IL-17 Is a Critical Component of Vaccine-induced Protection against Lung Infection by LPS-heterologous Strains of Pseudomonas aeruginosa

摘要

In a murine model of acute fatal pneumonia, we previously showed that nasal immunization with a live-attenuated aroA deletant of P. aeruginosa strain PAO1 elicited LPS serogroup-specific protection, indicating that opsonic antibody to the LPS O antigen 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 PA14ΔaroA, was constructed. PA14ΔaroA-immunized mice were protected against lethal pneumonia caused not only by the parental strain but also by cytotoxic variants of the O-antigen-heterologous P. aeruginosa strains PAO1 and PAO6a,d. Remarkably, serum from PA14ΔaroA-immunized mice had very low levels of opsonic activity against strain PAO1 and could not passively transfer protection, suggesting an antibody-independent mechanism was needed for the observed cross-serogroup protection. Compared with control mice, PA14ΔaroA-immunized mice had more rapid recruitment of neutrophils to the airways early after challenge. T cells isolated from P. aeruginosa ΔaroA-immunized mice proliferated and produced IL-17 in high quantities after co-culture with gentamicin-killed P. aeruginosa. Six hours following challenge, PA14ΔaroA-immunized mice had significantly higher levels of IL-17 in bronchoalveolar lavage fluid compared with unimmunized, E. coli-immunized, or PAO1ΔaroA-immunized mice. Antibody-mediated depletion of IL-17 prior to challenge or absence of the IL-17 receptor abrogated the PA14ΔaroA 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.