PDF(Pubmed)
Abstract：
Nontypeable Haemophilus influenzae (NTHi) is a major cause of community acquired pneumonia and exacerbation of chronic obstructive pulmonary disease. A current effort in NTHi vaccine development has focused on generating humoral responses and has been greatly impeded by antigenic variation among the numerous circulating NTHi strains. In this study, we showed that pulmonary immunization of mice with killed NTHi generated broad protection against lung infection by different strains. While passive transfer of immune antibodies protected only against the homologous strain, transfer of immune T cells conferred protection against both homologous and heterologous strains. Further characterization revealed a strong Th17 response that was cross-reactive with different NTHi strains. Responding Th17 cells recognized both cytosolic and membrane-associated antigens, while immune antibodies preferentially responded to surface antigens and were highly strain specific. We further identified several conserved proteins recognized by lung Th17 cells during NTHi infection. Two proteins yielding the strongest responses were tested as vaccine candidates by immunization of mice with purified proteins plus an adjuvant. Immunization induced antigen-specific Th17 cells that recognized different strains and, upon adoptive transfer, conferred protection. Furthermore, immunized mice were protected against challenge with not only NTHi strains but also a fully virulent, encapsulated strain. Together, these results show that the immune mechanism of cross-protection against pneumonia involves Th17 cells, which respond to a broad spectrum of antigens, including those that are highly conserved among NTHi strains. These mechanistic insights suggest that inclusion of Th17 antigens in subunit vaccines offers the advantage of inducing broad protection and complements the current antibody-based approaches.
摘要：
不可分型的流感嗜血杆菌（NTHi）是社区获得性肺炎和慢性阻塞性肺疾病恶化的主要原因。目前在NTHi疫苗开发中的努力集中在产生体液应答上,并且受到许多循环NTHi菌株之间的抗原变异的极大阻碍。在这项研究中,我们表明，用杀死的NTHi的小鼠的肺免疫产生了针对不同菌株的肺部感染的广泛保护。虽然免疫抗体的被动转移仅对同源菌株有保护作用，免疫T细胞的转移赋予了针对同源和异源菌株的保护。进一步表征揭示了与不同NTHi菌株交叉反应的强Th17反应。应答Th17细胞识别胞质和膜相关抗原，而免疫抗体优先响应表面抗原，并且具有高度的菌株特异性。我们进一步鉴定了在NTHi感染期间由肺Th17细胞识别的几种保守蛋白。通过用纯化的蛋白质加佐剂免疫小鼠,测试两种产生最强应答的蛋白质作为疫苗候选物。免疫诱导识别不同菌株的抗原特异性Th17细胞，在收养转移后，授予保护。此外，免疫小鼠不仅受到NTHi菌株的攻击，而且受到完全毒力的攻击，封装菌株。一起,这些结果表明，肺炎交叉保护的免疫机制涉及Th17细胞，对广谱的抗原有反应，包括在NTHi菌株中高度保守的那些。这些机制的见解表明，在亚单位疫苗中包含Th17抗原提供了诱导广泛保护的优势，并补充了当前基于抗体的方法。
