Department of Microbiology and Immunology, School of Medicine, Tulane University, 1430 Tulane Ave., New Orleans, LA, USA.
Department of Medicine, School of Medicine, Tulane University, 1430 Tulane Ave., New Orleans, LA, USA.
Vaccine. 2019 Feb 4;37(6):808-816. doi: 10.1016/j.vaccine.2018.12.053. Epub 2019 Jan 9.
Respiratory infections are a leading cause of morbidity and mortality globally. This is partially due to a lack of effective vaccines and a clear understanding of how vaccination route and formulation influence protective immunity in mucosal tissues such as the lung. Pseudomonas aeruginosa is an opportunistic pathogen capable of causing acute pulmonary infections and is a leading cause of hospital-acquired and ventilator-associated pneumonia. With multidrug-resistant P. aeruginosa infections on the rise, the need for a vaccine against this pathogen is critical. Growing evidence suggests that a successful P. aeruginosa vaccine may require mucosal antibody and Th1- and Th17-type CD4 T cells to prevent pulmonary infection. Intradermal immunization with adjuvants, such as the bacterial ADP-Ribosylating Enterotoxin Adjuvant (BARE) double mutant of E. coli heat-labile toxin (dmLT), can direct protective immune responses to mucosal tissues, including the lungs. We reasoned that intradermal immunization with P. aeruginosa outer membrane proteins (OMPs) adjuvanted with dmLT could drive neutralizing antibodies and migration of CD4 T cells to the lungs and protect against P. aeruginosa pneumonia in a murine model. Here we show that mice immunized with OMPs and dmLT had significantly more antigen-specific IgG and Th1- and Th17-type CD4 memory T cells in the pulmonary environment compared to control groups of mice. Furthermore, OMPs and dmLT immunized mice were significantly protected against an otherwise lethal lung infection. Protection was associated with early IFN-γ and IL-17 production in the lungs of immunized mice. These results indicate that intradermal immunization with dmLT can drive protective immunity to the lung mucosa and may be a viable vaccination strategy for a multitude of respiratory pathogens.
呼吸道感染是全球发病率和死亡率的主要原因。这在一定程度上是由于缺乏有效的疫苗，以及对疫苗接种途径和配方如何影响肺部等粘膜组织中的保护性免疫的认识不足。铜绿假单胞菌是一种机会性病原体，能够引起急性肺部感染，是医院获得性和呼吸机相关性肺炎的主要原因。随着多药耐药铜绿假单胞菌感染的增加，迫切需要针对这种病原体的疫苗。越来越多的证据表明，成功的铜绿假单胞菌疫苗可能需要粘膜抗体和 Th1 和 Th17 型 CD4 T 细胞来预防肺部感染。用佐剂（如细菌 ADP-核糖基化肠毒素佐剂（BARE）的大肠杆菌不耐热毒素（dmLT）双突变体）进行皮内免疫，可以将保护性免疫反应引导至粘膜组织，包括肺部。我们推断，用 dmLT 佐剂的铜绿假单胞菌外膜蛋白（OMPs）进行皮内免疫可以驱动中和抗体和 CD4 T 细胞向肺部迁移，并在小鼠模型中预防铜绿假单胞菌肺炎。在这里，我们表明，与对照组小鼠相比，用 OMPs 和 dmLT 免疫的小鼠肺部的抗原特异性 IgG 和 Th1 和 Th17 型 CD4 记忆 T 细胞明显更多。此外，OMPs 和 dmLT 免疫的小鼠对原本致命的肺部感染有明显的保护作用。保护作用与免疫小鼠肺部早期 IFN-γ 和 IL-17 的产生有关。这些结果表明，用 dmLT 进行皮内免疫可以驱动对肺部粘膜的保护性免疫，并且可能是针对多种呼吸道病原体的可行疫苗接种策略。
