Abstract
摘要:結核分枝桿菌 (結核菌) 是人類結核病的致病菌,每年造成全球約一百多萬人死亡。由小鼠模式,我們定位了一個染色體上能控制宿主對結核菌感染產生易感受性的基因座,sst1,並進一步找出位在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,顯示它們對此兩物種的免疫力是具有功能的。巨噬細胞是結核菌在人類宿主中主要的感染目標和細菌儲藏所。巨噬細胞細胞凋亡是宿主對結核菌感染時的一個重要防禦機制。表現 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變為細胞凋亡。然而 Ipr1 如何調控被感染的巨噬細胞死亡之分子機制則仍不清楚。在結核菌感染過程中 IFNγ 及 TNFα 可活化巨噬細胞以促進其抗菌活性。由結構推測 SP110b/Ipr1 可能為轉錄共調節子因而能參與調控細胞若干基因的表現。我們因而假設 SP110b/Ipr1 在結核菌感染時參與促炎细胞激素,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、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: Mycobacterium tuberculosis (Mtb), an intracellular pathogen responsible for human tuberculosis (TB), causes approximately 1.5 million people deaths worldwide annually. In mouse models, we have mapped a chromosomal region, sst1 locus (supersusceptibility to tuberculosis 1), which controls host susceptibility to Mtb infection, and further identified the candidate gene, Ipr1 (intracellular pathogen resistance 1), within the region. The expression of Ipr1 and SP110b, the nearest human orthologue of the mouse Ipr1 protein, is up-regulated by interferons, suggesting their possible function in immunity in both species. The macrophage is the primary target and critical reservoir of bacteria during Mtb infection in hosts. Accumulating evidence indicate that macrophage apoptosis is an important defense mechanism of hosts in controlling Mtb infection. Expression of the Ipr1 gene limits multiplications of Mtb in macrophages in vitro as well as switches cell death modes of Mtb infected-macrophages from necrosis to apoptosis. However, the detailed molecular mechanisms by which infected macrophages mediate to carry out the anti-microbial effect while they are undergoing apoptosis and Ipr1 regulates the infected-macrophage cell death remain largely unclear. Various cytokines are induced during Mtb infection, and some of them, including IFNγ and TNFα, can activate macrophages to promote their anti-mycobacterial activities. TNFα acts as a ‘double-edged sword’ during Mtb infection and a delicate balance of it is required to control Mtb infection. SP110b and Ipr1 proteins can be sorted as a transcriptional co-regulator on the basis of their structural features and thus might be involved in regulating expression of various genes critical for cellular functions. We therefore hypothesize that SP110b and Ipr1 proteins are involved in modulating the expression of genes including those for inflammatory cytokines and for regulating cell death in macrophages during Mtb infection and the modulation provides a properly balance of the local inflammatory milieu which controls the effector capacity of macrophages and other host cells. To test our hypothesis, we propose to investigate the SP110b/Ipr1-mediated regulation of cytokine production, macrophage cell death and their correlation as well as to exploring the underlying molecular mechanisms. The specific objectives of the proposal are the following: 1. To investigate the SP110b/Ipr1-mediated regulation of the production of cytokines 2. To investigate the SP110b/Ipr1-mediated regulation of macrophage cell death 3. To verify the effects of SP110b/Ipr1-mediated regulation of cytokine production and macrophage cell death on host immunity in vivo If successful, the proposed studies will not only clarify the potential roles of SP110b and Ipr1 in controlling innate immunity against Mtb infection but also uncover unknown mechanisms by which a background genetic determinant limit inflammation, prevent formation of necrotic lung lesions and alleviate disease progression.
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