The Salmonella SPI-2 type three secretion switch

沙门氏菌是一种引起人类（包括伤寒）和兽医家畜许多重要疾病的细菌病原体。细菌在宿主细胞内复制，在一个被称为液泡的膜结合的隔间里。为了复制，细菌必须干扰正常的细胞过程。它们通过在细胞表面组装一个针状结构来实现这一点，通过这个结构，毒力蛋白可以穿过液泡膜进入宿主细胞。但在此之前，一些其他细菌蛋白质穿过针，在液泡膜上形成一个小洞或“孔”。在此期间，毒力蛋白的分泌受到细菌细胞内特定的“安全捕获物”的控制。我们最近发现，一旦孔被组装起来，细菌就会识别宿主细胞质的温和pH值，并将其作为触发安全捕获物分解的信号，从而允许毒力蛋白被递送。这个过程对细菌来说绝对是至关重要的，因为如果它们不能传递这些蛋白质，它们就不能复制。因此，本提案的目的是在详细的分子水平上研究安全捕获物响应pH信号的方式。我们将采取的解决这个问题的方法在我的实验室里已经很好地建立起来了，研究结果可能在设计沙门氏菌疫苗和干扰细菌对pH信号反应能力的新抗生素方面有潜在的应用。

Salmonella is a bacterial pathogen that causes many important diseases in man (including typhoid fever) and veterinary livestock. The bacteria replicate inside host cells, in a membrane-bound compartment called a vacuole. In order to replicate, bacteria must interfere with normal cellular processes. They accomplish this by assembling a needle-like structure on their cell surface, through which virulence proteins can be discharged across the vacuole membrane into the host cell. But before this happens, some other bacterial proteins pass through the needle and make a small hole or 'pore' in the vacuole membrane. During this time, virulence protein secretion is held in check by a specific 'safety catch', within the bacterial cell. We found recently that once the pore is assembled, the bacteria recognize the mild pH of the host cytoplasm and exploit it as a signal to trigger disassembly of the safety catch, which then allows virulence proteins to be delivered. This process is absolutely crucial for the bacteria, because if they cannot deliver these proteins they cannot replicate. Therefore the purpose of this proposal is to study, at a detailed molecular level, the way in which the safety catch responds to the pH signal. The approaches that we will take to tackle this question are well established in my laboratory, and the results may have potential applications in the design of vaccines against Salmonella and also for new antibiotics that interfere with the ability of the bacteria to respond to the pH signal.