Cross-serotype protection against Streptococcus pneumoniae by induction of neutra

描述（由申请方提供）：肺炎链球菌是儿童和成人细菌性肺炎的最常见和最严重原因，其有效疫苗接种因引起疾病的大量抗原性不同的荚膜血清型而复杂化。多种荚膜血清型必须包括在疫苗中，但不能保护免受一种是疫苗的失败。此外，疾病和疫苗相关菌株正在向非疫苗类型转移，以应对疫苗压力。我们建议促进保护免受殖民化和随后的入侵性疾病的S。肺炎球菌血清型中保守的免疫原性蛋白。这种蛋白质，IgA1蛋白酶（IgA1P），可能有助于微生物的发病机制，破坏粘膜宿主的防御。事实上，我们和其他人已经表明，囊特异性伊加支持杀死S。pneumoniae肺炎链球菌的IgA_（1P）与肺炎链球菌的IgA_（1P）之间存在明显的相关性。肺炎克雷伯氏菌抑制这种IgA依赖性杀伤。此外，被蛋白酶切割的囊特异性伊加通过修饰细菌表面来增强对上皮表面的粘附，这可能会促进定植和随后的疾病。在我们的初步研究中，成人肺炎球菌菌血症产生的IgG抗体，中和蛋白水解活性的IgA1P。我们建议表征酶的多样性和宿主产生的IgA1P的IgG抗体抑制酶的能力和机制，并阻止蛋白酶相关的抑制杀伤和增强粘附。这项早期翻译研究将评估将IgA1P作为蛋白疫苗抗原以促进抗S.肺炎定植、肺炎和侵袭性疾病。 公共卫生相关性：肺炎球菌是全球儿童和成人细菌性肺炎的主要原因。感染开始于上呼吸道，在那里抗体试图结合并抑制细菌毒力因子。这种细菌通过产生一种酶，即IgA 1蛋白酶，将这些潜在的保护性局部抗体切割成两半。我们建议阻断IgA 1蛋白酶的活性，以提高当地疫苗和自然宿主防御的有效性。

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. PUBLIC HEALTH RELEVANCE: The pneumococcus is the leading cause of bacterial pneumonia worldwide in children and adults. The infection starts in the upper airway where antibodies attempt to bind and inhibit bacterial virulence factors. The bacteria disarm these potentially protective local antibodies by producing an enzyme, IgA1 protease that cuts them in half. We propose to block the activity of IgA1 protease to enhance the effectiveness of local vaccines and of natural host defenses.