MOLECULAR MECHANISMS OF BACTERIAL MEDIATED APOPTOSIS

描述（改编自申请人的摘要）：细菌性痢疾是 由革兰氏阴性菌引起的结肠急性炎症 志贺氏菌 志贺氏菌病具有很大的流行病学重要性， 特别是在婴儿和幼儿中，这可能是致命的。 这 感染是美国第二大最常见的肠道疾病 States. 志贺氏菌引发急性炎症，导致主要组织 破坏，促进细菌侵入组织，最终 根除他们。 志贺菌毒力诱导巨噬细胞快速凋亡及其机制的研究 伴随大量白细胞介素-I（IL-1）的释放。 IL-1是一种 志贺氏菌引发的炎症级联反应的主要成分。 的 侵袭质粒抗原B（Ipa B）是志贺氏菌侵袭素， 巨噬细胞凋亡 我们最近发现IpaB与IL-1 β结合， 转化酶（ICE）和ICE激活是必不可少的， 志贺氏菌感染中的巨噬细胞凋亡和IL-1 β释放。 近年来，伤寒沙门氏菌和S.鼠伤寒杆菌可诱导 并编码一种蛋白质，SipB，这是同源的 对IpaB和沙门氏菌细胞毒性所需的。 因此， 细胞凋亡似乎是这两种病毒共同的毒力机制 病原体 我们以前的研究结果表明，IpaB和ICE之间的相互作用 在志贺氏菌病的发病机制中至关重要。 在此，我们建议：研究 IpaB激活ICE的机制（目的1），启动了一个新的机制， IpaB结构-功能分析（目的2），鉴定其它巨噬细胞 IpaB诱导细胞凋亡所必需的组分（Aim 3），和 确定IpaB和SipB是否具有类似的功能（目的4）。 研究 IpaB和ICE之间的相互作用将使我们能够设计新颖的 更重要的是，新的痢疾疫苗， 其他传染病。

DESCRIPTION (Adapted from the applicant's abstract): Bacillary dysentery is an acute inflammatory disease of the colon caused by the Gram negative bacteria Shigella. Shigellosis has great epidemiological importance, especially among infants and young children where it can be fatal. This infection is the second most common enteric notifiable disease in the United States. Shigella initiates an acute inflammation that causes major tissue destruction, facilitates tissue invasion by the bacteria, and eventually eradicates them. Virulent Shigella induce rapid macrophage apoptosis and a concomitant release of large amounts of Interleukin-l (IL-1). IL-1 is a major component of the inflammatory cascade initiated by Shigella. The Invasion Plasmid Antigen B (IpaB) is the Shigella invasin that causes macrophage apoptosis. We have recently shown that IpaB binds to IL-1 beta converting enzyme (ICE) and that ICE activation is essential for both macrophage apoptosis and IL-1 beta release in Shigella infections. Recently, both Salmonella typhi and S. typhimurium were shown to induce apoptosis in macrophages and to encode a protein, SipB, that is homologous to IpaB and is required for Salmonella cytotoxicity. Thus, the induction of apoptosis appears to be a common virulence mechanism among these two pathogens. Our previous results indicate that the interaction between IpaB and ICE is crucial in the pathogenesis of shigellosis. Here, we propose to: study the mechanisms of ICE activation by IpaB (Aim 1), initiate a structure-function analysis of IpaB (Aim 2), identify other macrophage components necessary for the induction of apoptosis by IpaB (Aim 3), and determine whether IpaB and SipB have analogous function (Aim 4). The study of the interaction between IpaB and ICE will allow us to design novel therapies and, more importantly, new vaccines for dysentery and possibly other infectious diseases.