Our first project is based on the epidemiologic observation that the responses to pathogens differ between men and women. A recent large-scale study performed in mice infected with Coxiella burnetii, the agent of Q fever, provides a new basis for elucidating the role of sexual dimorphism in bacterial infections. We will screen a large number of gender-dependent genes and test their functional role in sexual dimorphism. This study will be extended to other infectious diseases known to be gender-dependent and for which we have cohorts of patients and large transcriptomic data. The concept of gender in infectious diseases illustrates the policy of our research team, which is clearly multidisciplinary and is based on questions resulting from the management of infectious diseases. The second project is also connected to the management of infectious diseases in which pregnancy increases the susceptibility to intracellular pathogens such as C. burnetii and Brucella, and may account for pathogen persistence. We will analyze in normal human pregnancy how Brucella and Coxiella are able to infect and persist in placenta cells (trophoblasts and/or macrophages), with a special attention to the mechanisms of uterine/placental immune defences using isolated T cells, NK cells and dendritic cells. A similar approach will be used in patients with Q fever or brucellosis to determine the placental response that leads to the disease. This may be useful to the follow-up of patients and therapeutics improvement. The third project will be dedicated to the study of mechanisms used by a pathogen such as C. burnetii to inhibit microbicidal responses of host cells. One of these strategies is to hijack phagosome maturation and immune response. Our goal is to investigate the effect of Coxiella lipopolysaccharides (LPS on the intracellular trafficking, to identify the cell effectors that are targeted by these LPSs and to understand the LPS structures involved in the survival of C. burnetii. The projects 4 and 5 will be dedicated to the establishment of convenient animal models of infections and the investigation of immune deficiency in infectious diseases such as Q fever. Finally, through the transcriptomic platform we directed, a translational research will be developed in several fields of infectious diseases.
La réponse aux agents infectieux est différente chez l’homme et la femme. Nous avons montré récemment que l’infection des souris mâles et femelles par Coxiella burnetii, l’agent de la fièvre Q, se traduit par une réponse transcriptionnelle largement dépendante du sexe. Nous analyserons cette réponse chez l’homme et le rôle potentiel des gènes spécifiquement modulés dans le dimorphisme sexuel. Cette étude sera étendue à d’autres maladies infectieuses pour lesquelles nous disposons de cohortes de malades et de données transcriptomiques. Cette étude illustre parfaitement notre objectif qui est clairement multidisciplinaire et basé sur des questions issues de la pratique clinique des maladies infectieuses. C’est dans le même esprit que nous entreprendrons le deuxième projet qui part du constat que la grossesse accroît la susceptibilité aux agents infectieux tels que C. burnetii et Brucella. Nous analyserons comment C. burnetii et Brucella infectent les cellules placentaires (trophoblastes et/ou macrophages) et le rôle des cellules de la réponse immune placentaire dans cette infection. Une approche similaire sera utilisée chez les femmes enceintes présentant une fièvre Q ou une brucellose, ce qui pourrait s’avérer utile pour leur traitement. Le troisième projet aura pour objectif de déterminer comment un agent pathogène tel que C. burnetii inhibe la réponse microbicide des cellules-hôtes, en particulier les macrophages, qu’il infecte. Une de ces stratégies est de bloquer la maturation phagosomale : nous étudierons l’effet du LPS de C. burnetii sur le trafic intracellulaire des bactéries, identifierons les effecteurs cellulaires ciblés par le LPS et entreprendrons une étude structure/fonction du LPS de C. burnetii. Nos autres projets consisteront à établir des modèles animaux pertinents d’infections par des bactéries telles que C. burnetii et d’étudier sur ces modèles les défauts de la réponse immune protectrice. Enfin, grâce à l’utilisation de la plate-forme «Transcriptome» que nous dirigeons, nous développerons une recherche translationnelle dans différents champs des maladies infectieuses.
The leadership of the team will change in the next project: Eric Ghigo will be co-director of the team. This co-direction is made to prepare him to be the only director in four years. The project of the team “Infection, Gender and Pregnancy” will be an amplification of the previous researches we developed during the last four years. Indeed, the convergence between clinicians from our team and the opportunities due to the development of technical platforms led us to introduce the concept of gender in bacterial infectious diseases. This concept illustrates the policy of our research team, which is clearly multidisciplinary and is based on questions resulting from the management of infectious diseases. The different projects will answer to following questions. The first project is based on the epidemiologic observation that the ability to mount a protective response to pathogens and the way to express this response to the disease differ between men and women. The second project is also connected to the management of infectious diseases in which pregnancy increases the susceptibility to intracellular pathogens and may account for pathogen persistence. This project will enable us to develop an approach of pregnancy pathologies. The third project will be dedicated to the study of hijacking mechanisms of microbicidal responses. The projects 4 and 5 will be dedicated to the establishment of convenient animal models of infections and the investigation of immune deficiency in infectious diseases such as Q fever. Finally, through the transcriptomic platform, a translational research will be developed in several fields of infectious diseases.
Social factors such as gender inequity can explain differences in the distribution of infectious diseases between men and women. As shown elsewhere, poor women may be at a disadvantage in their ability to access quality health care. However, biological differences are also responsible for part of the epidemiological variation observed between males and females in infectious diseases due to intra- and extracellular pathogens. Gender-based biological differences also affect host immune responses to pathogens. Women elicit more vigorous humoral and cell-mediated immune responses than men in response to antigenic challenges, while men have frequently been observed to exhibit more aggressive and harmful inflammatory responses to pathogens. Tuberculosis and Legionnaire’s disease are reported to be more prevalent and severe in men than in women. Although biological differences have been largely attributed to sex hormones, the precise nature of the cross-talk between gender and infection remains largely unknown. Q fever, a zoonosis due to Coxiella burnetii, is more frequent and severe in men than in women for a similar exposure. We studied the relationship between gender and infection in a model of intact and castrated mice infected by C. burnetii. In this study, we showed that the gene expression modulated by C. burnetii infection was mostly gender-dependent. Moreover, most of the modulation occured in males, and was widely dependent on sexual hormones as castration abolished 60% of gene modulation. Males highlighted an early anti-inflammatory response and we observed a perturbation of the circadian rhythm in females. This large-scale study reveals for the first time that circadian rhythm plays a major role in host response to C. burnetii, and provides a new basis for elucidating the role of sexual dimorphism in human infections.
The study will be extended to humans suffering from Q fever. We will investigate the expression of genes involved in circadian cycle. Preliminary results show that some circadian genes are differently expressed in males and females and the disease removed the sexual differences. We will screen a large number of genes known to be gender-dependent and test their functional role in sexual dimorphism. For instance, we have shown that macrophage polarization is critical in host defence against infection. We will analyze the contribution of gender in macrophage polarization. This study will be extended to other infectious diseases known to be gender-dependent and for which we have cohorts of patients and large data of transcriptomics.
The spreading of infectious diseases and bacterial persistence in chronic infectious diseases are a major problem of public health. Q fever and brucellosis, two zoonoses due to intracellular bacteria, Coxiella burnetii and Brucella sp. respectively, illustrate this question. Both diseases have obstetrical consequences on pregnancy in humans and animals leading to abortions, low birth rate and infertility. The microorganisms use their ability to infect placenta to spread among humans and animals and to create a favorable environment for their persistence, leading to chronic evolution of the diseases. Understanding how microorganisms infect placenta is essential but the main difficulty is linked to the isolation and the characterization of primary trophoblasts and immune cells (lymphocytes, macrophages, NK cells and dendritic cells (DCs)) from human placentas. The studies of interactions between bacterial pathogens and placenta cells are rare and no study has concerned C. burnetii and Brucella sp. In addition, we ignored if placenta immune cells are infected by microorganisms and which role they play in defense or pathogenicity. Few teams with expertise in both pathophysiology of the two infectious diseases and the cell biology of placenta cells can develop this approach. Our transdisciplinary project will use (1) cell biology and transcriptomics approach of intracellular life of bacterial pathogens within placenta and (2) clinical approach (cohort of pregnant patients with Q fever or brucellosis) to find new pathways for placental infection.
The project will have two focuses. First, we will analyze in normal human pregnancy how Brucella and Coxiella are able to infect and persist in placenta cells (trophoblasts and/or macrophages), with a special attention to the mechanisms of uterine/placental immune defences using isolated T cells, NK cells and DCs. Second, a similar approach will be used in patients with Q fever or brucellosis to determine the placental response that leads to the disease. This may be useful to the follow-up of patients and therapeutics improvement.
1. The first aim will be divided in different phases. The first one will consist to determine which types of placenta cells are able to be infected by C. burnetii and B. abortus. As trophoblasts and some immune cells (macrophages, DCs) are candidates, we will first isolate trophoblasts from human placentas at term with a method based on Percoll gradients and positive selection. Since the differentiation of trophoblasts would be different during the time of pregnancy, we will also select placentas from each trimester (women are mainly infected at the first trimester). As sensitive tools to characterize trophoblast subsets are lacking, we will develop monoclonal antibodies (mAb) to characterize trophoblast subsets and development stages. In parallel, we will isolate placental immune cells, macrophages, T cells, NK cells and DCs using tissue digestion, Ficoll gradient and positive selection. Trophoblasts and immune cells will be infected in vitro with C. burnetii and Brucella, and the infection will be measured by microbiological and molecular methods. They will be completed by the characterization of replicative compartments. Preliminary results in trophoblast cell lines have shown that both pathogens inhabit a vacuole that express Lamp-1 (a marker of late endosomes and lysosomes), but cathepsin D (a marker of lysosomes) is only present in cells infected with C. burnetii. In addition, the behavior of each bacterium in trophoblast cell lines is clearly distinct from that observed in human macrophages, which are known to be usual systemic replicative niche. It is likely that the replicative compartment is distinct in primary human trophoblasts and placental immune cells. The second phase will characterize the responses of infected cells to C. burnetii and Brucella using a global approach. In trophoblasts, we will define common and specific genes and their organization. We have already obtained preliminary results in which C. burnetii elicits a transcriptional program of 340 genes in which IL-6, MIF, IB, TNF and IL-13R pathways are engaged. We will also characterize the transcriptional profile of placental immune cells in response to C. burnetii and Brucella, and we will compare this profile with those of circulating cells. The last phase will consist to study cell interactions in the context of placental infection. We will establish co-culture of trophoblasts, macrophages and DCs on one hand, and lymphocytes and NK cells on another hand. NK cell and T cell activation will be monitored by flow cytometry (activation antigens and intracellular cytokines). In addition, the analysis of microarrays will provide specific parameters that will be assessed in co-cultures. The consequences of the project are to describe for the first time the responses of human trophoblasts and immune placental cells to two bacterial pathogens with placenta tropism. The project will also document the cross-talk between trophoblasts and cells from placental immune system, which will provide an integrated analysis of placenta infection. In addition, the project will enable the development of new tools to characterize trophoblasts.
2. The second aim of our project will be to analyze placentas from pregnant women with Q fever and brucellosis, according similar experimental procedures. The comparison of pathological placenta responses with in vitro infection may be useful to determine signatures of C. burnetii or Brucella infection, and potentially improve the follow-up and treatment of patients.
C. burnetii is the causative agent of Q fever, a human disease. The mechanisms which allow C. burnetii to replicate or survive within tissues, cells and organs are poorly understood. As other pathogens, C. burnetii is able to disturb the microbicidal function of host cells. Indeed, different pathogens have evolved distinct strategies to control their intracellular fate and enhance their survival within host cells. One of these strategies is to hijack the phagosome maturation and the immune response. Several bacterial factors have been identified to be involved in the prevention of the phagolysosome formation and the pertubation of the immune response. Thus, for Mycobacteria spp., Lieshmania spp. and Brucella spp., these activities have been attributed to bacterial membrane components, respectively the lipoarabinomannans (LAM), the LPG (lipophosphoglycan) and lipopolysacharide (LPS). In addition, it appears that micro RNA (miRNA) should be involved in the hijacking of microbicidal function of macrophages by the bacteria. We propose to investigate and elucidate the molecular mechanisms of the alteration of phagosome maturation by LPS using the LPS of Coxiella burnetii and the involvement of micro-RNA in the hijacking of microbicidal functions.
The intracellular localization of C. burnetii has been determined by our team . We are also able to purify the LPS of several C. burnetii strains, and to chemically modified these LPSs. The structure of these LPSs from C. burnetii is known and has been published by a collaborating team [2-4]. C. burnetii replicates within macrophages through the inhibition of the phagosome-lysosome fusion. Our goal is to investigate the effect of Coxiella LPSs on the intracellular trafficking, to identify the cell effectors that are targeted/altered by these LPSs and to understand the LPS structures involved in the survival of C. burnetii. To date, there is no study relating clearly the relationship between structure/function of LPS in the strategies used by gram negative bacteria to generate an environment suitable for their replication. In this respect, the elucidation of the trafficking of Coxiella LPSs and the identification of LPSs-containing compartments are necessary to better understand the role of LPSs in the intracellular fate of gram-negative bacteria.
To investigate and understand the effect of LPSs on the endocytic pathway, and identify the mechanisms leading the LPSs to modulate the endocytic pathway and generate an environment suitable for the bacterial replication, we have assigned the tree following objectives:
- Study of the intracellular localization of LPSs
- Effect of LPSs on the endocytic machinery
- Role of macrophage activation in the intracellular localization of LPSs
It has been recently described that bacteria might produce small non-coding RNAs (sRNA) [5, 6]. sRNAs are known as a large class of versatile gene regulators. Post-transcriptional regulation of gene expression by sRNA molecules has been demonstrated in a wide range of pathogenic bacteria and has been shown to play a significant role in the control of virulence. It is possible that bacteria are able to control the phagosome conversion and immune response using sRNAs. The microbicidal function interference by bacterial small non-coding RNAs might constitute a new strategy for bacteria to control their intracellular fate. In addition, cells are functionaly regulated through a miRNA-dependent mechanism. It is possible that bacterial infections perturb cell miRNA regulation leading to dysfunction of microbicidal activities.
To investigate and understand the effect of the C. burnetii small non-coding RNA and cell miRNA in bacterial infection, we have assigned the tree following objectives:
- In silico prediction of C. burnetii small non-coding RNAs and identification of potential targets
- Expression of C. burnetii small non-coding RNA in macrophages and functional consequences on the microbicidal machinery
- Determination of cellular non-coding RNA expression profile during in vitro infection and in patients with Q fever.
The idea is that we have the means to follow the infection by targeting some cells or tissues and the opportunity to genetically manipulate mice. We have developed murine models with C. burnetii (acute and chronic infection), R. prowazekii (initial infection and relapses) and T. whipplei (acute infection in normal and injured mice). All these studies are based on static studies and do not target specific tissues.
The URMITE and CIML teams usually study the interaction of intracellular bacteria with myeloid DCs. Hence, it has been shown that Brucella abortus interfere with the maturation of DCs , C. burnetii do not prevent DC maturation and T. whipplei is unable to activate DCs (manuscripts in preparation). The program will consist in the building of mice expressing human DCs and to follow the infection in these humanized mice. Besides Brucella and Coxiella, these mice will offer the opportunity to assess immune response to Rickettsia. Indeed, rickettsioses result from tick bites and likely Rickettsia are transferred to skin DCs and thereafter to lymph nodes. The availability of mice expressing human DCs will allow to study the natural history of rickettsioses and the recruitment of immunocompetent cells.
We will develop the strategy of humanized mice to express human macrophages in mice that will represent suitable model of infections. We studied the interaction of two bacterial pathogens, Coxiella and Tropheryma, with monocytes and macrophages, their usual targets, for several years. We described the natural history of C. burnetii infection including the internalization receptors, the type of activation (M1-type in monocytes and atypical M2-type in macrophages [8, 9]), the nature of the replication compartment and innate immune response in patients (IL-10 context) [10, 11]. More recently, we have developed an approach to investigate placenta macrophages and their infection with Coxiella and Brucella since both pathogens are responsible of obstetrical complications and bacterial persistence. This project is supported by a strong collaboration between our team and that of J.P. Gorvel (CIML). T. whipplei differently interacts with monocytes (elimination) and macrophages (replication). We provided a dissection of the molecular events related to bacterial replication in macrophages: M2-type of activation and overexpression of IL-16 [12, 13]. As the profiles of mouse and human infections are distinct, it is necessary to develop the humanization of macrophage compartment in mice. A strategy has been developed to reconstitute a human immune system in Rag-2-/-c-/- deficient mice by the Immunophenomic Center. The goal of the project will be to reconstitute human macrophage compartment in mice. A procedure has been recently described that create human-mouse chimera with CD34+ HSC (hematopoietic stem cells) and immunodeficient mice; a such approach generates macrophages expressing CD14 and CD68 that are able to infiltrate the tissues and to induce lesions . This approach will be pertinent to study the role of human macrophages in infectious diseases due to intracellular pathogens.
To follow the infection process in mice, the platform will create mice with modified genes by KI to express several fluorescent proteins. Such approach will enable to identify a given cell type and to define an activation or infection state. It will offer the opportunity to analyze and sort cells and/or bacteria expressing fluorescent proteins. We will target different tissues: intestine (Peyer patches), lung, skin and placenta.
The chronic evolution of infectious diseases due to intracellular pathogens is associated with a given level of immunodeficiency. The infectious diseases that are investigated by our team share an alteration of immune response. Indeed, Q fever is characterized by a chronic evolution and an impairment of cell-mediated responses, which is very likely related to an aberrant overproduction of IL-10. Recent publications renew the central role of IL-10 in chronic infectious diseases due to virus and bacteria. The Whipple’s disease is another example since several features of impaired microbicidal responses are found probably in susceptible subjects. The policy of the URMITE was the building of patient cohorts that make possible such studies.
The project will analyze the complexity of leukocyte population interaction using circulating mononuclear cells and multicolor cytometry (12 markers). This technology allows to identify simultaneously different cell populations (pDC, mDC, NK, monocytes and T cells) and to analyze their activation state (activation markers: CD69, CD83 and functional markers: IFNγ, IFNβ, TNF, IL-10, IL-12, CD107, CD163). This muliparametric approach will also allow the study of different pathogens with clinical relevance on different subpopulations of mononuclear cells. In addition, evidence showed that auxiliary molecules of immune response such as PD1/PDL1 are necessary for the overproduction of IL-10 in the context of chronic HIV infection. We think that similar mechanisms may be elicited in chronic Q fever and sepsis. We have cohorts of patients with Q fever and with sepsis (M. Leone) in which these two hypotheses may be studied.
The development of a transcriptomic platform has enlarged the collaborations of our team. Hence, collaborative projects have been performed with cardiologists (infective endocarditis) , physicians of infectious diseases (scrub typhus, mediterranean spotted fever) and more recently cell biologists (migration of macrophages and gene expression; macrophage fusion and giant multinuclear cells) . This policy will be maintained during the next 4 years.
Preeclampsia (PE) is a public health problem and can appear in up to 5% of pregnancies. This is still a major risk factor for maternal and neonatal mortality and morbidity. To predict PE is a major health goal because it can allow to select patients for therapeutics studies and improve papthophysiology knowledge. Because of the central role of placenta in the development of PE, most of the transcriptomic studies were initially focused on the analysis of gene expression in trophoblastic cells of patients. This analysis can only be obtained after the delivery and is therefore useless in predicting the disease. We propose to investigate which genes were differently expressed using a large-scale transcriptomic approach in whole blood obtained in early pregnancy, at time of diagnosis and 2 months after delivery.
The incidence of sepsis is rising, partly related to medical progress, which allows patients to survive longer, resulting in increased numbers of older, debilated, or immunocompromised patients passing through intensive care unit. Ten to 15 percent of intensive care unit patients develop septic shock, the form of acute circulatory shock that occurs secondary to severe infection. The mortality rate is 50% to 60%. In clinical studies, lower mortality rates have been reported but this is due to exclusion criteria such as cirrhosis, immunosuppression, or “do not resuscitate” order . The organisms involved in severe sepsis and septic shock are most often bacterial. The gram-negative bacilli are commonly implicated, although there is an increasing part of gram-positive cocci. The lung is the most common source of infection, followed by abdomen, catheter and urine . The pathophysiology of sepsis is complex and remains under investigation. The traditional approach was to consider septic shock as a major pro-inflammatory response. However, there is today some conflicts about this approach. Briefly, this excessive pro-inflammatory phase is probably of very short duration, even nonexistent in old and debilated patients. The second phase consists on a deep and prolonged inhibition of the immune response, favoring the development of secondary nosocomial infection, and leading to a progressive multi-organ failure [19, 20]. In the laboratory, we propose to participate to this debate by elaborating murine models and investigating intensive care unit patients. In patients, we will test part of our findings in animal models. We are currently looking at the immune response with on-going studies on the production of interleukin-16 in human sepsis. We also will investigate the expression of genes involved in the circadian rhythm in intensive care unit patients, with a special attention to gender and sepsis effects. We will next develop an axis on the immune cell response to stimulation in neutropenic patients, once again with a special focus on gender. In addition, we plan to develop clinical projects on the use of antibiotics in intensive care unit patients. Guidelines recommend to use broad spectrum antibiotics in the first hour after sepsis diagnosis, and to narrow the spectrum of antibiotics after pathogen identification (so-called desescalade) . However, there is no randomized clinical trial testing the impact of such policy on the outcomes. Hence, we propose to build a randomized clinical trial to test the desescalade in real life conditions, by using a network of French intensive care units. We will rely on the laboratory to manage the biological collections in this project, by elaborating for instance a transcriptional profile of treatment responding patients.
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8. Benoit M, Ghigo E, Capo C, Raoult D, Mege JL. The uptake of apoptotic cells drives Coxiella burnetii replication and macrophage polarization: a model for Q fever endocarditis. PLoS Pathog 2008. 4: e1000066.
9. Benoit M, Barbarat B, Bernard A, Olive D, Mege JL. Coxiella burnetii, the agent of Q fever, stimulates an atypical M2 activation program in human macrophages. Eur J Immunol 2008, 38: 1065-1070.
10. Mege JL, Meghari S, Honstettre A, Capo C, Raoult D. The two faces of interleukin 10 in human infectious diseases. Lancet Infect Dis 2006, 6: 557-569.
11. Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J Immunol 2008, 181: 3733-3739.
12. Desnues B, Raoult D, Mege JL. IL-16 is critical for Tropheryma whipplei replication in Whipple's disease. J Immunol 2005, 175: 4575-4582.
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