A System to Study Salmonella Typhi Infection and Immunity

伤寒沙门氏菌（S.伤寒（Typhi）是人类伤寒的病原体。全球估计数 表明每年发生2160万例伤寒，造成226，000人死亡。尽管抗生素 是主要的治疗选择，多药耐药S.伤寒菌株是 以惊人的速度在全球范围内发生。事实上，这是目前限制这种治疗选择，特别是在 疾病流行的国家。伤寒是一种疫苗可预防的疾病，高危人群接种疫苗 被认为是最有希望的控制策略，尽管持续的疫苗效力仍然难以捉摸。 关于伤寒的病理生理学机制或伤寒的相关性知之甚少。 接种疫苗的个体的免疫保护，进一步复杂化了理解疫苗介导的 保护推进伤寒治疗和预防的最大障碍之一是缺乏一个 适宜的实验动物模型研究S.伤寒感染。S.伤寒被认为是一种限制人类 病原体，并且不生产性感染常用的近交系实验室小鼠。人类遗传变异 比通常使用的近交系实验室小鼠中的要大得多，也更复杂，这可能部分地提供了 对人类和小鼠感染易感性和进展差异的解释。的 协作杂交（CC）是一组重组近交系小鼠品系，其并入了更广泛的 遗传多样性高于其他近交系小鼠品系。检测CC株是否对S. 伤寒感染后，我们从6个随机选择的CC系中感染小鼠，沿着8个CC祖细胞中的4个 近交系和一个非CC祖细胞（即BALB/c），具有良好表征的S.伤寒菌株Ty 2。我们发现 与常用的实验室小鼠如BALB/c、C57 BL/6或129 S1/Sv不同，CC品系中的两种， CC 003/Unc和CC 053/Unc在脾脏中的细菌负荷比对照组高几个数量级。 与感染过程中注射的细菌的实际数量，证明了S.中伤寒 这两种CC菌株对这些感染CC小鼠的肝组织学分析显示， 伤寒患者肝活检的组织学特征。我们还发现S.伤寒易感 CC菌株具有免疫活性，并且在免疫后产生保护性免疫应答， 能够杀死S。伤寒的体外实验和S.体内伤寒。本R21应用程序中的拟议工作将 使我们能够探索新的预防和治疗干预方法，以控制人类伤寒 并深入了解宿主遗传因素对S.伤寒感染。

Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever in humans. Global estimates indicate that 21.6 million cases of typhoid fever occur each year resulting in 226,000 deaths. Although antibiotics are the primary treatment option, the emergence as well as spreading of multidrug-resistant S. Typhi strains is occurring globally at an alarming rate. This is, in fact, currently limiting this treatment option, particularly in disease-endemic countries. Typhoid is a vaccine-preventable disease and vaccination of high-risk populations is considered the most promising strategy for control, although sustained vaccine efficacy has remained elusive. Little is known about the mechanisms governing the pathophysiology of typhoid or the correlates of immunological protection in vaccinated individuals, further complicating efforts to understand vaccine-mediated protection. One of the greatest barriers to advancing the treatment and prevention of typhoid is the lack of a suitable experimental animal model to study S. Typhi infection. S. Typhi is regarded as a human-restricted pathogen and does not productively infect commonly used inbred laboratory mice. Genetic variation in humans is far greater and more complex than that in commonly used inbred laboratory mice, which may in part provide an explanation for the differences in the infection susceptibility and progression in humans and mice. The Collaborative Cross (CC) is a large panel of recombinant inbred mouse strains that incorporate a wider range of genetic diversity than is present in other inbred mouse strains. To test whether CC strains are permissive to S. Typhi infection, we have infected mice from 6 randomly chosen CC lines, along with 4 of the 8 CC progenitor inbred lines and one non CC progenitor (i.e. BALB/c), with the well-characterized S. Typhi strain Ty2. We found that unlike commonly-used laboratory mice, such as BALB/c, C57BL/6 or 129S1/Sv, two of the CC strains, CC003/Unc and CC053/Unc, showed bacterial burdens several orders of magnitude higher in the spleen relative to the actual number of bacteria injected during infection, demonstrating survival and replication of S. Typhi in these two CC strains. Analysis of liver histology in these infected CC mice shows lesions that are consistent with the histological features found in liver biopsies of typhoid patients. We also found that the S. Typhi-susceptible CC strains are immune-competent and upon immunization generate protective immune responses that are capable of killing S. Typhi in vitro and controlling S. Typhi in vivo. The proposed work in this R21 application will permit us to explore novel prophylactic and therapeutic interventions approaches for typhoid control in humans and gain insights into host genetic factors influencing susceptibility and resistance to S. Typhi infection.