|Innate Host Defense and Inflammation - Inserm|
|HEAD||Dr Michel Chignard / email@example.com|
|MEMBERS||Dr Viviane Balloy, Diane Barbier, Dr Anne Burtey, Dr Michel Chignard, Dr Delphyne Descamps, Dr Ignacio Garcia Verdugo, Dominique Leduc, Dr Laurent Magne, Dr Julien Pothlichet, Eloïse Raoust, Benoît Raymond, Pr Jean-Michel Sallenave, Dr Mustapha Si-Tahar, Brigitte Solhonne, Dr Lhousseine Touqui, Josiane Villeneuve, Dr Yongzheng Wu
Introduction. The lung is the site of various infectious diseases for which mechanisms of innate defense and inflammation play a major role. Acute pneumonias from bacterial, fungal or viral origins and Chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF) are typical lung pathologies. The induction of innate defense is a beneficial process but its exacerbation may lead to a pathologic inflammatory status. Therefore, the aim of our research is to contribute to the qualitative and quantitative understanding of the mechanisms involved in these diseases, which would allow to target the events enhancing innate immunity without exacerbating the inflammatory process, or to down-regulate inflammation without compromising innate defense.
Role of Toll-like receptors (TLR) in fungal and bacterial infections. TLR recognize specific conserved molecular patterns expressed by microorganisms and trigger an innate immune response. We specifically studied the role of those receptors in the defense against microorganisms such as the opportunistic fungus Aspergillus fumigatus, and the Gram- bacteria Pseudomonas aeruginosa. Although it has been reported thatA. fumigatusinduces innate responses in vivothrough TLR2 (our own data in collaboration with the Unité des Aspergillus), TLR4 and MyD88, we observed that respiratory epithelial cells (REC) activated by A. fumigatusin vitroproduced IL-8 independently from these pathways. Besides, we looked also at the susceptibility of mice to P. aeruginosaacute lung infection and observed using TLR2 or TLR4 deficient mice and mutant bacteria lacking expression of flagellin, that either TLR4 or TLR5 redundantly defend the lung from P. aeruginosainfection.
Molecular mechanisms involved in innate immune response to influenza A virus (IAV) infection. Several evidences shows that genetic mutations are important determinants of increased susceptibility to viral diseases. Among them, single-nucleotide polymorphisms (SNPs) occur when a single nucleotide is altered. RIG-I is a pivotal receptor that detects numerous RNA and DNA viruses. Thus, its defectiveness may strongly impair the host antiviral immunity. Remarkably, RIG-I SNPs presenting a functional impact on host response have not been described. Thus, we conducted a study to characterize potential natural mutations in the coding sequence of RIG-I that could be associated with a modulated antiviral response and place individuals at distinct risk of viral infections. Using biochemical and structural modeling approaches, we identified two critical variants: (i) one frameshift mutation that generates a constitutively active receptor and (ii) one missense mutation that drastically inhibits antiviral signaling and exertsa dominant-negative effect, due to unintended stable complexes of RIG-I with itself and with MAVS, a key adapter molecule. Hence, we characterized twoSNPs as major functional RIG-I variants and potential genetic determinants of viral susceptibility.
In parallel, we also focus on the mechanisms of IAV entry into cells. This process is considered to be triggered by host cellular trypsin-type proteases, which proteolytically activate the viral surface hemagglutinin (HA). We performed studies to (i) characterize the cellular proteases involved in the maturation of HA in the infected host and (ii) analyze the effect of anti-proteases in vivo usingan adenovirus(Ad)-mediated gene transfer strategy as well as transgenic mice. Altogether, these studies may constitute a key step towards the identification of new targets for the treatment of IAV infections.
Mechanisms of regulation and roles of phospholipases A2. We pursued our investigation on the mechanisms by whichBacillus anthracis, the etiological agent of anthrax, subvert host defense. We showed that B. anthracisstimulates lung inflammation (cytokine production and PMN recruitment) and that these responses are repressed by a prior instillation of the Lethal Toxin (LT), a major virulence factor of this bacterium. This inhibiton is also observedin vitro using mouse and human pulmonary epithelial cells. These effects are associated to an alteration of ERK and p38-MAPK phosphorylation, but not JNK phosphorylation. We demonstrated that, although NF-κB is essential for IL-8 expression, LT down-regulates this expression without interfering with NF-κB activation in epithelial cells. Histone modifications are known to induce chromatin remodelling thereby enhancing NF-κB binding on promoters of a subset of genes involved in immune response. We showed that LT selectively prevents histone H3 phosphorylation, and recruitment of the p65 subunit of NF-κB at the IL-8 and KC promoters. We suggest thatB. anthracisrepresses the immune response, in part, by altering chromatin accessibility of IL-8 promoter to NF-κB in epithelial cells. This epigenetic reprogramming, in addition to previously reported effects of LT, may represent an efficient strategy used byB. anthracis for invading the host.
Modulation of the maladaptive host response in cystic fibrosis. The neutrophil is the major inflammatory cell type within the CF airway and this cell type is over-activated as indicated by the high levels of neutrophil elastase (NE) bioactivity released in lung secretions. This enzyme is therefore a key player in the perpetuation of maladaptive infection/inflammation cycle observed in CF. Using pleiotropic anti-NE/anti-infective molecules (SLPI and elafin : over-expression obtained by adenovirus and in transgenic mice) , we aim to correct ‘in vitro’ (‘CF cells’) and ‘in vivo’ (CFTR KO mice and ‘CFTR dF508 mice’) the maladaptive CF phenotype and restore normal inflammatory/ion conductance profiles in this pathology.
Keywords: Innate immunity, Lung, Infection, Signalling
- Balloy V, Sallenave JM, Wu Y, Touqui L, Latgé JP, Si-Tahar M, Chignard M. Aspergillus fumigatus-induced interleukin-8 synthesis by respiratory epithelial cells is controlled by the phosphatidylinositol 3-kinase, p38 MAPK, and ERK1/2 pathways and not by the toll-like receptor-MyD88 pathway. J Biol Chem. 2008;283:30513-21.
- Ramphal R, Balloy V, Jyot J, Verma A, Si-Tahar M, Chignard M. Control of Pseudomonas aeruginosa in the lung requires the recognition of either lipopolysaccharide or flagellin. J Immunol. 2008;181:586-92.
- Pothlichet J, Chignard M, Si-Tahar M. Cutting edge: innate immune response triggered by influenza A virus is negatively regulated by SOCS1 and SOCS3 through a RIG-I/IFNAR1-dependent pathway. J Immunol. 2008;180:2034-8.
- Raymond B, Leduc D, Ravaux L, Goffic RL, Candela T, Raymondjean M, Goossens PL, Touqui L. Edema Toxin Impairs Anthracidal Phospholipase A2 Expression by Alveolar Macrophages. PLoS Pathog. 2007;3:e187.
- Roghanian A, Drost EM, MacNee W, Howie SE, Sallenave JM. Inflammatory lung secretions inhibit dendritic cell maturation and function via neutrophil elastase. Am J Respir Crit Care Med. 2006;174:1189-98.
Activity Reports 2009 - Institut Pasteur
If you have problems with this Web page, please write to firstname.lastname@example.org