Regulation of bacterial polysaccharide-specific B cell responses

接种疫苗可诱导免疫记忆，是预防传染病最有效的手段。 记忆抗体反应的大小和动力学与抗体的数量和数量成正比 抗原特异性记忆B细胞的质量。宿主与细菌病原体的相互作用导致更多 与分离的细菌成分相比，复杂的免疫反应通常被结合到 疫苗。为了了解对整个细菌的免疫反应的复杂性，我们以前使用了一个 细菌感染系统，并发现了B1B细胞的新作用。而驱动这种病毒的特定抗原 这些细菌系统中的保护性B细胞反应已被鉴定，例如沙门氏菌Vi多糖。 伤寒，B细胞对这些T细胞非依赖抗原记忆的分子机制仍有待研究 明白了。已知，用包括VIPS和PPS在内的纯化多糖再次免疫会导致 反应迟钝，导致人们严重关注助推器战略的有效性 目前正在实践中的这类疫苗。最近，PPS和VIPS结合的疫苗接种策略失败了 在疾病流行地区诱导增强反应。我们之前曾假设，高效的T细胞- 独立的B细胞反应需要与B细胞抗原受体和共刺激分子结合 受体，如Toll样受体。事实上，我们发现表达VIP的细菌会诱导VIP增强- 特异性二次免疫球蛋白M和免疫球蛋白G反应与一次反应的比较，这表明PS特异性 B细胞记忆。与之形成鲜明对比的是，对伤寒Vi®的二次反应，一种由纯化的VIP组成的疫苗， 与原发反应相比严重受损表明B细胞低反应和 这种强化免疫策略从未在人类身上确定过。伤寒沙门氏菌是一种人类限制的 致病菌，不能有效地感染常用的近亲繁殖的实验室小鼠。这是一个很大的障碍 努力了解针对人类伤寒的保护性多糖特异性记忆反应。S。 鼠伤寒病毒感染系统已被用作人伤寒的小鼠模型。用一本小说 最近被改造成表达伤寒沙门氏菌表面特征的鼠伤寒沙门氏菌嵌合菌株， 我们能够证明，抗VIP反应的损害与不止一个数量级的 与整个细菌免疫相比，细菌负担要高出一个数量级。此外，使用新的和 我们鉴定的被称为合作杂交(CC)的重组近交系小鼠品系的扩展小组 两个独立的CC小鼠品系可以高效感染伤寒沙门氏菌并形成组织学 这些特征与从伤寒感染者身上提取的活检组织惊人地相似。初步结果显示 CC小鼠免疫可产生强大的VIPS特异性抗体反应。总而言之，这些发现 提示嵌合鼠伤寒沙门氏菌株和CC小鼠均可作为新的体内翻译 评估多糖特异性B细胞反应的功能特征的平台。

Vaccination induces immunological memory and is the most effective means of preventing infectious diseases. The magnitude and kinetics of anamnestic antibody responses is directly proportional to the quantity and quality of antigen-specific memory B cells. Host interactions with bacterial pathogens result in far more complex immune responses compared to isolated bacterial components that are commonly incorporated into vaccines. To understand the complexity of immune responses to whole bacteria we previously utilized a bacterial infection system and discovered a novel role for B1b cells. While the specific antigens driving the protective B cell responses in these bacterial systems have been identified, e.g. Vi polysaccharide (ViPS) of S. Typhi, the molecular mechanisms governing B cell memory to these T cell-independent antigens remains to be understood. It is known that re-immunization with purified polysaccharides including ViPS and PPS results in hyporesponsiveness, leading to serious concerns about the effectiveness of booster strategies that are currently in practice for such vaccines. More recently, PPS- and VIPS-conjugate vaccination strategy has failed to induce booster responses in disease endemic regions. We have previously hypothesized that efficient T cell- independent B cell responses require engagement with both B cell antigen receptor and co-stimulatory receptors such as Toll-like receptors. Indeed, we found that ViPS-expressing bacteria induce enhanced ViPS- specific secondary IgM and IgG responses compared to primary responses, which is indicative of PS-specific B cell memory. In striking contrast, secondary responses to Typhim Vi®, a vaccine composed of purified ViPS, severely impaired compared to the primary response indicating B cell hyporesponsiveness and the impact of this booster immunization strategy has never been determined in humans. S. Typhi is a human-restricted pathogen and does not productively infect commonly used inbred laboratory mice. This is a significant barrier to efforts to understand protective polysaccharide-specific memory responses against human typhoid. The S. Typhimurium infection system has been employed as a murine model of human typhoid. Using a novel chimeric strain of S. Typhimurium that was recently engineered to express surface characteristics of S. Typhi, we are able to demonstrate that the impairment in anti-VIPS responses correlates to more than an order of magnitude higher bacterial burden compared to whole bacterial immunization. Additionally, using a new and expansive panel of recombinant inbred mouse strains called the Collaborative Cross (CC) we have identified two independent CC mouse lines that can be productively infected with S. Typhi and develop histological features that are strikingly similar to biopsies taken from typhoid-infected humans. Preliminary results indicate that immunization of CC mice results in robust ViPS-specific antibody response. Collectively, these findings suggest that both the chimeric S. Typhimurium strain and CC mice can serve as novel in vivo translational platforms in which to assess the functional characteristics of polysaccharide-specific B cell responses.