Cross-serotype protection against Streptococcus pneumoniae by induction of neutra

描述(由申请人提供)：有效的肺炎链球菌疫苗接种是儿童和成人细菌性肺炎最常见和最严重的原因，但导致疾病的大量抗原性不同的衣壳血清型使接种疫苗变得复杂。一种疫苗必须包括多种衣壳血清型，但未能预防其中一种是疫苗的失败。此外，由于疫苗压力，与疾病和疫苗相关的菌株正在向非疫苗类型转移。我们建议用一种在肺炎球菌血清型中保守的免疫原性蛋白来促进对肺炎链球菌定植和随后侵袭性疾病的保护。这种蛋白，即IgA1蛋白酶(IgA1P)，可能通过颠覆粘膜宿主防御而参与微生物的发病。事实上，我们和其他人已经证明，胶囊特异性的IgA支持杀死肺炎链球菌，而肺炎链球菌的IgA1P抑制这种依赖于IgA的杀伤。此外，被蛋白酶裂解的囊膜特异性IgA通过修改细菌表面来增强对上皮表面的黏附，这可能会促进定植和随后的疾病。在我们的初步研究中，患有肺炎球菌菌血症的成年人产生了中和IgA1P蛋白分解活性的抗体。我们建议表征该酶的多样性，以及宿主产生的抗IgA1P的抗体抑制该酶、阻断与蛋白酶相关的杀伤抑制和增强黏附的能力和机制。这项早期的翻译研究将评估将IgA1P作为蛋白质疫苗抗原的可行性，以促进对肺炎链球菌定植、肺炎和侵袭性疾病的跨血清型保护。

DESCRIPTION (provided by applicant): Effective vaccination against Streptococcus pneumoniae, the most common and serious cause of bacterial pneumonia in children and adults, is complicated by the high number of antigenically-distinct capsular serotypes that cause disease. Multiple capsular serotypes must be included in a vaccine, but failure to protect against one is failure of the vaccine. Moreover, disease- and vaccine-associated strains are shifting toward non-vaccine types in response to vaccine pressure. We propose to promote protection against colonization and subsequent invasive disease by S. pneumoniae with an immunogenic protein that is conserved among pneumococcal serotypes. This protein, IgA1 protease (IgA1P), likely contributes to microbial pathogenesis by subverting mucosal host defense. Indeed, we and others have shown that capsule-specific IgA supports killing of S. pneumoniae, and that the IgA1P of S. pneumoniae inhibits such IgA-dependent killing. Moreover, capsule-specific IgA cleaved by the protease enhances adherence to epithelial surfaces by modifying the bacterial surface, which may promote colonization and subsequent disease. In our preliminary studies, adults with pneumococcal bacteremia generated IgG antibodies that neutralize the proteolytic activity of IgA1P. We propose to characterize the diversity of the enzyme and the ability of and mechanisms by which IgG antibodies to IgA1P generated by the host inhibit the enzyme, and block protease-related inhibition of killing and enhancement of adherence. This early translational study will evaluate the feasibility of incorporating IgA1P as a protein vaccine antigen to facilitate cross-serotype protection against S. pneumoniae colonization, pneumonia and invasive disease.