The structure-function relationships between capsular polysaccharides and the immune system during Streptococcus suis infections

强制减少牲畜抗生素的使用和疫苗的缺乏导致了造成重大经济损失的细菌病原体的重新出现，以及对动物福利的关注激增，特别是在养猪业。在这些病原体中，包裹的细菌具有挑战性，因为它们的荚膜多糖(CPS)具有伪装作用，它将抗原蛋白包裹在细菌表面，否则会引发保护性免疫反应。根据干预工具的需要，猪链球菌(S.suis)已被归类为养猪业的高优先级细菌之一。由于CPS，猪链球菌一般对吞噬清除具有高度抵抗力，除非存在调理抗体，这有助于细菌清除。尽管如此，猪链球菌感染期间适应性(体液)免疫的发展仍然知之甚少，因此导致缺乏商业疫苗来对抗猪的这种疾病。在适应性免疫反应中，B细胞通过抗原结合而被激活，而T细胞则起到帮助作用。生发中心的B细胞克隆性扩增与体细胞高突变和类切换重组一起，介导了最终抗体应答的适合性。除了这种经典的T细胞依赖机制外，抗体反应还可以来自T细胞非依赖的途径，特别是那些针对CPS的途径。在猪链球菌的背景下，这些方面在很大程度上是未知的。此外，根据目前对猪链球菌CPS血清型及其行为的了解，预期会有不同的B细胞反应。一般的假设是，猪链球菌囊化感染调节对病原体的适应性免疫反应的发展。此外，猪链球菌CPSS的作用因血清型不同而不同，这一特征影响抗体反应的动力学和功能。在我们专业知识的基础上，总的目标是剖析参与猪链球菌囊膜体液适应性免疫反应的分子和细胞途径。不同的方法将被用来了解包裹的猪链球菌如何调节B细胞的激活，从而调节抗体的多样化。对感染/免疫动物血液/组织动态景观的分子研究将与流式细胞仪分析相结合，以提供对B细胞激活的机制理解。选择的条件将被用来评估CPS类型对体液反应的影响。我们将描述抗体反应和诱导抗体的生物学特性。该计划将产生有关被包裹的生物体及其碳水化合物的免疫反应的基础知识，并为设计未来的猪链球菌疫苗策略提供机械上的理解-这一发展对旨在减少抗菌剂使用的生猪生产系统具有极其重要的意义。

The compulsory reduction in livestock antibiotic use and lack of vaccines have led to the re-emergence of bacterial pathogens responsible for significant economic loss and a surge in animal welfare concerns, particularly in the swine industry. Among these pathogens, encapsulated bacteria are challenging due to the camouflage conferred by their capsular polysaccharide (CPS), which cloaks antigenic proteins on the bacterial surface that would otherwise trigger a protective immune response. The encapsulated bacterium Streptococcus suis (S. suis) has been classified as one of the swine industry's high-priority bacterial species based on the need for intervention tools. Due to the CPS, S. suis is generally highly resistant to phagocytic clearance, except in the presence of opsonizing antibodies, which facilitate bacterial elimination. Even so, the development of adaptive (humoral) immunity during S. suis infection is still poorly understood and thus translates into a lack of commercial vaccines to fight this disease in pigs. During the adaptive immune response, B cells are activated through antigen engagement, and T cell help. Together with somatic hypermutation and class-switch recombination, B cell clonal expansion in germinal centers mediate final antibody response fitness. Besides this classical T cell-dependent mechanism, antibody responses can emerge from T cell-independent pathways, especially those directed against the CPS. In the context of S. suis, these aspects are largely unknown. Furthermore, based on current knowledge on S. suis CPS serotypes and their behaviours, divergent B cell responses are expected. The general hypothesis is that encapsulated S. suis infections modulate the development of the adaptive immune response to the pathogen. Moreover, the role of S. suis CPSs differs between serotypes, and this feature impacts the dynamics and functionality of the antibody response. Building on our expertise, the general aim is to dissect the molecular and cellular pathways involved in the humoral adaptive immune response to encapsulated S. suis. Different methods will be used to understand how encapsulated S. suis modulates B cell activation and, consequently, antibody diversification. Molecular studies of the dynamic landscape in blood/tissues of infected/immunized animals will be combined with FACS analyses to provide a mechanistic understanding of B cell activation. Selected conditions will be used to evaluate the influence of the CPS type on the humoral response. We will characterize the antibody response and biological properties of induced antibodies. This program will generate fundamental knowledge on the immune response to encapsulated organisms and their carbohydrates, as well as provide a mechanistic understanding to design future vaccine strategies against S. suis - a development that is of utmost significance for swine production systems aiming to reduce antimicrobial use.