Departments of Laboratory Medicine and Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15589-94. doi: 10.1073/pnas.1005566107. Epub 2010 Aug 16.
Salmonella enterica serovar Typhi, the cause of typhoid fever, is host-adapted to humans and unable to cause disease in mice. Here, we show that S. Typhi can replicate in vivo in nonobese diabetic (NOD)-scid IL2rgamma(null) mice engrafted with human hematopoietic stem cells (hu-SRC-SCID mice) to cause a lethal infection with pathological and inflammatory cytokine responses resembling human typhoid. In contrast, S. Typhi does not exhibit net replication or cause illness in nonengrafted or immunocompetent control animals. Screening of transposon pools in hu-SRC-SCID mice revealed both known and previously unknown Salmonella virulence determinants, including Salmonella Pathogenicity Islands 1, 2, 3, 4, and 6. Our observations indicate that the presence of human immune cells allows the in vivo replication of S. Typhi in mice. The hu-SRC-SCID mouse provides an unprecedented opportunity to gain insights into S. Typhi pathogenesis and devise strategies for the prevention of typhoid fever.
肠道沙门氏菌血清型 Typhi 是伤寒的病原体，它适应于人类宿主，而不能在小鼠中引起疾病。在这里，我们表明，沙门氏菌 Typhi 可以在非肥胖型糖尿病（NOD）-scid IL2rgamma（null）小鼠中植入人类造血干细胞（hu-SRC-SCID 小鼠）后在体内复制，引起类似于人类伤寒的致死性感染，并伴有病理和炎症细胞因子反应。相比之下，沙门氏菌 Typhi 在未植入或免疫功能正常的对照动物中没有表现出净复制或引起疾病。在 hu-SRC-SCID 小鼠中筛选转座子池揭示了已知和以前未知的沙门氏菌毒力决定因素，包括沙门氏菌致病性岛 1、2、3、4 和 6。我们的观察表明，人类免疫细胞的存在允许沙门氏菌 Typhi 在小鼠体内进行复制。hu-SRC-SCID 小鼠为深入了解沙门氏菌 Typhi 的发病机制和制定伤寒预防策略提供了前所未有的机会。
