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IL-17 Is a Critical Component of Vaccine-Induced Protection against Lung Infection by Lipopolysaccharide-Heterologous Strains of Pseudomonas aeruginosa¹

Gregory P. Priebe^2,*,,, Rebecca L. Walsh^*, Terra A. Cederroth^*, Akinobu Kamei^*, Yamara S. Coutinho-Sledge^*, Joanna B. Goldberg and Gerald B. Pier^*,

^* Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Departments of Anesthesia (Critical Care) and Medicine (Infectious Diseases), Children’s Hospital Boston, and Harvard Medical School, Boston, MA 02115; and Department of Microbiology, University of Virginia, Charlottesville, VA 22908

In a murine model of acute fatal pneumonia, we previously showed that nasal immunization with a live-attenuated aroA deletant of Pseudomonas aeruginosa strain PAO1 elicited LPS serogroup-specific protection, indicating that opsonic Ab to the LPS O Ag was the most important immune effector. Because P. aeruginosa strain PA14 possesses additional virulence factors, we hypothesized that a live-attenuated vaccine based on PA14 might elicit a broader array of immune effectors. Thus, an aroA deletant of PA14, denoted PA14aroA, was constructed. PA14aroA-immunized mice were protected against lethal pneumonia caused not only by the parental strain but also by cytotoxic variants of the O Ag-heterologous P. aeruginosa strains PAO1 and PAO6a,d. Remarkably, serum from PA14aroA-immunized mice had very low levels of opsonic activity against strain PAO1 and could not passively transfer protection, suggesting that an antibody-independent mechanism was needed for the observed cross-serogroup protection. Compared with control mice, PA14aroA-immunized mice had more rapid recruitment of neutrophils to the airways early after challenge. T cells isolated from P. aeruginosa aroA-immunized mice proliferated and produced IL-17 in high quantities after coculture with gentamicin-killed P. aeruginosa. Six hours following challenge, PA14aroA-immunized mice had significantly higher levels of IL-17 in bronchoalveolar lavage fluid compared with unimmunized, Escherichia coli-immunized, or PAO1aroA-immunized mice. Antibody-mediated depletion of IL-17 before challenge or absence of the IL-17 receptor abrogated the PA14aroA vaccine’s protection against lethal pneumonia. These data show that IL-17 plays a critical role in antibody-independent vaccine-induced protection against LPS-heterologous strains of P. aeruginosa in the lung.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants K08 AI50036 and R21 HL079423 (to G.P.P.), R01AI068112 (to J.B.G.), and AI22535 (to G.B.P.).

² Address correspondence and reprint requests to Dr. Gregory P. Priebe, Brigham and Women’s Hospital, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail address: gpriebe{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: TSA, tryptic soy agar; KO, knockout; BALF, bronchoalveolar lavage fluid.