【摘要】：先天免疫系統(tǒng)為機(jī)體抵抗病毒感染提供重要的保護(hù)。通過(guò)對(duì)病毒核酸的模式識(shí)別,機(jī)體激活先天免疫反應(yīng)產(chǎn)生大量的一型干擾素。后者在抗病毒免疫中具有舉足輕重的作用。然而到目前為止仍然不清楚的是一型干擾素是否通過(guò)調(diào)控機(jī)體的細(xì)胞代謝從而作為機(jī)體抵抗病毒的一種機(jī)制。葡萄糖代謝作為細(xì)胞能量代謝的中心,近些年來(lái)越來(lái)越多的被認(rèn)為參與調(diào)控細(xì)胞生命活動(dòng)的各個(gè)方面。葡萄糖的無(wú)氧分解代謝也被稱(chēng)為糖酵解是葡萄糖代謝過(guò)程中最初的步驟,不但為細(xì)胞的生命活動(dòng)快速地提供能量ATP,而且生成中間產(chǎn)物參與各種生物大分子的合成,為細(xì)胞增殖提供物質(zhì)基礎(chǔ)。越來(lái)越多的證據(jù)表明糖酵解在不同的細(xì)胞的生命活動(dòng)過(guò)程中是被精確調(diào)控的。因此,我們的研究重點(diǎn)主要關(guān)注在不同類(lèi)型的細(xì)胞中葡萄糖代謝與抗病毒先天免疫的關(guān)聯(lián)以及相互作用。我們的研究發(fā)現(xiàn)抗病毒先天免疫新的代謝關(guān)聯(lián),病毒感染產(chǎn)生的一型干擾素(IFN)選擇性的在巨噬細(xì)胞而不是小鼠胚胎成纖維細(xì)胞中上調(diào)糖酵解。研究發(fā)現(xiàn)這一現(xiàn)象是由于一型干擾素在巨噬細(xì)胞中特異性的上調(diào)6-磷酸果糖-2激酶／果糖-2,6-二磷酸酶(PFKFB3)基因的表達(dá)。功能獲得性以及功能缺失性實(shí)驗(yàn)表明,PFKFB3是糖酵解流量的控制的關(guān)鍵酶。有趣的是來(lái)源于PFKFB3突變的雜合子小鼠的巨噬細(xì)胞而不是胚胎成纖維細(xì)胞表現(xiàn)出對(duì)病毒感染的易感性。后者的實(shí)驗(yàn)結(jié)果表明盡管糖酵解有助于生物合成的過(guò)程和病毒在宿主細(xì)胞內(nèi)的增殖,PFKFB3蛋白水平適中地下降并不影響病毒相關(guān)的合成。進(jìn)一步研究證實(shí)PFKFB3驅(qū)動(dòng)的糖酵解是通過(guò)提升巨噬細(xì)胞的吞噬能力來(lái)促進(jìn)其抗病毒功能。的確我們的實(shí)驗(yàn)結(jié)果表明IFN誘導(dǎo)的糖酵解會(huì)增強(qiáng)巨噬細(xì)胞的吞噬效率使受病毒感染的細(xì)胞更有效的被吞噬清除掉。在吞噬過(guò)程中,PFKFB3會(huì)即時(shí)地被招募到吞噬小泡周?chē)滦纬傻募?dòng)蛋白微絲上,可能為快速的肌動(dòng)蛋白聚合提供能量ATP。此外,因?yàn)榱字＜〈?-激酶(PI3K)信號(hào)通路的活性調(diào)控對(duì)吞噬作用的完成是必須的條件,我們發(fā)現(xiàn)PFKFB3表達(dá)水平與PI3K的信號(hào)通路的活性呈正相關(guān)性。因此PFKFB3調(diào)控PI3K信號(hào)通路可能也是PFKFB3促進(jìn)巨噬細(xì)胞的吞噬的機(jī)制。綜上所述,我們的實(shí)驗(yàn)結(jié)果表明巨噬細(xì)胞特異性的代謝調(diào)控有助于抗病毒先天免疫。這一研究有助于我們更好的理解細(xì)胞代謝與先天免疫的相互關(guān)聯(lián)與作用。這兩者間的相互調(diào)控機(jī)制為抗病毒天然免疫藥物的開(kāi)發(fā)提供潛在的靶點(diǎn)。
[Abstract]:Innate immune system provides important protection against virus infection. By pattern recognition of viral nucleic acids, the body activates the innate immune response to produce a large number of interferon-1 types. The latter plays an important role in anti-viral immunity. However, it is still unclear whether interferon I may act as a mechanism for virus resistance by regulating cell metabolism. As the center of cell energy metabolism, glucose metabolism is considered to be involved in various aspects of cell life in recent years. Anaerobic catabolism of glucose, also known as glycolysis, is the first step in glucose metabolism. It not only provides energy for cell life activities rapidly, but also produces intermediates to participate in the synthesis of various biomolecules. To provide material basis for cell proliferation. There is growing evidence that glycolysis is precisely regulated in the life of different cells. Therefore, our research focuses on the relationship and interaction between glucose metabolism and antiviral innate immunity in different types of cells. Our study found a new metabolic association of innate immunity against viruses. Type I interferon (IFN) produced by viral infection selectively upregulated glycolysis in macrophages rather than mouse embryonic fibroblasts. This phenomenon is due to the specific up-regulation of fructose-2-kinase / fructose-2-diphosphatase (PFKFB3) gene expression in macrophages. The results of functional acquisition and functional deletion showed that PFKFB3 was the key enzyme in the control of glycolysis flow. Interestingly, macrophages from heterozygous mice derived from PFKFB3 mutations, rather than embryonic fibroblasts, showed susceptibility to viral infection. The results of the latter study showed that although glycolysis contributed to the biosynthesis process and the moderate decrease in the protein level of PFKFB3 in host cells did not affect the virus-related synthesis. Further studies have demonstrated that PFKFB3-driven glycolysis promotes the antiviral function of macrophages by enhancing their phagocytosis. Indeed, our results suggest that IFN-induced glycolysis enhances the phagocytosis of macrophages so that virus-infected cells are more effectively phagocytized and eliminated. During phagocytosis, PFKFB3 is immediately recruited to the newly formed actin microfilaments around the phagocytic vesicles, which may provide energy for rapid actin polymerization. In addition, since the activity regulation of phosphatidylinositol 3-kinase (PI3K) signaling pathway is necessary for the completion of phagocytosis, we found that the level of PFKFB3 expression was positively correlated with the activity of PI3K signaling pathway. Therefore, the regulation of PI3K signaling pathway by PFKFB3 may also be the mechanism of PFKFB3 promoting phagocytosis of macrophages. In conclusion, our results suggest that macrophage specific metabolic regulation contributes to anti-viral innate immunity. This study helps us to better understand the relationship between cellular metabolism and innate immunity. The mutual regulation mechanism between the two provides a potential target for the development of antiviral innate immunopharmaceuticals.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R392

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