Bertot Gustavo M, Restelli Marcela A, Galanternik Laura, Aranibar Urey Rene C, Valvano Miguel A, Grinstein Saúl
Laboratorio de Virología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, 1425 Buenos Aires, Argentina.
Infect Immun. 2007 Jun;75(6):2740-52. doi: 10.1128/IAI.01668-06. Epub 2007 Feb 12.
Chronic lung infection by opportunistic pathogens, such as Pseudomonas aeruginosa and members of the Burkholderia cepacia complex, is a major cause of morbidity and mortality in patients with cystic fibrosis. Outer membrane proteins (OMPs) of gram-negative bacteria are promising vaccine antigen candidates. In this study, we evaluated the immunogenicity, protection, and cross-protection conferred by intranasal vaccination of mice with OMPs from B. multivorans plus the mucosal adjuvant adamantylamide dipeptide (AdDP). Robust mucosal and systemic immune responses were stimulated by vaccination of naive animals with OMPs from B. multivorans and B. cenocepacia plus AdDP. Using a mouse model of chronic pulmonary infection, we observed enhanced clearance of B. multivorans from the lungs of vaccinated animals, which correlated with OMP-specific secretory immunoglobulin A responses. Furthermore, OMP-immunized mice showed rapid resolution of the pulmonary infection with virtually no lung pathology after bacterial challenge with B. multivorans. In addition, we demonstrated that administration of B. multivorans OMP vaccine conferred protection against B. cenocepacia challenge in this mouse infection model, suggesting that OMPs provide cross-protection against the B. cepacia complex. Therefore, we concluded that mucosal immunity to B. multivorans elicited by intranasal vaccination with OMPs plus AdDP could prevent early steps of colonization and infection with B. multivorans and also ameliorate lung tissue damage, while eliciting cross-protection against B. cenocepacia. These results support the notion that therapies leading to increased mucosal immunity in the airways may help patients with cystic fibrosis.
由铜绿假单胞菌和洋葱伯克霍尔德菌复合体成员等机会致病菌引起的慢性肺部感染，是囊性纤维化患者发病和死亡的主要原因。革兰氏阴性菌的外膜蛋白（OMPs）是很有前景的疫苗抗原候选物。在本研究中，我们评估了用多食伯克霍尔德菌的OMPs加黏膜佐剂金刚烷基酰胺二肽（AdDP）对小鼠进行鼻内接种所赋予的免疫原性、保护作用和交叉保护作用。用多食伯克霍尔德菌和洋葱伯克霍尔德菌的OMPs加AdDP对未接触过抗原的动物进行接种，可刺激产生强大的黏膜和全身免疫反应。使用慢性肺部感染小鼠模型，我们观察到接种疫苗的动物肺部多食伯克霍尔德菌的清除增强，这与OMP特异性分泌型免疫球蛋白A反应相关。此外，用OMP免疫的小鼠在受到多食伯克霍尔德菌攻击后，肺部感染迅速消退，几乎没有肺部病理变化。此外，我们证明在该小鼠感染模型中，给予多食伯克霍尔德菌OMP疫苗可提供针对洋葱伯克霍尔德菌攻击的保护作用，这表明OMPs可提供针对洋葱伯克霍尔德菌复合体的交叉保护作用。因此，我们得出结论，用OMPs加AdDP进行鼻内接种引发的对多食伯克霍尔德菌的黏膜免疫可预防多食伯克霍尔德菌定植和感染的早期阶段，还可改善肺组织损伤，同时引发针对洋葱伯克霍尔德菌的交叉保护作用。这些结果支持这样一种观点，即导致气道黏膜免疫增强的疗法可能有助于囊性纤维化患者。
