A System to Study Salmonella Typhi Infection and Immunity

伤寒沙门氏菌(S.Typhi)是人类伤寒的病原体。全球估计数 数据显示，每年发生2160万例伤寒病例，导致226,000人死亡。虽然抗生素 是主要的治疗选择，耐多药伤寒沙门氏菌株的出现和传播是 在全球范围内以惊人的速度发生。事实上，这限制了这种治疗选择，特别是在 疾病流行的国家。伤寒是一种疫苗可预防的疾病，是高危人群接种疫苗的对象 被认为是最有希望的控制策略，尽管疫苗的持续效力仍然难以捉摸。 关于伤寒的病理生理学机制或与伤寒的相关性知之甚少。 对接种疫苗的个体的免疫保护，进一步使理解疫苗介导的努力复杂化 保护。推进伤寒治疗和预防的最大障碍之一是缺乏 适宜研究伤寒沙门氏菌感染的实验动物模型。伤寒沙门氏菌被认为是人类限制的 致病菌，不能有效地感染常用的近亲繁殖的实验室小鼠。人类的遗传变异 比通常使用的近交系实验室小鼠要大得多，也更复杂，这可能在一定程度上提供了 对人类和小鼠感染易感性和进展差异的解释。这个 协作杂交(CC)是一大组重组近交系小鼠品系，它包含了更广泛的 遗传多样性高于其他近交系小鼠品系。检测CC菌株对S。 伤寒杆菌感染，我们已经从6个随机选择的CC系以及8个CC祖细胞中的4个感染了小鼠 近交系和一个非CC祖代(即BALB/c)，以及特征良好的伤寒沙门氏菌株TY2。我们发现 与常用的实验室小鼠，如BALB/c，C57BL/6或129S1/Sv不同，CC的两个菌株， CC003/UNC和CC053/UNC在脾中的细菌负荷相对高出几个数量级 在感染过程中实际注射的细菌数量，证明伤寒沙门氏菌在 这两株CC菌株。对这些感染CC小鼠的肝脏组织学分析显示，病变与 伤寒患者肝活检的组织学特点。我们还发现对伤寒沙门氏菌敏感的 CC菌株具有免疫活性，在免疫后产生保护性免疫反应 能够在体外杀死伤寒沙门氏菌，在体内控制伤寒沙门氏菌。此R21应用程序中提议的工作将 允许我们探索控制人类伤寒的新的预防和治疗干预方法 并深入了解影响伤寒沙门氏菌感染敏感性和抵抗力的宿主遗传因素。

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.