| Budget Amount *help |
¥56,000,000 (Direct Cost: ¥56,000,000)
Fiscal Year 2005: ¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2004: ¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2003: ¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000)
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| Research Abstract |
It has been shown that bacterial effectors secreted via the type III secretion system (TTSS) play pivotal roles in establishing bacterial colonization of host cells. In this study we undertook investigation of the roles of some of the effectors secreted via the type III secretion system of Shigella, and found that IpgB1, VirA, IpaH9.8 and IcsB effectors play crucial role in establishing bacterial infection. For example, IpgB1 was found to have a capacity to interact with ELMO, an adaptor interacting with Dock 180 and RhoG, and activate Racl, thus leading to membrane ruffles and promoting bacterial invasion of epithelial cells. VirA, which we previously found to have an activity to induce microtubule destruction, played pivotal role in promoting bacterial intracellular spreading by destroying surrounding microtubule networks. IpaH9.8, which we also previously reported to be translocated into the host nucleus and able to interact with U2AF35, a splicing factor, resulted in down regulatin
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g the expression of numerous genes including those encoded inflammatory chemokines and cytokines. In a mouse infection model, we found that Shigella mutant lacking the ipaH9.8 gene caused stronger inflammatory responses than the wild type, however, the rate of bacterial colonization of the ipH9.8 mutant was less compared with that of the wild type. Therefore, it is likely that the bacterial activity is important for optimizing the host inflammatory responses and promoting bacterial colonization. Upon multiplication of Shigella within epithelial cells, the host cells was activated autophagic pathway for which one of the autophagic protein, Atg5 targeted the Shigella VirG protein, required for mediating actin-based motility. We found that the pathogen delivered IcsB via TTSS, by which Shigella was able to escape from recognition by autophagy. Our results thus indicate that the bacterial effectors involve in at least two key aspects of infection, one requires promotion of bacterial infection, and the other one requires bacterial circumvention of the host innate immune system. Less
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