Toll-Like Receptor 9 Deficiency Protects Mice against Pseudomonas aeruginosa Lung Infection

Fatima Benmohamed (1) , Mathieu Medina (1) , Yongzheng Wu (1) , Sophia Maschalidi (2) , Gregory Jouvion (3) , Laurent Guillemot (1) , Michel Chignard (1) , Bénédicte Manoury (2) , Lhousseine Touqui (1)

1 Défense innée et inflammation
2 INSERM - Institut National de la Santé et de la Recherche Médicale
3 Histopathologie humaine et Modèles animaux

Pseudomonas aeruginosa is an opportunistic pathogen involved in nosocomial infections. While a number of studies have demonstrated the roles of TLR2, TLR4 and TLR5 in host defense againt P. aeruginosa infection, the implication of TLR9 in this process has been overlooked. Here, we show that P. aeruginosa DNA stimulates the inflammatory response through TLR9 pathway in both a cell line and primary alveolar macrophages (AMs). This activation requires asparagine endopeptidase- and endosomal acidification. Interestingly, TLR9-/- mice resisted to lethal lung infection by P. aeruginosa, compared to WT C57BL/6 mice. The resistance of TLR9-/- mice to P. aeruginosa infection was associated with: (i) a higher ability of TLR9-/- AMs to kill P. aeruginosa; (ii) a rapid increase in the pro-inflammatory cytokines such as TNFα, IL-1β and IL-6 production; and (iii) an increase in nitric oxide (NO) production and inductible NO synthase expression in AMs. In addition, inhibition of both IL-1β and NO production resulted in a significant decrease of P. aeruginosa clearance by AMs. Altogether these results indicate that TLR9 plays a detrimental role in pulmonary host defense toward P. aeruginosa by reducing the AMs clearance activity and production of IL-1β and NO necessary for bacteria killing.

Domaines: Immunité innée; Bactériologie; Maladies infectieuses

Fatima Benmohamed, Mathieu Medina, Yongzheng Wu, Sophia Maschalidi, Gregory Jouvion, et al.. Toll-Like Receptor 9 Deficiency Protects Mice against Pseudomonas aeruginosa Lung Infection. PLoS ONE, 2014, 9 (3), pp.e90466. ⟨10.1371/journal.pone.0090466⟩. ⟨pasteur-02863037⟩