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

猪链球菌感染过程中荚膜多糖与免疫系统的结构-功能关系

• 批准号: RGPIN-2021-03020
• 负责人: Segura, Mariela
• 金额: $ 4.23万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760665
• 关键词: structure; function; relationships; between; capsular

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.

牲畜抗生素使用的强制性减少和疫苗的缺乏导致了细菌性病原体的重新出现，造成了重大的经济损失和动物福利问题的激增，特别是在养猪业。在这些病原体中，被包裹的细菌是具有挑战性的，因为它们的荚膜多糖（CPS）赋予了伪装，它掩盖了细菌表面的抗原蛋白，否则会引发保护性免疫反应。基于对干预工具的需求，猪链球菌（S. suis）已被归类为养猪业的高优先细菌物种之一。由于CPS的存在，猪链球菌通常对吞噬清除具有高度抗性，除非存在有利于细菌清除的调节抗体。即便如此，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。在适应性免疫应答过程中，B细胞通过抗原接合而被激活，T细胞帮助。与体细胞超突变和类转换重组一起，生发中心的B细胞克隆扩增介导了最终的抗体应答适应度。除了这种经典的T细胞依赖机制，抗体反应可以从T细胞非依赖性途径出现，特别是那些针对CPS的途径。在瑞士的背景下，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，预计会有不同的B细胞反应。一般的假设是包裹的猪链球菌感染调节了对病原体的适应性免疫反应的发展。此外，猪链球菌cps的作用在不同的血清型中是不同的，这一特征影响了抗体反应的动态和功能。基于我们的专业知识，总体目标是剖析参与囊化猪链球菌体液适应性免疫反应的分子和细胞途径。将使用不同的方法来了解包裹的猪链球菌如何调节B细胞活化，从而使抗体多样化。感染/免疫动物血液/组织动态景观的分子研究将与FACS分析相结合，以提供对B细胞活化的机制理解。选定的条件将用于评估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。该项目将产生对包裹生物体及其碳水化合物的免疫反应的基础知识，并为设计未来针对猪链球菌的疫苗策略提供机制理解——这一发展对旨在减少抗菌素使用的猪生产系统具有至关重要的意义。