Innate Host Defense and Inflammation - Inserm U874  


  HEADDr CHIGNARD Michel / chignard@pasteur.fr
  MEMBERSBALLOY Viviane / BARBIER Diane / BOUTILLON Florence/ Dr DIF Fariel / Dr LE GOFFIC Ronan / Dr POTHLICHET Julien / RAOUST Eloïse / RAYMOND Benoît / Pr SALLENAVE Jean-Michel / Dr SI-TAHAR Mustapha / TATTERMUCH Sonja / Dr TOUQUI Lhousseine / Dr WU Zhongzeng


  Annual Report

Introduction. The lung is the site of various infectious diseases for which mechanisms of innate defense and inflammation play a major role. Chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and different acute infectious pneumonias from bacterial, fungal or viral origins, 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 recently 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. IAV is the etiological agent of a contagious acute respiratory disease. We have recently shown that the sensing of IAV by human REC depends on TLR3, which primarily regulates a pro-inflammatory response and on the RNA helicase RIG-I (but not MDA-5), which mediates both an antiviral signaling and a pro-inflammatory response.Interestingly, although IAV-associated lethality is likely due to an excessive host inflammatory response, the negative feedback mechanisms aimed to regulate such response are unknown. Accordingly, we investigated the role of the eight “suppressor of cytokine signaling” (SOCS) regulatory proteins in IAV-triggered cytokine expression in REC. Using distinct molecular approaches (qRT-PCR, RNA interference, transient SOCS over-expression), we found the critical role of SOCS1 and SOCS3 as negative regulators of IAV-mediated lung mucosal innate immune response. Besides, we also focused 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 undertook studies to (i) characterize the cellular proteases involved in the maturation of HA in the infected host and (ii) analyze theeffect 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. Pulmonary infection by Bacillus anthracis, the agent of anthrax, is the most life-threatening form of this disease causing near 100 % mortality in absence of therapy. Infection can occur either accidentally or as a potential consequence of a terrorism threat.We have shown that alveolar macrophages (AMs) produce an enzyme named phospholipase A2-IIA (sPLA2-IIA) that plays a key role in innate defense against B. anthracis. We recently showed that B. anthracisstimulates the synthesis of sPLA2-IIA by AMs, this stimulation being counterbalanced by the inhibitory effect of the edema toxin produced by germinated spores and bacilli of B. anthracis. Our study suggests that inhibition of sPLA2-IIA synthesis by the edema toxin is a mechanism by which B. anthraciscan escape innate host defense. These pioneering data provide new molecular targets for future intervention against this deadly pathogen.

Keywords: Innate immunity, Lung, Infection

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  Publications

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

Le Goffic R, Pothlichet J, Vitour D, Fujita T, Meurs E, Chignard M, Si-Tahar M. Cutting Edge: Influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells. J Immunol. 2007;178:3368-72.

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.

Ramphal R, Balloy V, Huerre M, Si-Tahar M, Chignard M. TLRs 2 and 4 are not involved in hypersusceptibility to acute Pseudomonas aeruginosa lung infections. J Immunol. 2005;175:3927-34.

Balloy V, Si-Tahar M, Takeuchi O, Philippe B, Nahori MA, Tanguy M, Huerre M, Akira S, Latgé JP, Chignard M. Involvement of toll-like receptor 2 in experimental invasive pulmonary aspergillosis. Infect Immun. 2005;73:5420-5.





Activity Reports 2007 - Institut Pasteur
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