"Genetic Approaches for Improving Tuberculosis Vaccines"

结核病需要一种有效而安全的疫苗。这个项目的目标是开发一种新型的结核病 结核分枝杆菌和污垢分枝杆菌的疫苗候选菌株。安全是通过生成 在免疫受损的小鼠中无法生长的减毒突变株。以产生更有效的结核病 疫苗方面，该项目将产生增强免疫原性的突变体。增强的免疫原性 可以通过识别使逃避宿主先天和适应性的决定因素失活的突变来实现 免疫反应。结核分枝杆菌具有主动抑制THI细胞因子诱导的能力。目标 1利用使用包含编码绿色荧光的基因的巨噬细胞系的屏幕 融合到IL-12可诱导启动子的蛋白。减毒M.转座子和零缺失突变体 将对结核病进行诱生IL-12的能力筛查。结核分枝杆菌积极防止细胞凋亡。 AIM 2使用基因筛查来识别凋亡阻断效应因子(ABE)突变。分离到的突变体 Aim 1和Aim 2都将评估它们在保护小鼠免受雾化M。 使用来自南非的结核分枝杆菌H37Rv和KZN毒株挑战结核病。初步 AIM 3的数据已经在耻垢分枝杆菌中发现了一组新的基因，名为IKE，用于先天逃避杀戮。这个 耻垢分枝杆菌Aike缺失小鼠免疫耻垢分枝杆菌Aike突变体 结核基因(命名为IKEPLUS)可诱导抗结核分枝杆菌的杀菌免疫。 本课程将探讨使用ILEPLUS和减毒结核分枝杆菌的异种引产和增强剂。 相关性(请参阅说明)：

An efficacious and safe vaccine is needed for Tuberculosis. The goal of this project is to develop a novel TB vaccine candidate strains of M. tuberculosis and M. smegmatis. Safety is achieved by generating attenuated mutants that fail to grow in immunocompromised mice. To generate a more efficacious TB vaccine, this project will generate mutants that have enhanced immunogenicity. Enhanced immunogenicity can be achieved by identifying mutations that inactivate determinants that evade host innate and adaptive immune responses. M. tuberculosis has the ability to actively suppress the induction of THI cytokines. Aim 1 utilizes a screen employing a macrophage cell line containing the gene encoding the green fluorescent protein fused to the IL-12 inducible promoter. Transposon and null deletion mutants of attenuated M. tuberculosis will be screened for the ability to induce IL-12. M. tuberculosis actively prevents apoptosis. Aim 2 uses a genetic screen to identify apoptotic blocking effectors (abe) mutations. The mutants isolated in both Aim 1 and Aim 2 will be evaluated for their efficacy in protecting mice against aerosolized M. tuberculosis challenges using both M. tuberculosis H37Rv and the KZN strain from South Africa. Preliminary data for Aim 3 has identified a novel set of genes in M. smegmatis named ike for innate killing evasion. The M. smegmatis Aike deletion Mice immunized with M. smegmatis Aike mutant containing a set of M. tuberculosis genes (named IKEPLUS) elicits a bactericidal immunity against M. tuberculosis. Heterologous prime and boosts with ILEPLUS and attenuated M. tuberculosis will be explored. RELEVANCE (See instmctions):