鼠伤寒沙门氏菌的致病性有显著的宿主特异性：感染人引起肠炎，感染小鼠引起致死性的系统性疾病。巨噬细胞内复制是该菌引起系统性疾病的关键要素。我们前期发现鼠伤寒沙门氏菌的必需毒力因子致病岛2基因在鼠巨噬细胞内的表达水平显著高于在人巨噬细胞内的水平，从而使该菌在鼠细胞内高水平复制，引起鼠的系统性疾病。鼠巨噬细胞内已知的调控致病岛2表达的信号在人细胞内都存在，我们推测未知的调控体系和鼠巨噬细胞内特有的信号能诱导致病岛2的高表达。本研究将探究该菌在鼠巨噬细胞内致病岛2高表达相关的信号调控系统。非洲最近出现的ST313型鼠伤寒沙门氏菌有引起人系统性疾病的能力，我们发现该型在人巨噬细胞内的复制力有明显提高，但致病岛2的表达水平不变，表明ST313有其它提高复制力的机制。本研究将对ST313进化为人系统性致病菌的机理进行研究。项目成果对理解鼠伤寒沙门氏菌这一重要致病菌的宿主特异性和毒力进化机制具有重要意义。

Salmonella enterica serovar Typhimurium (S. Typhimurium) exhibits notable host-specific pathogenicity. It causes severe systemic infection in mice, but inducing only mild gastroenteritis in humans. The ability to replicate within host macrophages is the key step for developing systemic Salmonella infection. Our preliminary research showed that the major virulence factor of S. Typhimurium, Salmonella pathogenicity island -2 (SPI-2) genes express at much higher levels in murine macrophages than levels in human macrophages, leading to strongly enhanced replication of the pathogen in murine macrophages, consequently systemic infection to mice. As the known signal systems for SPI-2 induction are present both in murine and human macrophages, other unknown regulatory systems and/or host specific signaling systems are likely involved in the induction of SPI-2 genes in murine macrophages. This project aims to investigate regulatory systems and host signals underlying the higher SPI-2 expression of S. Typhimurium in murine macrophages. A high virulent S. Typhimurium isolates ST313 recently emerged in sub-Saharan Africa that has evolved to induce systemic human disease. Our preliminary research found that intracellular expression levels of SPI-2 genes in ST313 were not changed while the virulence strain showed increased replication in human macrophages, indicating that ST313 utilized other mechanisms to enhance its replication ability. This work will also investigate mechanisms for the evolving of ST313 as a more virulent human pathogen. The outcome of this project is expected to contribute largely to understand mechanisms for host specificity of S. Typhimurium pathogenicity and its adaptive evolution in humans.