Expérimentation animale: la recette d'une polémique scientifique
Opinion, La Libre, 20 aout 2018
Diversity Generator Mechanisms Are Essential Components of Biological Systems: The Two Queen Hypothesis
Diversity is widely known to fuel adaptation and evolutionary processes and increase robustness at the population, species and ecosystem levels. The Neo-Darwinian paradigm proposes that the diversity of biological entities is the consequence of genetic changes arising spontaneously and randomly, without regard for their usefulness. However, a growing body of evidence demonstrates that the evolutionary process has shaped mechanisms, such as horizontal gene transfer mechanisms, meiosis and the adaptive immune system, which has resulted in the regulated generation of diversity among populations. Though their origins are unrelated, these diversity generator (DG) mechanisms share common functional properties. They (i) contribute to the great unpredictability of the composition and/or behavior of biological systems, (ii) favor robustness and collectivism among populations and (iii) operate mainly by manipulating the systems that control the interaction of living beings with their environment. The definition proposed here for DGs is based on these properties and can be used to identify them according to function. Interestingly, prokaryotic DGs appear to be mainly reactive, as they generate diversity in response to environmental stress. They are involved in the widely described Red Queen/arms race/Cairnsian dynamic. The emergence of multicellular organisms harboring K selection traits (longer reproductive life cycle and smaller population size) has led to the acquisition of a new class of DGs that act anticipatively to stress pressures and generate a distinct dynamic called the "White Queen" here. The existence of DGs leads to the view of evolution as a more "intelligent" and Lamarckian-like process. Their repeated selection during evolution could be a neglected example of convergent evolution and suggests that some parts of the evolutionary process are tightly constrained by ecological factors, such as the population size, the generation time and the intensity of selective pressure. The ubiquity of DGs also suggests that regulated auto-generation of diversity is a fundamental property of life. Frontiers in Microbiology. 2018
STAT6 Mediates Footpad Immunopathology in the Absence of IL-12p40 Following Infection of Susceptible BALB/c Mice With Leishmania major
Frontiers in Immunology, 2018
L'expérimentation animale ne se fait pas en dehors de tout contrôle
Opinion. La Libre. 11 avril 2018.
Le code Wallon du bien être animal facteur de délocalisation
Opinion. La Libre. 29 mars 2018
La souris, le patient, et le faux expert. Décryptage d'une mystification.
Opinion. Le Vif. 27 avril 2018.
L'expérimentation animale en question
Exposé "L'expérimentation animale en question", Académie Royale de Médecine de Belgique, le 8 mai 2018.
Antispécisme et véganisme constituent-ils des projets de sociétés réalistes ?
The conversation. 5 juillet 2018
Sale temps pour la science
Sale temps pour la science. Jouant sur l’émotion et des pseudo-controverses scientifiques, des associations prétendent à l’inutilité de l’usage d’animaux dans la recherche scientifique. Une campagne de dénigrement qui en rappelle d’autres. Opinion. La Libre. 1 aout 2018
Allergic Asthma Favors Brucella Growth in the Lungs of Infected Mice
Allergic asthma is a chronic Th2 inflammatory disease of the lower airways affecting a growing number of people worldwide. The impact of infections and microbiota composition on allergic asthma has been investigated frequently. Until now, however, there have been few attempts to investigate the impact of asthma on the control of infectious microorganisms and the underlying mechanisms. In this work, we characterize the consequences of allergic asthma on intranasal (i.n.) infection by Brucella bacteria in mice. We observed that i.n. sensitization with extracts of the house dust mite Dermatophagoides farinae or the mold Alternaria alternata (Alt) significantly increased the number of Brucella melitensis, Brucella suis, and Brucella abortus in the lungs of infected mice. Microscopic analysis showed dense aggregates of infected cells composed mainly of alveolar macrophages (CD11c+ F4/80+ MHCII+) surrounded by neutrophils (Ly-6G+). Asthma-induced Brucella susceptibility appears to be dependent on CD4+ T cells, the IL-4/STAT6 signaling pathway and IL-10, and is maintained in IL-12- and IFN-γR-deficient mice. The effects of the Alt sensitization protocol were also tested on Streptococcus pneumoniae and Mycobacterium tuberculosis pulmonary infections. Surprisingly, we observed that Alt sensitization strongly increases the survival of S. pneumoniae infected mice by a T cell and STAT6 independent signaling pathway. In contrast, the course of M. tuberculosis infection is not affected in the lungs of sensitized mice. Our work demonstrates that the impact of the same allergic sensitization protocol can be neutral, negative, or positive with regard to the resistance of mice to bacterial infection, depending on the bacterial species. Frontiers in Imunology. 2018
Investigation of inflammatory and allergic responses to common mold species: Results from in vitro experiments, from a mouse model of asthma, and from a group of asthmatic patients
Indoor Air. 2017, doi: 10.1111/ina.12385
L’expérimentation animale en question
De nombreuses associations militant en faveur des droits des animaux présentent l'expérimentation animale comme une pratique moralement inacceptable, inutile et en conséquence, à proscrire. De manière surprenante, ce message trouve un écho grandissant dans la population et chez les représentants politiques. Il est pourtant aisé de démontrer que l'expérimentation animale est une étape essentielle et incontournable de la recherche fondamentale en biologie et médecine et qu'elle constitue une importante source d'innovation en santé humaine et animale. S'en priver reviendrait à amputer les sciences du vivant d'un de leurs principaux outil d'investigation. Néanmoins, le refus de l'expérimentation animale est en passe de devenir chez un nombre croissant d'individus un "marqueur identitaire", au même titre que le refus des organismes génétiquement modifiés ou de la vaccination. Cette polarisation empêche toute réflexion critique et débat rationnel sur le sujet, laissant le champ libre à la désinformation. Cet article vise à informer sur les origines historiques de l'expérimentation animale, son importance en recherche fondamentale, ses apports scientifiques et sociétaux ainsi que son encadrement légal, en vue de donner aux citoyens la possibilité de se faire un avis rationnel sur un enjeu de société majeur. Revue des Questions Scientifiques, 2017, 188 (2) : 129-156
Erythritol Availability in Bovine, Murine and Human Models Highlights a Potential Role for the Host Aldose Reductase during Brucella Infection
Front Microbiol. 2017;8:1088.
Trypanosoma Infection Favors Brucella Elimination via IL-12/IFNγ-Dependent Pathways
This study develops an original co-infection model in mice using Brucella melitensis, the most frequent cause of human brucellosis, and Trypanosoma brucei, the agent of African trypanosomiasis. Although the immunosuppressive effects of T. brucei in natural hosts and mice models are well established, we observed that the injection of T. brucei in mice chronically infected with B. melitensis induces a drastic reduction in the number of B. melitensis in the spleen, the main reservoir of the infection. Similar results are obtained with Brucella abortus- and Brucella suis-infected mice and B. melitensis-infected mice co-infected with Trypanosoma cruzi, demonstrating that this phenomenon is not due to antigenic cross-reactivity. Comparison of co-infected wild-type and genetically deficient mice showed that Brucella elimination required functional IL-12p35/IFNγ signaling pathways and the presence of CD4+ T cells. However, the impact of wild type and an attenuated mutant of T. brucei on B. melitensis were similar, suggesting that a chronic intense inflammatory reaction is not required to eliminate B. melitensis. Finally, we also tested the impact of T. brucei infection on the course of Mycobacterium tuberculosis infection. Although T. brucei strongly increases the frequency of IFNγ+CD4+ T cells, it does not ameliorate the control of M. tuberculosis infection, suggesting that it is not controlled by the same effector mechanisms as Brucella. Thus, whereas T. brucei infections are commonly viewed as immunosuppressive and pathogenic, our data suggest that these parasites can specifically affect the immune control of Brucella infection, with benefits for the host. Front. Immunol., 31 July 2017
The nonspecific face of adaptive immunity
Memory T cells generated by infection or immunization persist in the organism and mediate specific protection upon rechallenge with microbial pathogens expressing the same molecular structures. However, multiple lines of evidence indicate that previously encountered or persisting pathogens influence the immune response to unrelated pathogens. We describe the acquisition of non-antigen specific memory features by both innate and adaptive immune cells explaining these phenomena. We also focus on the different mechanisms (homeostatic or inflammatory cytokine-driven) that lead to acquisition of memory phenotype and functions by antigen-inexperienced T lymphocytes. We discuss the implications of these new concepts for host defense, auto-immunity and vaccination strategies. Curr Opin Immunol. 2017;48:38-43.
La gestion de la coopération au sein des systèmes biologiques
Bien que les relations symbiotiques de type coopératives soient ubiquitaires dans la nature et leur intérêt pour la survie des entités biologiques bien établi, la manière dont celles-ci ont été sélectionnées au cours de l'évolution trouble et divise les théoriciens de l'évolution depuis des décennies. Une association coopérative entre individus d'une même espèce ou d'espèces différentes, nous parlerons de consortium, génère des biens communs, par exemple des nutriments ou des mécanismes de protections. Un partenaire égoïste peut, en accaparant sans contrepartie ces biens, augmenter considérablement son avantage sélectif aux détriments des individus coopérateurs. Quand le nombre d'individus agissant de manière égoïste dépasse un point critique, la survie du consortium est menacée. Comment éviter cette "tragédie des communs"? Cet article propose une synthèse originale des principales théories expliquant la stabilisation des relations coopératives entre individus non apparentés au cours de l'évolution. Dans de nombreux systèmes biologiques, les gains provenant des processus coopératifs auraient favorisé au cours de l'évolution la sélection de mécanismes de contrôle social visant à la neutralisation ou à l’exclusion des partenaires égoïstes. Ces mécanismes seraient à l'origine de l'instauration de normes sociales au sein des systèmes biologiques. Les causes de la sélection des religions durant l'évolution humaine sont analysées dans ce cadre conceptuel. Revue des Questions Scientifiques, 2017, 188 (3) : 331-372
Chronic Brucella Infection Induces Selective and Persistent Interferon Gamma-Dependent Alterations of Marginal Zone Macrophages in the Spleen
The spleen is known as an important filter for blood-borne pathogens that are trapped by specialized macrophages in the marginal zone (MZ): the CD209+ MZ macrophages (MZMs) and the CD169+ marginal metallophilic macrophages (MMMs). Acute systemic infection strongly impacts MZ populations and the location of T and B lymphocytes. This phenomenon has been linked to reduced chemokine secretion by stromal cells. Brucella spp. are the causative agent of brucellosis, a widespread zoonotic disease. Here, we used Brucella melitensis infection as a model to investigate the impact of chronic stealth infection on splenic MZ macrophage populations. During the late phase of Brucella infection, we observed a loss of both MZMs and MMMs, with a durable disappearance of MZMs, leading to a reduction of the ability of the spleen to take up soluble antigens, beads, and unrelated bacteria. This effect appears to be selective as every other lymphoid and myeloid population analyzed increased during infection, which was also observed following Brucella abortus and Brucella suis infection. Comparison of wild-type and deficient mice suggested that MZ macrophage population loss is dependent on interferon gamma (IFN-γ) receptor but independent of T cells or tumor necrosis factor alpha receptor 1 (TNF-αR1) signaling pathways and is not correlated to an alteration of CCL19, CCL21, and CXCL13 chemokine mRNA expression. Our results suggest that MZ macrophage populations are particularly sensitive to persistent low-level IFN-γ-mediated inflammation and that Brucella infection could reduce the ability of the spleen to perform certain MZM- and MMM-dependent tasks, such as antigen delivery to lymphocytes and control of systemic infection. Infect Immun. 2017;85(11).
L’expérimentation animale reste indispensable
Opinion. La Libre. 22 novembre 2017
L'excellence scientifique en question
La vision occidentale du monde, notre construction de la réalité, une grande part des aspects tant matériels que sociaux de la vie moderne découlent de la recherche scientique. De nombreuses études lient la prospérité des nations à leur productivité scientique, faisant de la recherche scientique l’un des moteurs de la croissance économique. Pourtant, la méthodologie et l’organisation de la recherche scientique restent peu connues des citoyens. Le mythe d’individus isolés, subissant de brèves illuminations,tels Archimède et son bain, Newton et sa pomme, persiste dans l’imaginaire collectif. Cet article présente les principaux acteurs de la recherche scientique et questionne le choix des critères de son financement actuellement en vigueur. Il analyse l’impact de ces critères sur son organisation dans les universités et les services que la recherche fournit à la société. La recherche en Fédération Wallonie-Bruxelles (FW-B), en Belgique, est prise en exemple. Revue des Questions Scientifiques, 2016, 187(4): 529-548
Identification of immune effectors essential to the control of primary and secondary intranasal infection with Brucella melitensis in mice
The mucosal immune system represents the first line of defense against Brucella infection in nature. We used genetically deficient mice to identify the lymphocytes and signaling pathways implicated in the control of primary and secondary intranasal infection with B. melitensis Our analysis of primary infection demonstrated that the effectors implicated differ at the early and late stages and are dependent on the organ. TCR-δ, TAP1, and IL-17RA deficiency specifically affects early control of Brucella in the lungs, whereas MHC class II (MHCII) and IFN-γR deficiency impairs late control in the lungs, spleen, and liver. Interestingly, IL-12p35(-/-) mice display enhanced Brucella growth in the spleen but not in the lungs or liver. Secondary intranasal infections are efficiently contained in the lung. In contrast to an i.p. infectious model, in which IL-12p35, MHCII, and B cells are strictly required for the control of secondary infection, we observed that only TCR-β deficiency or simultaneous neutralization of IL-12p35- and IL-17A-dependent pathways impairs the memory protective response against a secondary intranasal infection. Protection is not affected by TCR-δ, MHCII, TAP1, B cell, IL-17RA, or IL-12p35 deficiency, suggesting that CD4(+) and CD8(+) α/β(+) T cells are sufficient to mount a protective immune response and that an IL-17A-mediated response can compensate for the partial deficiency of an IFN-γ-mediated response to control a Brucella challenge. These findings demonstrate that the nature of the protective memory response depends closely on the route of infection and highlights the role of IFN-γ-and IL-17RA-mediated responses in the control of mucosal infection by Brucella. J Immunol. 2016 196(9):3780-93
Maintenance of B cells during chronic murine Trypanosoma brucei gambiense infection
Parasite Immunol. 2016 38(10):642-647. doi: 10.1111/pim.12344
In vivo characterization of two additional Leishmania donovani strains using the murine and hamster model
Parasite Immunol. 2016 38(5):290-302.
The Unspecific Side of Acquired Immunity Against Infectious Disease: Causes and Consequences
Acquired immunity against infectious disease (AIID) has long been considered as strictly dependent on the B and T lymphocytes of the adaptive immune system. Consequently, AIID has been viewed as highly specific to the antigens expressed by pathogens. However, a growing body of data motivates revision of this central paradigm of immunology. Unrelated past infection, vaccination, and chronic infection have been found to induce cross-protection against numerous pathogens. These observations can be partially explained by the poly-specificity of antigenic T and B receptors, the Mackaness effect and trained immunity. In addition, numerous studies highlight the importance of microbiota composition on resistance to infectious disease via direct competition or modulation of the immune response. All of these data support the idea that a non-negligible part of AIID in nature can be nonspecific to the pathogens encountered and even of the antigens expressed by pathogens. As this protection may be dependent on the private T and B repertoires produced by the random rearrangement of genes, past immune history, chronic infection, and microbiota composition, it is largely unpredictable at the individual level. However, we can reasonably expect that a better understanding of the underlying mechanisms will allow us to statistically predict cross-protection at the population level. From an evolutionary perspective, selection of immune mechanisms allowing for partially nonspecific AIID would appear to be advantageous against highly polymorphic and rapidly evolving pathogens. This new emerging paradigm may have several important consequences on our understanding of individual infectious disease susceptibility and our conception of tolerance, vaccination and therapeutic strategies against infection and cancer. It also underscores the importance of viewing the microbiota and persisting infectious agents as integral parts of the immune system. Front Microbiol. 2016 6:1525. Review.
In Situ Characterization of Splenic Brucella melitensis Reservoir Cells during the Chronic Phase of Infection in Susceptible Mice
Brucella are facultative intracellular Gram-negative coccobacilli that chronically infect humans as well as domestic and wild-type mammals, and cause brucellosis. Alternatively activated macrophages (M2a) induced by IL-4/IL-13 via STAT6 signaling pathways have been frequently described as a favorable niche for long-term persistence of intracellular pathogens. Based on the observation that M2a-like macrophages are induced in the spleen during the chronic phase of B. abortus infection in mice and are strongly infected in vitro, it has been suggested that M2a macrophages could be a potential in vivo niche for Brucella. In order to test this hypothesis, we used a model in which infected cells can be observed directly in situ and where the differentiation of M2a macrophages is favored by the absence of an IL-12-dependent Th1 response. We performed an in situ analysis by fluorescent microscopy of the phenotype of B. melitensis infected spleen cells from intranasally infected IL-12p40-/- BALB/c mice and the impact of STAT6 deficiency on this phenotype. Most of the infected spleen cells contained high levels of lipids and expressed CD11c and CD205 dendritic cell markers and Arginase1, but were negative for the M2a markers Fizz1 or CD301. Furthermore, STAT6 deficiency had no effect on bacterial growth or the reservoir cell phenotype in vivo, leading us to conclude that, in our model, the infected cells were not Th2-induced M2a macrophages. This characterization of B. melitensis reservoir cells could provide a better understanding of Brucella persistence in the host and lead to the design of more efficient therapeutic strategies. PLoS One. 2015 10(9):e0137835.
Brucella melitensis invades murine erythrocytes during infection
Brucella spp. are facultative intracellular Gram-negative coccobacilli responsible for brucellosis, a worldwide zoonosis. We observed that Brucella melitensis is able to persist for several weeks in the blood of intraperitoneally infected mice and that transferred blood at any time point tested is able to induce infection in naive recipient mice. Bacterial persistence in the blood is dramatically impaired by specific antibodies induced following Brucella vaccination. In contrast to Bartonella, the type IV secretion system and flagellar expression are not critically required for the persistence of Brucella in blood. ImageStream analysis of blood cells showed that following a brief extracellular phase, Brucella is associated mainly with the erythrocytes. Examination by confocal microscopy and transmission electron microscopy formally demonstrated that B. melitensis is able to invade erythrocytes in vivo. The bacteria do not seem to multiply in erythrocytes and are found free in the cytoplasm. Our results open up new areas for investigation and should serve in the development of novel strategies for the treatment or prophylaxis of brucellosis. Invasion of erythrocytes could potentially protect the bacterial cells from the host's immune response and hamper antibiotic treatment and suggests possible Brucella transmission by bloodsucking insects in nature. Infect Immun. 2014 82(9):3927-38
Humoral immunity and CD4+ Th1 cells are both necessary for a fully protective immune response upon secondary infection with Brucella melitensis
Brucella spp are intracellular bacteria that cause brucellosis, one of the most common zoonoses in the world. Given the serious medical consequences of this disease, a safe and effective human vaccine is urgently needed. Efforts to develop this vaccine have been hampered by our lack of understanding of what constitutes a protective memory response against Brucella. In this study, we characterize the cells and signaling pathways implicated in the generation of a protective immune memory response following priming by the injection of heat-killed or live Brucella melitensis 16M. Using a panel of gene-deficient mice, we demonstrated that during a secondary recall response, both the Brucella-specific humoral response and CD4+ Th1 cells must act together to confer protective immunity in the spleen to B. melitensis infection. Humoral protective immunity is induced by the inoculation of both heat-killed and live bacteria, and its development does not require T cells, MyD88/IL-12p35 signaling pathways, or an activation-induced deaminase-mediated isotype switch. In striking contrast, the presence of memory IFN-γ-producing CD4+ Th1 cells requires the administration of live bacteria and functional MyD88/IL-12p35 pathways. In summary, our work identifies several immune markers closely associated with protective immune memory and could help to define a rational strategy to obtain an effective human vaccine against brucellosis. J Immunol. 2014 192(8):3740-52
TH1/TH2 paradigm extended: macrophage polarization as an unappreciated pathogen-driven escape mechanism?
The classical view of the Th1/Th2 paradigm posits that the pathogen nature, infectious cycle, and persistence represent key parameters controlling the choice of effector mechanisms operating during an immune response. Thus, efficient Th1 responses are triggered by replicating intracellular pathogens, while Th2 responses would control helminth infection and promote tissue repair during the resolution phase of an infectious event. However, this vision does not account for a growing body of data describing how pathogens exploit the polarization of the host immune response to their own benefit. Recently, the study of macrophages has illustrated a novel aspect of this arm race between pathogens and the immune system, and the central role of macrophages in homeostasis, repair and defense of all tissues is now fully appreciated. Like T lymphocytes, macrophages differentiate into distinct effectors including classically (M1) and alternatively (M2) activated macrophages. Interestingly, in addition to represent immune effectors, M1/M2 cells have been shown to represent potential reservoir cells to a wide range of intracellular pathogens. Subversion of macrophage cell metabolism by microbes appears as a recently uncovered immune escape strategy. Upon infection, several microbial agents have been shown to activate host metabolic pathways leading to the production of nutrients necessary to their long-term persistence in host. The purpose of this review is to summarize and discuss the strategies employed by pathogens to manipulate macrophage differentiation, and in particular their basic cell metabolism, to favor their own growth while avoiding immune control. Front Immunol. 2014 5:603. Review.
Generation of individual diversity: a too neglected fundamental property of adaptive immune system
The fitness gains resulting from development of the adaptive immune system (AIS) during evolution are still the subject of hot debate. A large random repertoire of antigenic receptors is costly to develop and could be the source of autoimmune reactions. And yet, despite their drawbacks, AIS-like systems seem to have been independently acquired in several phyla of metazoans with very different anatomies, longevities, and lifestyles. This article is a speculative attempt to explore the selective pressures, which favored this striking convergent evolution. It is well known that the AIS enables an organism to produce a specific immune response against all natural or artificial antigenic structures. However, it is frequently neglected that this response is highly variable among individuals. In practice, each individual possesses a "private" adaptive immune repertoire. This individualization of immune defenses implies that invasion and escape immune mechanisms developed by pathogens will certainly not always be successful as the specific targets and organization of the immune response are somewhat unpredictable. In a population, where individuals display heterogeneous immune responses to infection, the probability that a pathogen is able to infect all individuals could be reduced compared to a homogeneous population. This suggests that the individual diversity of the immune repertoire is not a by-product of the AIS but of its fundamental properties and could be in part responsible for repeated selection and conservation of the AIS during metazoan evolution. The capacity of the AIS to improve the management of cooperative or parasitic symbiotic relationships at the individual level could be a secondary development due to its progressive integration into the innate immune system. This hypothesis constitutes a new scenario for AIS emergence and explains the selection of MHC restriction and MHC diversification. Front Immunol. 2014 5:208. Opinion.
Complete Genome Sequence of the Escherichia coli PMV-1 Strain, a Model Extraintestinal Pathogenic E. coli Strain Used for Host-Pathogen Interaction Studies
Genome Announc. 2013 1(5). pii: e00913-13.
Redefining the immune system as a social interface for cooperative processes
Viewed from a neo-Darwinian perspective, the main function of the metazoan immune system (IS) is to insure host integrity against invading microorganisms, which are only considered as selfish competitors that reduce the host's resources, inflict tissue damage, and ultimately compromise host fitness. Coevolution of the host and these competitors has been described as a perpetual arms race (known as the Red Queen hypothesis, Van Valen). This vision implicitly suggests that “The IS evolved under selective pressure imposed by infectious microorganisms" (Janeway) and that the ultimate objective of the IS is to conserve the integrity and sterility of the host. In fact, numerous observations from microbiology and ecology have challenged this paradigm and suggest that infectious organisms and the IS play a crucial, unexpected role in evolution. PLoS Pathog. 2013 9(3):e1003203. Opinion.
Crucial role of gamma interferon-producing CD4+ Th1 cells but dispensable function of CD8+ T cell, B cell, Th2, and Th17 responses in the control of Brucella melitensis infection in mice
Brucella spp. are facultative intracellular bacterial pathogens responsible for brucellosis, a worldwide zoonosis that causes abortion in domestic animals and chronic febrile disease associated with serious complications in humans. There is currently no approved vaccine against human brucellosis, and antibiotic therapy is long and costly. Development of a safe protective vaccine requires a better understanding of the roles played by components of adaptive immunity in the control of Brucella infection. The importance of lymphocyte subsets in the control of Brucella growth has been investigated separately by various research groups and remains unclear or controversial. Here, we used a large panel of genetically deficient mice to compare the importance of B cells, transporter associated with antigen processing (TAP-1), and major histocompatibility complex class II-dependent pathways of antigen presentation as well as T helper 1 (Th1), Th2, and Th17-mediated responses on the immune control of Brucella melitensis 16 M infection. We clearly confirmed the key function played by gamma interferon (IFN-γ)-producing Th1 CD4(+) T cells in the control of B. melitensis infection, whereas IFN-γ-producing CD8(+) T cells or B cell-mediated humoral immunity plays only a modest role in the clearance of bacteria during primary infection. In the presence of a Th1 response, Th2 or Th17 responses do not really develop or play a positive or negative role during the course of B. melitensis infection. On the whole, these results could improve our ability to develop protective vaccines or therapeutic treatments against brucellosis. Infect Immun. 2012 80(12):4271-80
In situ microscopy analysis reveals local innate immune response developed around Brucella infected cells in resistant and susceptible mice
Brucella are facultative intracellular bacteria that chronically infect humans and animals causing brucellosis. Brucella are able to invade and replicate in a broad range of cell lines in vitro, however the cells supporting bacterial growth in vivo are largely unknown. In order to identify these, we used a Brucella melitensis strain stably expressing mCherry fluorescent protein to determine the phenotype of infected cells in spleen and liver, two major sites of B. melitensis growth in mice. In both tissues, the majority of primary infected cells expressed the F4/80 myeloid marker. The peak of infection correlated with granuloma development. These structures were mainly composed of CD11b⁺ F4/80⁺ MHC-II⁺ cells expressing iNOS/NOS2 enzyme. A fraction of these cells also expressed CD11c marker and appeared similar to inflammatory dendritic cells (DCs). Analysis of genetically deficient mice revealed that differentiation of iNOS⁺ inflammatory DC, granuloma formation and control of bacterial growth were deeply affected by the absence of MyD88, IL-12p35 and IFN-γ molecules. During chronic phase of infection in susceptible mice, we identified a particular subset of DC expressing both CD11c and CD205, serving as a reservoir for the bacteria. Taken together, our results describe the cellular nature of immune effectors involved during Brucella infection and reveal a previously unappreciated role for DC subsets, both as effectors and reservoir cells, in the pathogenesis of brucellosis. PLoS Pathog. 2012;8(3):e1002575.
Probiotic Escherichia coli Nissle 1917 activates DC and prevents house dust mite allergy through a TLR4-dependent pathway
Eur J Immunol. 2010 40(7):1995-2005. doi: 10.1002/eji.200939913.
Direct visualization of peptide/MHC complexes at the surface and in the intracellular compartments of cells infected in vivo by Leishmania major
PLoS Pathog. 2010 6(10):e1001154.
Immunomodulatory properties of Lactobacillus plantarum and its use as a recombinant vaccine against mite allergy
Allergy. 2009 64(3):406-14. doi: 10.1111/j.1398-9995.2008.01825.x.
iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic Leishmania major infection phase of C57BL/6 resistant mice
PLoS Pathog. 2009 5(6):e1000494.
DiC14-amidine cationic liposomes stimulate myeloid dendritic cells through Toll-like receptor 4.
Eur J Immunol. 2008 38(5):1351-7. doi: 10.1002/eji.200737998
Normal development and function of dendritic cells in mice lacking IDO-1 expression.
Immunol Lett. 2008 118(1):21-9. doi: 10.1016/j.imlet.2008.02.006
MyD88-dependent activation of B220-CD11b+LY-6C+ dendritic cells during Brucella melitensis infection
IFN-gamma is a key cytokine controlling Brucella infection. One of its major function is the stimulation of Brucella-killing effector mechanisms, such as inducible NO synthase (iNOS)/NOS2 activity, in phagocytic cells. In this study, an attempt to identify the main cellular components of the immune response induced by Brucella melitensis in vivo is made. IFN-gamma and iNOS protein were analyzed intracellularly using flow cytometry in chronically infected mice. Although TCRbeta(+)CD4(+) cells were the predominant source of IFN-gamma in the spleen, we also identified CD11b(+)LY-6C(+)LY-6G(-)MHC-II(+) cells as the main iNOS-producing cells in the spleen and the peritoneal cavity. These cells appear similar to inflammatory dendritic cells recently described in the mouse model of Listeria monocytogenes infection and human psoriasis: the TNF/iNOS-producing dendritic cells. Using genetically deficient mice, we demonstrated that the induction of iNOS and IFN-gamma-producing cells due to Brucella infection required TLR4 and TLR9 stimulation coupled to Myd88-dependent signaling pathways. The unique role of MyD88 was confirmed by the lack of impact of Toll-IL-1R domain-containing adaptor inducing IFN-beta deficiency. The reduction of IFN-gamma(+) and iNOS(+) cell frequency observed in MyD88-, TLR4-, and TLR9-deficient mice correlated with a proportional lack of Brucella growth control. Taken together, our results provide new insight into how immune responses fight Brucella infection. J Immunol. 2007 178(8):5182-91
Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF
J Biol Chem. 2007 282(43):31131-46
Bacterial c-di-GMP is an immunostimulatory molecule
J Immunol. 2007 178(4):2171-81
Cytosolic expression of SecA2 is a prerequisite for long-term protective immunity
Cell Microbiol. 2007 9(6):1445-54
Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes
Eur J Immunol. 2005 35(5):1463-71
TLR4 and Toll-IL-1 receptor domain-containing adapter-inducing IFN-beta, but not MyD88, regulate Escherichia coli-induced dendritic cell maturation and apoptosis in vivo
J Immunol. 2005 175(2):839-46
Myd88-dependent in vivo maturation of splenic dendritic cells induced by Leishmania donovani and other Leishmania species
Infect Immun. 2004 72(2):824-32
Amastigote load and cell surface phenotype of infected cells from lesions and lymph nodes of susceptible and resistant mice infected with Leishmania major
Infect Immun. 2003 71(5):2704-15
Genetically resistant mice lacking MyD88-adapter protein display a high susceptibility to Leishmania major infection associated with a polarized Th2 response
J Immunol. 2003 170(8):4237-41.
Endogenous interleukin-12 is critical for controlling the late but not the early stage of Leishmania mexicana infection in C57BL/6 mice
Infect Immun. 2002 70(9):5075-80.
T cell-dependent maturation of dendritic cells in response to bacterial superantigens
J Immunol. 2002 168(9):4352-60
The SH2 domain-containing 5-phosphatase SHIP2 is expressed in the germinal layers of embryo and adult mouse brain: increased expression in N-CAM-deficient mice
Neuroscience. 2001 105(4):1019-30
The SH2 domain containing inositol 5-phosphatase SHIP2 associates to the immunoreceptor tyrosine-based inhibition motif of Fc gammaRIIB in B cells under negative signaling
Immunol Lett. 2000 72(1):7-15
Downregulation of antigen-presenting cell functions after administration of mitogenic anti-CD3 monoclonal antibodies in mice
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Carbohydrate-bearing cell surface receptors involved in innate immunity: interleukin-12 induction by mitogenic and nonmitogenic lectins
Cell Immunol. 1999 10;191(1):1-9.
Distribution of the src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells
Biochem J. 1999 342 Pt 3:697-705
Role and regulation of IL-12 in the in vivo response to staphylococcal enterotoxin B
Int Immunol. 1999 11(9):1403-10 BACTERIAL SUPERANTIGEN
Revisiting the Th1/Th2 paradigm
Scand J Immunol. 1998 47(1):1-9. Review
Staphylococcal enterotoxin B induces an early and transient state of immunosuppression characterized by V beta-unrestricted T cell unresponsiveness and defective antigen-presenting cell functions
J Immunol. 1997 158(6):2638-47 Bacterial superantigen
Toxicity and neuroendocrine regulation of the immune response: a model analysis
J Theor Biol. 1996 183(3):285-305
Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo
J Exp Med. 1996 184(4):1413-24
Costimulation regulates the kinetics of interleukin-2 response to bacterial superantigens
Immunology. 1996 89(2):245-9
Co-stimulation lowers the threshold for activation of naive T cells by bacterial superantigens
Int Immunol. 1995 7(2):295-304
Glucocorticoids down-regulate dendritic cell function in vitro and in vivo
Eur J Immunol. 1995 25(10):2818-24.
B7.2 provides co-stimulatory functions in vivo in response to staphylococcal enterotoxin B
Eur J Immunol. 1995 25(7):2111-4
Activation of murine T cells by bacterial superantigens requires B7-mediated costimulation
Cell Immunol. 1995 162(2):315-20