Innate Host Defense and Inflammation - INSERM U874  


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


  Annual Report

Introduction. Innate immune mechanisms play major roles in defense of the lungs against infectious diseases caused by bacteria, fungi and viruses. This evolutionarily conserved initial response of the host is intended to eradicate pathogens, however, by its very nature, in eliciting an inflammatory cascade, it may cause injury and be the main reason for disease manifestations. Our objectives are thus to understand the molecular mechanisms and the contribution of innate immunity to microbial lung disease and to design strategies to prevent or treat them.

Role of the Toll-like receptors (TLRs). TLRs recognize distinct conserved motifs on microorganisms. We specifically studied the role of TLRs in lung disease caused by the opportunistic fungus Aspergillus fumigatus, the Gram- bacterium Pseudomonas aeruginosa and Influenza A virus (IAV). We found that (i) A. fumigatus induces innate responses in alveolar macrophages (AM) through the MAPK pathway independently of TLR2 and TLR4 (collaboration with the unit of Aspergillus); (ii) that the susceptibility of mice to P. aeruginosa lung infection does not depend on TLR2 or TLR4, implying that an innate immune response to Pseudomonas LPS is not the most important virulence mechanism. By contrast, the use of mutants lacking flagellin, suggested a role for TLR5; and (iii) IAV infected TLR3-/- mice show reduced amounts of lung inflammatory mediators and an unexpected survival advantage compared to wild-type mice, confirming a previous in vitro study that revealed a role of TLR3 as a key IAV sensor.

Implication of the urokinase receptor (uPAR/CD87). During lung infection, proteinases released by host cells and bacteria (e.g. P. aeruginosa) play roles as effectors of immunity, but may be deleterious. We (i) demonstrated the capacity of proteinases secreted by pulmonary epithelial cells and by P. aeruginosa to cleave CD87, a receptor involved in the recruitment of inflammatory cells and in tissue repair and (ii) identified their cleavage sites on CD87.

Regulation and roles of phospholipase A2. PLA2s release fatty acids, e.g. arachidonic acid (AA), which modulate inflammation. PLA2s consist of cytosolic (cPLA2) and secreted (sPLA2) forms e.g. sPLA2-IIA. We showed that sPLA2-IIA kills Bacillus anthracis, the etiological agent of anthrax, but its edema toxin inhibits the expression of sPLA2-IIA by AM. This inhibition may help the bacterium to escape the bactericidal activity of sPLA2-IIA. We also observed that cPLA2, via AA release, plays a role in mucus hypersecretion in the lungs of Cystic Fibrosis (CF) mice. This hypersecretion is a key process in the pathophysiology of CF. Thus our findings suggest that cPLA2 inhibitors may have a potential therapeutic benefit in the treatment of CF.

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  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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