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Reference : UMR7355-ISACOU-001
Workplace : ORLEANS
Date of publication : Friday, August 02, 2019
Scientific Responsible name : Isabelle Couillin
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 November 2019
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
Chronic obstructive pulmonary disease (COPD), primarily caused by cigarette smoking (CS), is punctuated by life-threatening clinical exacerbations mainly elicited by bacterial or viral infections. The underlying mechanisms and mediators that drive the induction of inflammation leading to chronic inflammation, exacerbation and impaired lung function, are poorly understood. A sustained cellular inflammation characterized by airway neutrophilic recruitment is commonly correlated with bad prognosis in chronic lung inflammation and COPD exacerbation. Paradoxically, this strong inflammatory response is associated with impaired bacterial clearance due to ineffective neutrophils which do not prevent the occurrence of exacerbations caused by infections, frequently due to Streptococcus pneumoniae. These episodes strongly accelerate disease progression through their impact on health status, lung function, and comorbidities. In this context, we reported that the development of bacterial infection during COPD exacerbations in CS exposed mice is due to an altered production of IL-22, which is essential for bacterial clearance. This defective response is related to an altered ability of antigen-presenting cells (APC) including alveolar macrophages and conventional dendritic cells to produce Th17-promoting cytokines in response to bacteria.
The intracytosolic sensor NLRP6 controls gut microbiota and mucus secretion, however knowledge of its lung functions are starting to emerge. We generated solid preliminary data showing that the NLRP6 is central in lung inflammation following CS exposure in mice by controlling the neutrophil chemoattractant CXCL5 secretion in airway epithelial cells (AEC). In addition, in antigen presenting cells, we observed that NLRP6 inhibits inflammatory cytokine production suggesting that NLRP6 may negatively regulate bacterial clearance and COPD exacerbation. We will conduct experiments to assess the mechanisms of NLRP6-driven inflammation after CS-exposure and its contribution upon exacerbation after infection. We will decipher the impact on NLRP6 interplay between neutrophil, AEC and APC and their consequences on the production of Th17 cytokines.
Combining multidisciplinary approaches, Smoke6 project integrates 4WP aiming to:
1) describe the consequences of Nlrp6 deficiency on inflammation consecutive to acute or prolonged CS-exposure and on bacterial infection by S. pneumonia in CS-exposed mice; 2) identify lung NLRP6-expressing cells controlling inflammation in response to CS-exposure and bacterial infection by S. pneumoniae in CS exposed mice; 3) decipher the mechanisms by which NLRP6 regulates immune response to CS exposure and/or to bacterial infection; 4) evaluate the contribution of NLRP6 in COPD in humans.
By addressing the association between environmental stress (exposure to CS) and bacterial infection, Smoke6 project will decipher the unknown mechanisms by which i) NLRP6 receptor regulates the development of chronic inflammation, COPD and COPD exacerbation ii) NLRP6 controls respiratory infection by S. pneumoniae. Our data mining strategies will allow to better understand the biology of lung epithelial cells and antigen-presenting cells and interplay with Th17 lymphocyte activation in response to stress, bacterial infection or to the combination of both factors. In summary, our project is dedicated to greatly improve our knowledge about the physiopathological mechanisms of COPD and COPD exacerbations. It may allow the discovery of new biomarkers predicting the emergence or the progression of this disease and their exacerbations and to propose new therapeutic targets. This project could lead to suggest innovative therapeutic strategy in order to limit detrimental effects of chronic cigarette smoke exposure and furthermore, susceptibility to subsequent bacterial infection.
The doctorant will be recruited in the context of a 4 years project funded by the "Agence National de Recherche" (ANR). The Doctorant recruited for duration of 36 months will take care, in association with CRCN, MCF, AI and TCN of the team, of the realization of the experiments of Task 1, 3 and 4. This doctorant must have training in experiments in vivo and in vitro. Doctoral fellow should have expertise in lung inflammation, immunology, cellular biology and biochemistry. The realization of experiments in vivo with several groups of 5-10 mice by group, implicate several persons and a lot of manipulations during animal euthanasia and for evaluation of inflammation and remodeling parameters (danger signals, chemokin, cytokine, MMP, TIMP ELISA, Luminex dosage). The doctorant will also perform mice treatments, histology and biochemistry (western blot analysis). Moreover, he will have to derive primary cell lines from mice and to stimulate these cells in vitro. He will also participate to experiments in molecular biology (RT-PCR, qPCR) and FACS. A candidate with the knowledge in the fields of inflammation, tissue remodelling and lung disease will be preferred.
Constraints and risks
Work using mouse models of pathologies in particular mouse model of exposure to cigarette smoke and /or infection with Streptococcus pneumoniae.
A 4 years project funded by the "Agence National de Recherche" (ANR) during 48 months that start on october 2019
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