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Alveolar Response to Pseudomonas aeruginosa: Role of the Type III Secretion System

F. Ader,^1,2, R. Le Berre,^1,3, K. Faure,¹ P. Gosset,⁴ O. Epaulard,⁵ B. Toussaint,⁵ B. Polack,⁵ E. Nowak,⁶ N. B. Viget,¹ E. Kipnis,⁷ and B. P. Guery^1*

Laboratoire de Recherche en Pathologie Infectieuse, EA 2689, Faculté de Médecine de Lille, 59045 Lille, France,¹ Département de Médecine Aiguë Spécialisée, CHU Raymond Poincaré (AP-HP), 92380 Garches, France,² Service de Maladies Infectieuses, CHU de la Cavale Blanche, 29609 Brest, France,³ INSERM U416, Institut Pasteur, Lille, France,⁴ Groupe d'Etude et de Recherche du Processus Inflammatoire (GREPI, EA2938), Labo Enzymologie-DBPC, CEA CHU-Grenoble BP217, 38043 Grenoble, France,⁵ Laboratoire de Statistique et Informatique, ISA, 41 Rue du Port, 59046 Lille, France,⁶ Department of Anesthesia and Perioperative Care, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, California 94143-0542⁷

Received 1 December 2004/ Returned for modification 17 January 2005/ Accepted 7 March 2005

The type III secretion system (TTSS) is a specialized cytotoxin-translocating apparatus of gram-negative bacteria which is involved in lung injury, septic shock, and a poor patient outcome. Recent studies have attributed these effects mainly to the ExoU effector protein. However, few studies have focused on the ExoU-independent pathogenicity of the TTSS. For the present study, we compared the pathogenicities of two strains of Pseudomonas aeruginosa in a murine model of acute lung injury. We compared the CHA strain, which has a functional TTSS producing ExoS and ExoT but not ExoU, to an isogenic mutant with an inactivated exsA gene, CHA-D1, which does not express the TTSS at all. Rats challenged with CHA had significantly increased lung injury, as assessed by the wet/dry weight ratio for the lungs and the protein level in bronchoalveolar lavage fluid (BALF) at 12 h, compared to those challenged with CHA-D1. Consistent with these findings, the CHA strain was associated with increased in vitro cytotoxicity on A549 cells, as assessed by the release of lactate dehydrogenase. CHA was also associated at 12 h with a major decrease in polymorphonuclear neutrophils in BALF, with a proinflammatory response, as assessed by the amounts of tumor necrosis factor alpha and interleukin-1ß, and with decreased bacterial clearance from the lungs, ultimately leading to an increased mortality rate. These results demonstrate that the TTSS has a major role in P. aeruginosa pathogenicity independent of the role of ExoU. This report underscores the crucial roles of ExoS and ExoT or other TTSS-related virulence factors in addition to ExoU.

Editor: J. B. Bliska

F. Ader and R. Le Berre gave equivalent contributions to this work.

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