Le poumon est sensible aux effets locaux et à distance des microbiotes

International audienceThe respiratory physiology is influenced by flows of microorganisms originating mainly from the bucconasal sphere but also by bacterial signals produced locally in the lung and remotely by the intestinal microbiota. This review describes the composition, establishment and functions of the lung microbiota as well as the relationships between the intestinal and pulmonary microbiota underlying the intestine–lung axis.La physiologie respiratoire est influencée par des flux de micro-organismes provenant principalement de la sphère bucco-nasale mais aussi par des signaux bactériens produits localement dans le poumon et à distance par le microbiote intestinal. Cette revue décrit la composition, la mise en place et les fonctions du microbiote du poumon ainsi que les relations entre le microbiote intestinal et le microbiote pulmonaire déterminant l’axe intestin–poumon

La muqueuse pulmonaire en période périnatale : un monde à comprendre pour lutter contre la sensibilité du jeune à la bronchiolite

International audienceDue to infection with the respiratory syncytial virus (RSV), bronchiolitis is the main respiratory disease in infants, and no effective treatments currently exist. The perinatal period is an important stage in the maturation of the lung mucosa, insofar as it largely determines the host's pulmonary reactivity to pathogens. Understanding the physiological, immunological and microbiological characteristics of the lungs in early life may lead to new innovative strategies against infectious agents. We hypothesize that the lung microbiota represents a regulatory factor of paramount importance in young people's health.La bronchiolite est la principale maladie respiratoire du nourrisson contre laquelle il n’existe pas de traitements efficaces. C’est une infection due au virus respiratoire syncytial (VRS). La période périnatale est une phase importante dans la maturation de la muqueuse pulmonaire exerçant un déterminisme sur la réactivité des poumons de l’hôte exposés à des pathogènes. Comprendre les caractéristiques physiologiques, immunologiques et microbiologiques des poumons au début de la vie peut conduire à de nouvelles stratégies innovantes contre les agents infectieux. Nous faisons l’hypothèse que le microbiote pulmonaire est un acteur déterminant de la santé des jeunes

Microbiota educates innate immune response to Toll-like receptors ligands and RSV infection in lung

Since the apparition of new technologies permitting the precise characterization of microorganisms, studies involving microbiotas’ influence swarmed in the literature. It has also brought evidences to raise the emerging concept that the lung is not a sterile compartment and possesses its own microbiota. It has been shown that the lung microbiota could be altered in patients suffering of respiratory diseases, such as asthma or bronchiolitis induced by respiratory syncytial virus (RSV). However, we still don’t know if it is pathologies that influences the dysbiosis or the reverse. Despite this fundamental question, we know that microbiota is able to affect the immune response. But, the manner by which this phenomenon occurs remains elusive. First, using lung explants from specific pathogen free (SPF) and germ-free (GF) mice exposed to Toll-like receptors (TLRs) ligands or RSV, we show a higher production of pro-inflammatory cytokines, notably IL-6 and TNF by lung explants from GF mice compared to SPF mice. These data suggest that microbiota educates innate immune response in lung by reducing pro-inflammatory pathways. We have also observed a more abundant expression of TLR4 in the lungs of GF mice compared to SPF mice, which could predispose the innate immune system of GF mice to react strongly to environmental stimuli. In this context, the microbiota seems to modulate innate immune receptors expression. Not only these data partially explain how the microbiota educates the immune system, but they also allow to strengthen the emerging concept of immunomodulation by probiotics bacteria to prevent respiratory pathology development

Microbiota educates innate immune response to Toll-like receptors ligands and RSV infection in lung

International audienceSince the apparition of new technologies permitting the precise characterization of microorganisms, studies involving microbiotas’ influence swarmed in the literature. It has also brought evidences to raise the emerging concept that the lung is not a sterile compartment and possesses its own microbiota. It has been shown that the lung microbiota could be altered in patients suffering of respiratory diseases, such as asthma or bronchiolitis induced by respiratory syncytial virus (RSV). However, we still don’t know if it is pathologies that influences the dysbiosis or the reverse. Despite this fundamental question, we know that microbiota is able to affect the immune response. But, the manner by which this phenomenon occurs remains elusive. First, using lung explants from specific pathogen free (SPF) and germ-free (GF) mice exposed to Toll-like receptors (TLRs) ligands or RSV, we show a higher production of pro-inflammatory cytokines, notably IL-6 and TNF by lung explants from GF mice compared to SPF mice. These data suggest that microbiota educates innate immune response in lung by reducing pro-inflammatory pathways. We have also observed a more abundant expression of TLR4 in the lungs of GF mice compared to SPF mice, which could predispose the innate immune system of GF mice to react strongly to environmental stimuli. In this context, the microbiota seems to modulate innate immune receptors expression. Not only these data partially explain how the microbiota educates the immune system, but they also allow to strengthen the emerging concept of immunomodulation by probiotics bacteria to prevent respiratory pathology development

Bacteria isolated from lung as biotherapeutics in asthma

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Control of IFN-I responses by the aminopeptidase IRAP in neonatal C57BL/6 alveolar macrophages during RSV infection

International audienceRespiratory Syncytial Virus (RSV) is the major cause of lower respiratory tract infection in infants, in whom, the sensing of RSV by innate immune receptors and its regulation are still poorly described. However, the severe bronchiolitis following RSV infection in neonates has been associated with a defect in type I interferons (IFN-I) production, a cytokine produced mainly by alveolar macrophages (AMs) upon RSV infection in adults. In the present study, neonatal C57BL/6 AMs mobilized very weakly the IFN-I pathway upon RSV infection in vitro and failed to restrain virus replication. However, IFN-I productions by neonatal AMs were substantially increased by the deletion of Insulin-Responsive AminoPeptidase (IRAP), a protein previously involved in the regulation of IFN-I production by dendritic cells. Moreover, neonatal IRAP KO AMs showed a higher expression of IFN-stimulated genes than their wild-type C57BL/6 counterpart. Interestingly, depletion of IRAP did not affect adult AM responses. Finally, we demonstrated that newborn IRAP KO mice infected with RSV had more IFN-I in their lungs and eliminated the virus more efficiently than WT neonates. Taken together, early-life susceptibility to RSV infection may be related to an original age-dependent suppressive function of IRAP on the IFN-I driven-antiviral responses in neonatal AMs

The microbiota plays a critical role in the reactivity of lung immune components to innate ligands

International audienceThe gut microbiota contributes to shaping efficient and safe immune defenses in the gut. However, little is known about the role of the gut and/or lung microbiota in the education of pulmonary innate immune responses. Here, we tested whether the endogenous microbiota in general can modulate the reactivity of pulmonary tissue to pathogen stimuli by comparing the response of specific-pathogen-free (SPF) and germ-free (GF) mice. Thus, we observed earlier and greater inflammation in the pulmonary compartment of GF mice than that of SPF mice after intranasal instillation to lipopolysaccharide (LPS), a component of Gram-negative bacteria. Toll-like receptor 4 (TLR4) was more abundantly expressed in the lungs of GF mice than those of SPF mice at steady state, which could predispose the innate immunity of GF mice to strongly react to the environmental stimuli. Lung explants were stimulated with different TLR agonists or infected with the human airways pathogen, respiratory syncytial virus (RSV), resulting in greater inflammation under almost all conditions for the GF explants. Finally, alveolar macrophages (AM) from GF mice presented a higher innate immune response upon RSV infection than those of SPF mice. Overall, these data suggest that the presence of microbiota in SPF mice induced a process of innate immune tolerance in the lungs by a mechanism which remains to be elucidated. Our study represents a step forward to establishing the link between the microbiota and the immune reactivity of the lungs