927PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909292PMC
October 2014

Lung microenvironment contributes to the resistance of alveolar macrophages to develop tolerance to endotoxin*.

Crit Care Med 2012 Nov;40(11):2987-96

Department of Infection and Epidemiology, Unit Cytokines & Inflammation, Institut Pasteur, Paris, France.

Objective: Endotoxin tolerance corresponds to reprogramming of mononuclear phagocytes after iterative encounters with toll-like receptor agonists aimed to dampen the inflammatory response. We investigated why this phenomenon cannot be observed with murine alveolar macrophages.

Design: Animal study.

Setting: Research institution laboratory.

Subjects: rag2-/-, rag2γc-/-, cd3ε-/-, µ-/-, il-15-/-, Jα18-/-, ifnγr-/-, il-18r-/-, and wild-type mice.

Interventions: Alveolar macrophages were harvested from untreated mice or after injection of endotoxin. Alveolar macrophages were activated in vitro with endotoxin (lipopolysaccharide), and tumor necrosis factor production was monitored.

Measurements And Main Results: In contrast to monocytes or peritoneal macrophages, alveolar macrophages did not display endotoxin tolerance in an ex vivo model after injection of endotoxin. An in vivo systemic inhibition of granulocyte-macrophage colony-stimulating factor or interferon-γ allowed the induction of alveolar macrophage endotoxin tolerance, which was also observed in interferon-γ receptor-deficient mice. Using mice missing different leukocyte subsets and adoptive cell transfers, we demonstrated the involvement of B lymphocytes in interferon-γ production within the lung microenvironment and in the prevention of alveolar macrophage endotoxin tolerance. Furthermore, we demonstrated the importance of interleukin-18 in preventing alveolar macrophage endotoxin tolerance through studies of interleukin-18 messenger RNA expression in il-18r-/- mice and injection of interleukin-18 in rag2-/- and µ-/- mice.

Conclusions: Our results support the conclusion that at homeostasis in the lungs, constitutive expression of granulocyte-macrophage colony-stimulating factor, interleukin-18, interferon-γ and possibly interleukin-15, and a cross-talk between B lymphocytes and alveolar macrophages create a microenvironment specific to the lungs that prevents alveolar macrophages from becoming tolerant to endotoxin.
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http://dx.doi.org/10.1097/CCM.0b013e31825b8d57DOI Listing
November 2012

The WalKR system controls major staphylococcal virulence genes and is involved in triggering the host inflammatory response.

Infect Immun 2012 Oct 23;80(10):3438-53. Epub 2012 Jul 23.

Institut Pasteur, Biology of Gram-Positive Pathogens, Department of Microbiology, Paris, France.

The WalKR two-component system is essential for the viability of Staphylococcus aureus, playing a central role in controlling cell wall metabolism. We produced a constitutively active form of WalR in S. aureus through a phosphomimetic amino acid replacement (WalR(c), D55E). The strain displayed significantly increased biofilm formation and alpha-hemolytic activity. Transcriptome analysis was used to determine the full extent of the WalKR regulon, revealing positive regulation of major virulence genes involved in host matrix interactions (efb, emp, fnbA, and fnbB), cytolysis (hlgACB, hla, and hlb), and innate immune defense evasion (scn, chp, and sbi), through activation of the SaeSR two-component system. The impact on pathogenesis of varying cell envelope dynamics was studied using a murine infection model, showing that strains producing constitutively active WalR(c) are strongly diminished in their virulence due to early triggering of the host inflammatory response associated with higher levels of released peptidoglycan fragments. Indeed, neutrophil recruitment and proinflammatory cytokine production were significantly increased when the constitutively active walR(c) allele was expressed, leading to enhanced bacterial clearance. Taken together, our results indicate that WalKR play an important role in virulence and eliciting the host inflammatory response by controlling autolytic activity.
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http://dx.doi.org/10.1128/IAI.00195-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3457574PMC
October 2012

DNAemia detection by multiplex PCR and biomarkers for infection in systemic inflammatory response syndrome patients.

PLoS One 2012 15;7(6):e38916. Epub 2012 Jun 15.

Unit Cytokines & Inflammation, Department of Infection and Epidemiology, Institut Pasteur, Paris, France.

Fast and reliable assays to precisely define the nature of the infectious agents causing sepsis are eagerly anticipated. New molecular biology techniques are now available to define the presence of bacterial or fungal DNA within the bloodstream of sepsis patients. We have used a new technique (VYOO®) that allows the enrichment of microbial DNA before a multiplex polymerase chain reaction (PCR) for pathogen detection provided by SIRS-Lab (Jena, Germany). We analyzed 72 sepsis patients and 14 non-infectious systemic inflammatory response syndrome (SIRS) patients. Among the sepsis patients, 20 had a positive blood culture and 35 had a positive microbiology in other biological samples. Of these, 51.4% were positive using the VYOO® test. Among the sepsis patients with a negative microbiology and the non-infectious SIRS, 29.4% and 14.2% were positive with the VYOO® test, respectively. The concordance in bacterial identification between microbiology and the VYOO® test was 46.2%. This study demonstrates that these new technologies offer great hopes, but improvements are still needed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038916PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376137PMC
December 2012

NK cell tolerance to TLR agonists mediated by regulatory T cells after polymicrobial sepsis.

J Immunol 2012 Jun 7;188(12):5850-8. Epub 2012 May 7.

Institut Pasteur, Unité Cytokines et Inflammation, Département Infection et Epidémiologie, F-75015 Paris, France.

As sensors of infection, innate immune cells are able to recognize pathogen-associated molecular patterns by receptors such as TLRs. NK cells present in many tissues contribute to inflammatory processes, particularly through the production of IFN-γ. They may display a protective role during infection but also a detrimental role during sterile or infectious systemic inflammatory response syndrome. Nevertheless, the exact status of NK cells during bacterial sepsis and their capacity directly to respond to TLR agonists remain unclear. The expression of TLRs in NK cells has been widely studied by analyzing the mRNA of these receptors. The aim of this study was to gain insight into TLR2/TLR4/TLR9 expression on/in murine NK cells at the protein level and determine if their agonists were able to induce cytokine production. We show, by flow cytometry, a strong intracellular expression of TLR2 and a low of TLR4 in freshly isolated murine spleen NK cells, similar to that of TLR9. In vitro, purified NK cells respond to TLR2, TLR4, and TLR9 agonists, in synergy with activating cytokines (IL-2, IL-15, and/or IL-18), and produce proinflammatory cytokines (IFN-γ and GM-CSF). Finally, we explored the possible tolerance of NK cells to TLR agonists after a polymicrobial sepsis (experimental peritonitis). For the first time, to our knowledge, NK cells are shown to become tolerant in terms of proinflammatory cytokines production after sepsis. We show that this tolerance is associated with a reduction of the CD27(+)CD11b(-) subset in the spleen related to the presence of regulatory T cells and mainly mediated by TGF-β.
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http://dx.doi.org/10.4049/jimmunol.1103616DOI Listing
June 2012

Combined loss of cRel/p50 subunits of NF-κB leads to impaired innate host response in sepsis.

Innate Immun 2012 Oct 9;18(5):753-63. Epub 2012 Mar 9.

CNRS, UMR 8104, INSERM, U1016, Institut Cochin, Paris, France.

NF-κB, which comprises homo- and hetero-dimers of the five members of the Rel family, plays a crucial role in immunity to infection. The cRel and p50 subunits have been implicated in the development and function of the immune cells, but their in vivo importance remains poorly explored in sepsis. We aimed to study the impact of the combined loss of these two subunits on the innate response to infection in a cecal ligation and puncture model of sepsis. We have explored the possible defects in host defense, including pathogen clearance, bacterial phagocytosis and cytokine plasma release. We also performed gene profiling of cRel(-/-)p50(-/-) and wild-type LPS-stimulated peritoneal macrophages. Deficiency of cRel and p50 led to enhanced mortality to sepsis that was associated with defective macrophages phagocytosis, decreased bacterial clearance and moderate cytokine response. Transcription profile analysis revealed a common inflammatory response but a significant down-regulated transcription of genes encoding for pathogen recognition receptors and antimicrobial molecules, supporting the in vivo findings in mice. In conclusion, the cRel and p50 subunits of NF-κB play an important combined role in the innate response and are crucial for survival and pathogen clearance in polymicrobial sepsis.
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http://dx.doi.org/10.1177/1753425912440296DOI Listing
October 2012

Early systemic bacterial dissemination and a rapid innate immune response characterize genetic resistance to plague of SEG mice.

J Infect Dis 2012 Jan 16;205(1):134-43. Epub 2011 Nov 16.

Yersinia Research Unit, Institut Pasteur, Paris, France.

Background: Although laboratory mice are usually highly susceptible to Yersinia pestis, we recently identified a mouse strain (SEG) that exhibited an exceptional capacity to resist bubonic plague and used it to identify immune mechanisms associated with resistance.

Methods: The kinetics of infection, circulating blood cells, granulopoiesis, lesions, and cellular populations in the spleen, and cytokine production in various tissues were compared in SEG and susceptible C57BL/6J mice after subcutaneous infection with the virulent Y. pestis CO92.

Results: Bacterial invasion occurred early (day 2) but was transient in SEG/Pas mice, whereas in C57BL/6J mice it was delayed but continuous until death. The bacterial load in all organs significantly correlated with the production of 5 cytokines (granulocyte colony-stimulating factor, keratinocyte-derived chemokine (KC), macrophage cationic peptide-1 (MCP-1), interleukin 1α, and interleukin 6) involved in monocyte and neutrophil recruitment. Indeed, higher proportions of these 2 cell types in blood and massive recruitment of F4/80(+)CD11b(-) macrophages in the spleen were observed in SEG/Pas mice at an early time point (day 2). Later times after infection (day 4) were characterized in C57BL/6J mice by destructive lesions of the spleen and impaired granulopoiesis.

Conclusion: A fast and efficient Y. pestis dissemination in SEG mice may be critical for the triggering of an early and effective innate immune response necessary for surviving plague.
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http://dx.doi.org/10.1093/infdis/jir696DOI Listing
January 2012

Mycobacterium bovis Bacillus Calmette-Guérin killed by extended freeze-drying reduces colitis in mice.

Gastroenterology 2011 Aug 14;141(2):642-52, 652.e1-4. Epub 2011 May 14.

Institut Pasteur, Laboratoire d'Immunothérapie, Paris, France.

Background & Aims: Mycobacterium bovis Bacillus Calmette-Guérin (BCG), killed by extended freeze-drying (EFD), induces secretion of interleukin-10 and reduces lung inflammation in a mouse model of asthma. We investigated the effects of EFD BCG in mouse models of inflammatory bowel disease.

Methods: EFD BCG was administered subcutaneously to mice with colitis induced by dextran sodium sulfate (DSS), oxazolone, or adoptive transfer of CD4(+)CD45RB(high)Foxp3(-) T cells from C57Bl/6 Foxp3GFP mice to RAG2(-/-) mice.

Results: EFD BCG, administered either before induction of DSS and oxazolone colitis or after development of acute or chronic DSS-induced colitis, reduced symptom scores, loss of body weight, and inflammation. Although transfer of CD4(+)CD45RB(high)Foxp3(-) cells induced colitis in RAG2(-/-) mice, administration of EFD BCG at the time of the transfer converted Foxp3(-) T cells to Foxp3(+) T cells and the mice did not develop colitis. EFD BCG protected mice from colitis via a mechanism that required expansion of T regulatory cells and production of interleukin-10 and transforming growth factor β. EFD BCG activated the retinoid X receptor (RXR)-α-peroxisome proliferator-activated receptor (PPAR)-γ heterodimer, blocked translocation of nuclear factor κB to the nucleus, and reduced colonic inflammation; it did not increase the number of colon tumors that formed in mice with chronic DSS-induced colitis.

Conclusions: EFD BCG controls severe colitis in mice by expanding T regulatory cell populations and PPAR-γ and might be developed to treat patients with inflammatory bowel disease.
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http://dx.doi.org/10.1053/j.gastro.2011.05.002DOI Listing
August 2011

Placental malaria-associated suppression of parasite-specific immune response in neonates has no major impact on systemic CD4 T cell homeostasis.

Infect Immun 2011 Jul 25;79(7):2801-9. Epub 2011 Apr 25.

Faculté de Pharmacie, Institut de Recherche pour le Développement UMR216 Santé de la Mère et l'Enfant en Milieu Tropical, Université Paris Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France.

In areas where Plasmodium falciparum is endemic, pregnancy is associated with accumulation of infected red blood cells (RBCs) in the placenta, a condition referred to as placental malaria (PM). Infants born to PM-positive mothers are at an increased risk of malaria, which is putatively related to the transplacental passage of parasite-derived antigens, with consequent tolerization of the fetal immune system. Here we addressed the impact of PM on the regulation of neonatal T cell responses. We found that the frequency of regulatory CD25(+) CD127(-/low) Foxp3(+) CD4(+) T cells was significantly decreased in neonates born to mothers with high levels of P. falciparum-induced placental inflammation, consisting mainly of primigravid mothers. However, at the individual level, the ratio between regulatory and effector (CD25(+) CD127(+) Foxp3(-)) CD4(+) T cells was unaffected by PM. In addition, parasite-induced CD4(+) T cell activation and production of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-10 were strongly reduced in neonates born to PM-positive mothers. Thus, our results show that active PM at delivery is associated with a marked suppression of P. falciparum-specific cellular neonatal immune responses, affecting secretion of both pro- and anti-inflammatory cytokines. Additionally, our results suggest that, as in adults, effector and regulatory CD4(+) T cell populations are tightly coregulated in all neonates, irrespective of the maternal infection status.
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http://dx.doi.org/10.1128/IAI.00203-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191961PMC
July 2011

Critical role of cRel subunit of NF-κB in sepsis survival.

Infect Immun 2011 May 22;79(5):1848-54. Epub 2011 Feb 22.

Département de Biologie Cellulaire des Interactions Hôte-Pathogène, Institut Cochin, Paris, France.

NF-κB is a critical regulator of gene expression during severe infections. NF-κB comprises homo- and heterodimers of proteins from the Rel family. Among them, p50 and p65 have been clearly implicated in the pathophysiology of sepsis. In contrast, the role of cRel in sepsis is still controversial and has been poorly studied in single-pathogen infections. We aimed to investigate the consequences of cRel deficiency in a cecal ligation and puncture (CLP) model of sepsis. We have approached the underlying mechanisms of host defense by analyzing bacterial clearance, systemic inflammation, and the distribution of spleen dendritic cell subsets. Moreover, by using a genome-wide technology, we have also analyzed the CLP-induced modifications in gene expression profiles both in wild-type (wt) and in rel(-/-) mice. The absence of cRel enhances mortality due to polymicrobial sepsis. Despite normal pathogen clearance, cRel deficiency leads to an altered systemic inflammatory response associated with a sustained loss of the spleen lymphoid dendritic cells. Furthermore, a whole-blood microarray study reveals that the differential outcome between wt and rel(-/-) mice during sepsis is preceded by remarkable changes in the expression of hundreds of genes involved in aspects of host-pathogen interaction, such as host survival and lipid metabolism. In conclusion, cRel is a key NF-κB member required for host antimicrobial defenses and a regulatory transcription subunit that controls the inflammatory and immune responses in severe infection.
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http://dx.doi.org/10.1128/IAI.00021-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088128PMC
May 2011

Mechanisms of TNF induction by heat-killed Staphylococcus aureus differ upon the origin of mononuclear phagocytes.

Am J Physiol Cell Physiol 2011 Apr 5;300(4):C850-9. Epub 2011 Jan 5.

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

Mononuclear phagocytes are among the first immune cells activated after pathogens invasion. Although they all derive from the same progenitor in the bone marrow, their characteristics differ on the compartment from which they are derived. In this work, we investigated the contribution of phagocytosis for tumor necrosis factor (TNF) production by murine mononuclear phagocytes (monocytes, peritoneal and alveolar macrophages) in response to heat-killed Staphylococcus aureus (HKSA). Mononuclear phagocytes behaved differently, depending on their compartment of residence. Indeed, when bacterial uptake or phagosome maturation was blocked, activation through membrane receptors was sufficient for a maximal production of TNF and interleukin-10 by peritoneal macrophages. In contrast, monocytes, and to a lesser extent alveolar macrophages, required phagocytosis for optimal cytokine production. While investigating the different actors of signalization, we found that p38 kinase and phosphatidylinositol 3-kinase were playing an important role in HKSA phagocytosis and TNF production. Furthermore, blocking the α(5)β(1)-integrin significantly decreased TNF production in response to HKSA in all three cell types. Finally, using mononuclear phagocytes from NOD2 knockout mice, we observed that TNF production in response to HKSA was dependent on NOD2 for monocytes and peritoneal macrophages. In conclusion, we demonstrate that the mechanisms of activation leading to TNF production in response to HKSA are specific for each mononuclear phagocyte population and involve different recognition processes and signaling pathways. The influence of the compartments on cell properties and behavior should be taken into account, to better understand cell physiology and host-pathogen interaction, and to define efficient strategies to fight infection.
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http://dx.doi.org/10.1152/ajpcell.00187.2010DOI Listing
April 2011

Contribution of NOD2 to lung inflammation during Staphylococcus aureus-induced pneumonia.

Microbes Infect 2010 Sep 21;12(10):759-67. Epub 2010 May 21.

Institut Pasteur, Unité Cytokines & Inflammation, Département Infection et épidémiologie, 28 rue du Dr Roux, F-75015 Paris, France.

Staphylococcus aureus is the most commonly found Gram-positive bacterium in patients admitted in intensive-care units, causing septicaemia or pneumonia. In this work, we investigated the role of NOD2 in S. aureus-induced pneumonia. We found that the absence of NOD2 affected weight loss and recovery speed. Nod2-/- mice showed a reduced lung inflammation in comparison to wild-type animals, with lower presence of cytokines in broncho-alveolar lavage fluids and reduced recruitment of neutrophils. Furthermore, histological analysis of the lungs revealed less severe lesions in Nod2-/- mice at day 2 and day 7 post-infection. In conclusion, we demonstrated that NOD2 is not a crucial receptor to fight S. aureus-induced pneumonia, but that it contributes to the inflammatory response in the lungs. Interestingly, the absence of NOD2 led to a lesser inflammation and was finally beneficial for the animal recovery.
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http://dx.doi.org/10.1016/j.micinf.2010.05.003DOI Listing
September 2010

Resilience to bacterial infection: difference between species could be due to proteins in serum.

J Infect Dis 2010 Jan;201(2):223-32

Infectious Disease Unit, Institut Pasteur, Paris, France.

Vertebrates vary in resistance and resilience to infectious diseases, and the mechanisms that regulate the trade-off between these often opposing protective processes are not well understood. Variability in the sensitivity of species to the induction of damaging inflammation in response to equivalent pathogen loads (resilience) complicates the use of animal models that reflect human disease. We found that induction of proinflammatory cytokines from macrophages in response to inflammatory stimuli in vitro is regulated by proteins in the sera of species in inverse proportion to their in vivo resilience to lethal doses of bacterial lipopolysaccharide over a range of 10,000-fold. This finding suggests that proteins in serum rather than intrinsic cellular differences may play a role in regulating variations in resilience to microbe-associated molecular patterns between species. The involvement of circulating proteins as key molecules raises hope that the process might be manipulated to create better animal models and potentially new drug targets.
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http://dx.doi.org/10.1086/649557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798011PMC
January 2010

Biofilm-forming Pseudomonas aeruginosa bacteria undergo lipopolysaccharide structural modifications and induce enhanced inflammatory cytokine response in human monocytes.

Innate Immun 2010 Oct 26;16(5):288-301. Epub 2009 Aug 26.

Unité Cytokines & Inflammation, Institut Pasteur, Paris, France.

To determine whether growth of bacteria in biofilms triggers a specific immune response, we compared cytokine induction in human monocytes and mouse macrophages by planktonic and biofilm bacteria. We compared Pseudomonas aeruginosa and Staphylococcus aureus, two bacteria often colonizing the airways of cystic fibrosis patients. Planktonic and biofilm S. aureus induced equivalent amounts of cytokine in human monocytes. In contrast, biofilm-forming P. aeruginosa induced a higher production of tumor necrosis factor and interleukin-6 than their planktonic counterpart, both for clinical isolates and laboratory strains. This increased cytokine production was partly dependent on phagocytosis. In contrast, no difference in cytokine induction was observed with mouse macrophages. We investigated the structures of the lipopolysaccharides (LPSs) of these Gram-negative bacteria in biofilm and planktonic cultures of P. aeruginosa. Switch between the two life-styles was shown to cause several reversible LPS structure modifications affecting the lipid A and polysaccharide moieties of both clinical isolates and laboratory strains. In addition, LPS isolated from biofilm-grown bacteria induced slightly more inflammatory cytokines than that extracted from its planktonic counterpart. Our results, therefore, show that P. aeruginosa biofilm LPS undergoes structural modifications that only partially contribute to an increased inflammatory response from human monocytes.
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http://dx.doi.org/10.1177/1753425909341807DOI Listing
October 2010

Wild-derived mouse strains, a valuable model to study B cell responses.

Mol Immunol 2009 Feb 31;46(4):601-12. Epub 2008 Oct 31.

Unité de Biologie des Populations Lymphocytaires, Institut Pasteur, Dept. Immunologie, CNRS: URA 1961, Paris 75724 Cedex 15, France.

In the present report, we revisited the B cell responsiveness of 7 wild-derived mouse strains to various toll-like receptor ligands (TLR-L). We found that 2 of them, namely PWK and STF presented profound defects in B cell proliferative responses to most of the TLR-L. Yet, their macrophage responses were largely unaffected, suggesting that regulation of TLR pathways are distinct in B cells and macrophages. We also showed that, anti-CD40 mAbs rescued the low proliferative responses to CpG in both PWK and STF B cells. In the other hand, CpG synergized with LPS to induce high levels of proliferation in STF B cells, which did not respond to LPS alone. Cytokine or immunoglobulin (Ig) productions, in vitro, were less impaired than the proliferative responses to LPS or CpG alone. In STF B cells, both ERK, P38 and JNK pathways were affected following in vitro TLR4 or TLR9 signaling. Moreover, while the basal levels of Ig secreting cells and of serum Igs were similar to that of control mice, antibody responses to both TI and TD antigens were severely affected, mainly in STF mice. Our findings therefore highlight the relevance of wild-derived mouse strains and TLR-L to study B cell physiology.
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http://dx.doi.org/10.1016/j.molimm.2008.07.027DOI Listing
February 2009