Abstract
摘要:人類結核病是由結核分枝桿菌 (結核菌) 感染所造成,為全球十大死亡原因之一。由小鼠模式,我們定位了一個控制宿主對結核菌感染產生易感受性的基因座,sst1,並進一步找出此區域內的候選基因,Ipr1。Ipr1 和人類相對應蛋白 SP110b 之表現會受到干擾素的誘導,顯示它們對免疫力具有功能性。巨噬細胞是結核菌在人類宿主中主要的感染目標和儲藏所。此細胞細胞凋亡是宿主對結核菌感染的一個重要防禦機制。Ipr1 能抑制結核菌在巨噬細胞內的增殖,並將被感染的巨噬細胞從可能形成細胞壞死轉為細胞凋亡。然而這些分子機制則仍不清楚。細胞激素IFNγ 及 TNFα 可活化巨噬細胞以促進其抗菌活性。我們先前的研究顯示 SP110b 可藉由微調 NF-κB 的活性抑制 TNFα 的表現並促進抗細胞凋亡基因的表現。我們因而假設 SP110b/Ipr1 在結核菌感染及發炎反應時可藉由微調 NF-κB 的活性來參與促炎细胞激素 如 TNFα 的產生及巨噬細胞細胞死亡之調控,進而建立一個有利於巨噬細胞控制結核菌感染的微環境。為驗證此假設,本計畫將探討 SP110b/Ipr1 如何調控细胞激素的產生、減緩巨噬細胞細胞死亡、及兩者的相關性,並找出它們的分子作用機制。本計畫將助於釐清SP110b/Ipr1 在調控宿主先天免疫的角色,並能了解一背景基因如何避免宿主過度發炎而導致疾病。
Abstract: Tuberculosis (TB), a disease caused by intracellular pathogen Mycobacterium tuberculosis (Mtb)infection, is one of the top 10 causes of death worldwide. In mouse models, we have mapped achromosomal region, sst1 locus (supersusceptibility to tuberculosis 1), which controls hostsusceptibility to Mtb infection, and further identified the candidate gene, Ipr1 (intracellularpathogen resistance 1), within the region. The expression of Ipr1 and SP110b, the closest humanorthologue of the mouse Ipr1 protein, is up-regulated by interferons (IFNs), suggesting theirpossible function in immunity in both species. The macrophage is the primary target and criticalreservoir of Mtb in hosts during infection. Accumulating evidence indicate that macrophageapoptosis is an important defense mechanism of hosts in controlling Mtb infection. Expression ofthe Ipr1 gene limits multiplications of Mtb in macrophages in vitro as well as switches cell deathmodes of Mtb infected-macrophages from necrosis to apoptosis. However, the detailed molecularmechanisms by which infected macrophages mediate to carry out the anti-microbial effect whilethey are undergoing apoptosis and Ipr1 regulates the infected-macrophage cell death remainlargely unclear. IFNγ and TNFα are key pro-inflammatory cytokines that are induced during Mtbinfection, and both of them can activate macrophages to promote their anti-mycobacterialactivities. TNFα acts as a ‘double-edged sword’ during Mtb infection and a delicate balance of itsproduction is required to control Mtb infection. SP110b and Ipr1 proteins can be sorted as atranscriptional co-regulator on the basis of their structural features and thus might be involved inregulating expression of various genes critical for cellular functions. Our previous studiesdemonstrate that SP110b suppressed IFNγ-mediated macrophage cell death via fine-tuning NF-κBactivity that results in the down-regulation of TNFα production and concomitant up-regulation ofNF-κB-induced anti-apoptotic gene expression. We therefore hypothesize that SP110 and Ipr1proteins, via fine-tuning NF-κB activity, are involved in modulating the expression of genesincluding those for inflammatory cytokines and for regulating cell death in macrophagesfollowing primed with IFNs or Mtb infection and that the modulation provides a properbalance of the local inflammatory milieu which controls the effector capacity of macrophagesand other host cells. To test our hypothesis, we propose to investigate the SP110b/Ipr1-mediatedregulation of cytokine production, macrophage cell death and their correlation as well as toexplore the underlying molecular mechanisms. The specific aims of the proposal are as follows:1. To investigate the SP110-mediated regulation of the production of TNFα cytokine2. To investigate the SP110b/Ipr1-mediated regulation of macrophage cell death3. To investigate the effects of SP110b/Ipr1-mediated regulation of cytokine production andmacrophage cell death in primary human macrophages and in mouse models in vivoIf successful, the proposed studies will not only clarify the potential roles of SP110b and Ipr1 incontrolling innate immunity against Mtb infection but also uncover unknown mechanisms bywhich a background genetic determinant limits inflammation, prevents the formation of necroticlung lesions and alleviates disease progression during Mtb infection.
Keyword(s)
結核分枝桿菌
巨噬細胞
先天性的免疫力
細胞死亡
細胞激素
Mycobacterium tuberculosis
macrophage
innate immunity
cell death
cytokine