Host Cell Responses To Salmonella Enterica Serovar Typhi

鼠伤寒沙门氏菌是胃肠炎的常见原因。毒力由细菌染色体上编码的五个沙门氏菌致病性岛（SPI）决定。SPI 1和SPI 2编码两个三型分泌系统（TTSS）的结构组分，所述三型分泌系统（TTSS）将效应物转运到宿主细胞中。SPI 1效应子SigD是一种肌醇磷酸酶，可诱导Akt/PKB（一种哺乳动物丝氨酸苏氨酸激酶）的激活。Akt激活在发病机制中的作用仍不清楚，然而，在培养的上皮细胞中，它似乎参与预防感染细胞中细胞凋亡的发生。更具体地说，我们已经发现，与野生型相比，sigD缺失突变体诱导半胱天冬酶3活化。这对于细胞内细菌的存活和复制可能是重要的。在巨噬细胞中，沙门氏菌对Akt的激活更为复杂，因为脂多糖将在不存在SigD的情况下激活激酶。对这两种途径的比较揭示了重要的差异。特别地，SigD介导的活化对渥曼青霉素不敏感，渥曼青霉素是一种充分描述的经由磷脂酰肌醇-3-激酶的Akt活化的抑制剂。因此，SigD依赖性Akt激活似乎通过一种新的途径发生。

monella enterica serovar Typhimurium is a common cause of gastroenteritis. Virulence is determined by five Salmonella Pathogenicity Islands (SPI) encoded on the bacterial chromosome. SPI1 and SPI2 encode the structural components of two Type Three Secretion Sytems (TTSS) that translocate effectors into the host cell. The SPI1 effector SigD is an inositol phosphatase that induces the activation of Akt/PKB a mammalian serine threonine kinase. The role of Akt activation in pathogenesis remains unclear, however, in cultured epithelial cells it appears to be involved in preventing the onset of apoptosis in infected cells. More specifically we have found that a sigD deletion mutant induces Caspase 3 activation compared to wild type. This may be important for the survival and replication of intracellular bacteria. In macrophages activation of Akt by Salmonella is more complex since lipopolysaccharide will activate the kinase in the absence of SigD. Comparison of the two pathways has revealed important differences. In particular, SigD-mediated activation is insensitive to Wortmannin a well described inhibitor of Akt activation via phosphatidylinositol-3-kinase. Thus SigD-dependent Akt activation appears to occur via a novel pathway.