2012-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/703351摘要：結核分枝桿菌是人類結核病的致病菌，每年在全球造成約二百萬人死亡。由小 鼠模式, 我們定位了一個染色體上能控制宿主對結核分枝桿菌感染產生易感受 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 的相對應蛋白 SP110 之表現會受到干擾素的誘導，顯示它們對此兩物種的免疫 力可能是有功能的。巨噬細胞是結核分枝桿菌在人類宿主中主要的感染目標和 細菌儲藏所。研究指出，巨噬細胞凋亡是宿主對結核分枝桿菌感染時的一個重 要防禦機制。表現 Ipr1 能抑制結核分枝桿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。然而巨噬細胞在進行細胞 凋亡過程中的抗菌活性及 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。巨噬細胞在結核分枝桿菌感染過程中被誘導產生的 IFN-γ 及 TNF-α 可活化它們以促進其抗菌活性。由結構推測 SP110 和 IPR1 可能為轉錄共調節 子因而參與調控細胞激素的產生。根據 SP110 和 IPR1 結構上的特徵、 它們 在宿主被結核分枝桿菌感染時控制先天性免疫力的可能角色、加上 IFN-γ 或 TNF-α 可增進巨噬細胞抗菌能力的事實，我們因而假設 SP110 和 IPR1 參與 促炎细胞激素如 TNF-α 等在結核分枝桿菌感染時的產生之調控，進而建立一個 有利於巨噬細胞控制結核分枝桿菌感染的環境。<br> Abstract: Mycobacterium tuberculosis (Mtb), an intracellular pathogen responsible for humantuberculosis (TB), causes approximately two million people deaths annually in the world. 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 SP110, the nearest human homologue 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 antimicrobial effect while they are undergoing apoptosis and Ipr1 modulates the cell death of Mtb infected-macrophages remain largely unclear. Various cytokines are induced during Mtb infection, and some of them, including IFN-γ and TNF-α, can activate macrophages to promote their anti-mycobacterial activities. TNF-α acts as a ‘double-edged sword’ during Mtb infection and a delicate balance of it is required to control Mtb infection. SP110 and IPR1 proteins can be sorted as a transcriptional co-regulator on the basis of their structural features and thus might be involved in regulation of various cellular functions, such as cytokine production. Based on the structural characteristic of SP110 and IPR1 proteins, their potential roles in controlling innate immunity against Mtb infection, possibly through the modulation of the cell death of macrophages, as well as the fact that IFN-γ or TNF-α can promote anti-mycobacterial killing by macrophages, we hypothesize that SP110 and IPR1 proteins are involved in regulating the production of pro-inflammatory cytokines, such as TNF-α, during Mtb infection and through which creates a cytokine milieu that favors the control of Mtb infection by macrophages. In our model, SP110 downregulates the TNF-α production possibly via regulating JAK/STATs, NFκB or unknown mechanisms to limit lung inflammation, prevent formation of necrotic lung lesions and alleviate disease progression.結核分枝桿菌巨噬細胞先天性的免疫力細胞凋亡細胞 激素Mycobacterium tuberculosis (Mtb)macrophageinnate immunityapoptosiscytokine