本文選題：白念珠菌 + 固有免疫應(yīng)　； 參考：《第二軍醫(yī)大學(xué)》2016年博士論文

【摘要】：白念珠菌是一種寄生于人體粘膜和皮膚表面的條件致病菌。正常情況下,其并不引起感染性疾病,但當(dāng)機(jī)體免疫力下降或受到抑制時(shí),白念珠菌趁虛而入,輕則引起各種癬病,重則引起系統(tǒng)性的念珠菌感染。系統(tǒng)性念珠菌感染病情兇險(xiǎn),治療十分棘手,患者往往預(yù)后較差。白念珠菌穿過人體的皮膚和粘膜屏障后,首先被免疫系統(tǒng)的抗原遞呈細(xì)胞(APC)所感知。常見的APC包括巨噬細(xì)胞、單核細(xì)胞、樹突狀細(xì)胞等,其表面表達(dá)高水平的模式識別受體(PRR),負(fù)責(zé)在第一時(shí)間感知入侵機(jī)體的白念珠菌。PRR感知白念珠菌的分子基礎(chǔ)是識別器表面的病原體相關(guān)分子模式(PAMP)。根據(jù)分子結(jié)構(gòu)和功能,PRR分為很多種,包括Toll樣受體(TLR)、維甲酸誘導(dǎo)基因樣受體(RLRs)和NOD樣受體(NLR)。由于白念珠菌的體積較大,PAMP的種類較多,因此參與其免疫識別的PRR也較多。以前的研究表明TLR家族的TLR2、TLR4和TLR6均參與了念珠菌的免疫識別。此外,NLR家族的Dectin-1、Dectin-2等也參與了白念珠菌的免疫識別。當(dāng)白念珠菌與APC表面的PRR結(jié)合后,胞內(nèi)多條信號通路被迅速活化,最終導(dǎo)致APC在感染部位迅速釋放各種炎癥因子,比如白細(xì)胞介素1(IL-1),腫瘤壞死因子α(TNF-α)和I型干擾素等,在第一時(shí)間促進(jìn)白念珠菌的免疫清除。另一方面,APC將白念珠菌吞噬,對其抗原進(jìn)行消化處理,并將抗原片段遞交給T細(xì)胞,同時(shí)分泌各種細(xì)胞因子,如IL-12,轉(zhuǎn)化生長因子β(TGF-β)等,在局部形成特定的細(xì)胞因子格局,指導(dǎo)后續(xù)的獲得性免疫應(yīng)答過程。針對白念珠菌的免疫應(yīng)答必須處在精細(xì)的調(diào)控之中。一方面,炎癥反應(yīng)過度會(huì)導(dǎo)致機(jī)體的免疫病理損傷。另一方面,如果炎癥反應(yīng)強(qiáng)度不足或持續(xù)時(shí)間過短,則無法清除入侵機(jī)體的病原菌,最終導(dǎo)致病原菌擴(kuò)散。microRNA是一類長度在18-25個(gè)堿基的短鏈非編碼RNA。以往的研究表明其廣泛地參與了免疫細(xì)胞的分化發(fā)育以及免疫應(yīng)答的調(diào)控過程。多個(gè)研究表明miR-146a是一個(gè)免疫調(diào)節(jié)功能十分活躍的分子,廣泛參與了TLR信號通路、RIG-I信號通路的負(fù)向調(diào)節(jié)過程。在前期研究中,我們采用microRNA芯片分析了熱滅活白念珠菌刺激人單核源性樹突狀細(xì)胞(Mo-DCs)的microRNA表達(dá)譜,發(fā)現(xiàn)miR-146a表達(dá)上調(diào),但該結(jié)果尚未得到PCR的證實(shí),且miR-146a表達(dá)增高的生物學(xué)意義仍不明確。在本研究中,我們對miR-146a在白念珠菌引發(fā)的固有免疫應(yīng)答中的作用進(jìn)行了探討。第一部分熱滅活白念珠菌通過NF-κB依賴性的方式上調(diào)細(xì)胞內(nèi)miR-146a的表達(dá)我們首先以熱滅活白念珠菌刺激THP-1細(xì)胞、RAW 264.3,單核源性樹突狀細(xì)胞和PMA誘導(dǎo)的巨噬細(xì)胞,然后采用RT-PCR檢測miR-146a的表達(dá)變化情況,發(fā)現(xiàn)白念珠菌刺激可以上調(diào)細(xì)胞內(nèi)miR-146a的表達(dá)。我們采用NF-κB的抑制劑PDTC預(yù)處理細(xì)胞,然后再以白念珠菌進(jìn)行刺激,觀察NF-κB被抑制后,miR-146a的表達(dá)變化情況,結(jié)果發(fā)現(xiàn)PDTC可以部分下調(diào)miR-146a的表達(dá),說明白念珠菌上調(diào)miR-146a的表達(dá)在一定程度上依賴于NF-κB。此外,由于此前的研究表明Dectin-1是參與白念珠菌免疫識別的PRR之一,因此我們采用昆布多糖封閉Dectin-1,再用白念珠菌進(jìn)行刺激,觀察miR-146a的表達(dá)變化情況。結(jié)果發(fā)現(xiàn)昆布多糖對miR-146a的表達(dá)無影響。我們還采用Dectin-1激動(dòng)劑Curdlan活化THP-1細(xì)胞,也發(fā)現(xiàn)細(xì)胞內(nèi)miR-146a的表達(dá)豐度不受影響。這些結(jié)果說明,白念珠菌可以通過NF-κB上調(diào)細(xì)胞內(nèi)miR-146a的表達(dá),但這種上調(diào)miR-146a表達(dá)的功能與Dectin-1無關(guān)。第二部分miR-146a負(fù)向調(diào)節(jié)熱滅活白念珠菌誘導(dǎo)THP-1細(xì)胞釋放干擾素β的能力之后,我們進(jìn)一步分析了白念珠菌上調(diào)miR-146a表達(dá)的生物意義。我們用熱滅活白念珠菌刺激THP-1細(xì)胞,采用ELISA法檢測培養(yǎng)基內(nèi)干擾素β(IFN-β)的表達(dá)水平,用RT-PCR法檢測IFN-β、干擾素刺激基因(ISG)基因2-5-寡腺苷酸合成酶(OAS-1)和抗粘病毒蛋白1(MX1)的表達(dá)。結(jié)果發(fā)現(xiàn)熱滅活白念珠菌可以促進(jìn)THP-1細(xì)胞釋放IFN-β,上調(diào)OAS-1和MX1的表達(dá)。我們將miR-146a mimic和inhibitor轉(zhuǎn)染入THP-1細(xì)胞,再用熱滅活白念珠菌進(jìn)行刺激,并用ELISA計(jì)策培養(yǎng)基內(nèi)的IFN-β水平,以RT-PCR法檢測OAS-1和MX1 m RNA的表達(dá)。發(fā)現(xiàn)miR-146a mimic可以抑制白念珠菌誘導(dǎo)THP-1細(xì)胞釋放IFN-β的能力,而miR-146a inhibitor則可以增強(qiáng)白念珠菌誘導(dǎo)THP-1細(xì)胞釋放IFN-β的能力,說明miR-146a是IFN-β的負(fù)向調(diào)節(jié)因子。此外,我們還發(fā)現(xiàn),miR-146a mimic可以抑制白念珠菌上調(diào)OAS-1和MX1的能力,而miR-146a inhibitor則發(fā)揮了相反的作用。這些結(jié)果表明,在熱滅活白念珠菌刺激的THP-1細(xì)胞中,miR-146a表達(dá)上調(diào)的生物學(xué)意義可能在于負(fù)向調(diào)節(jié)IFN-β的釋放,并由此負(fù)向調(diào)控了ISG的表達(dá)。第三部分miR-146a作用靶點(diǎn)分析由于此前有研究表明白念珠菌刺激單核源性樹突狀細(xì)胞表達(dá)IFN-β與干擾素調(diào)節(jié)因子5(IRF5)有關(guān),而生物信息學(xué)預(yù)測又發(fā)現(xiàn)IRF5是miR-146a的作用靶點(diǎn)。因此我們擬進(jìn)一步分析IRF5是否是miR-146a的作用靶點(diǎn)。我們采用熱滅活白念珠菌刺激THP-1細(xì)胞后,發(fā)現(xiàn)IRF5在m RNA和蛋白水平的表達(dá)并沒有明顯的變化。將miR-146a mimic或inhibitor轉(zhuǎn)染入THP-1細(xì)胞后,然后用熱滅活白念珠菌進(jìn)行刺激,IRF5的表達(dá)也沒有受到影響。因此我們確定IRF5并非miR-146a的作用靶點(diǎn)。接下來,我們用生物信息學(xué)軟件預(yù)測到一個(gè)名為IFIT3的ISG是miR-146a的作用靶點(diǎn)。用熱滅活白念珠菌刺激THP-1細(xì)胞后,我們發(fā)現(xiàn)IFIT3的m RNA和蛋白均呈現(xiàn)出先增高,后降低的趨勢,提示miR-146a可以調(diào)節(jié)IFIT3的表達(dá)。我們將miR-146a mimic或inhibitor轉(zhuǎn)染入THP-1細(xì)胞,并以外源性的IFN-β進(jìn)行刺激,發(fā)現(xiàn)miR-146a的確可以下調(diào)IFIT3的表達(dá)。我們進(jìn)一步采用報(bào)告基因技術(shù)驗(yàn)證miR-146a與IFIT3 m RNA的3’UTR是否有相互作用,卻發(fā)現(xiàn)二者之間無相互作用。因此,miR-146a調(diào)節(jié)可能是通過間接作用調(diào)節(jié)IFIT3的表達(dá)。綜上,我們認(rèn)為在白念珠菌刺激的THP-1細(xì)胞中,miR-146a并不是通過IRF5調(diào)節(jié)IFN-β的表達(dá),其雖然可以調(diào)節(jié)IFIT3的表達(dá),但是并不是直接的相互作用,而是通過間接作用調(diào)節(jié)其表達(dá)。第四部分mi-146a通過IFIT3調(diào)節(jié)THP-1細(xì)胞的凋亡考慮到miR-146a可以調(diào)節(jié)IFIT3的表達(dá),而以往的研究表明IFIT3與細(xì)胞凋亡有關(guān)。因此,我們接下來研究了miR-146a是否調(diào)節(jié)了THP-1細(xì)胞的凋亡,同時(shí)也分析了miR-146a調(diào)節(jié)THP-1細(xì)胞的凋亡是否與IFIT3有關(guān)。我們首先將miR-146ainhibitor或mimic轉(zhuǎn)染入THP-1細(xì)胞,然后用白念珠菌對其進(jìn)行刺激,采用Annexin V-PI法檢測細(xì)胞的凋亡狀況。結(jié)果我們發(fā)現(xiàn):miR-146a mimic可以促進(jìn)細(xì)胞的凋亡,而miR-146a inhibitor對細(xì)胞凋亡影響不顯著。這些結(jié)果表明miR-146a是促進(jìn)細(xì)胞凋亡的因素。隨后,我們采用siRNA技術(shù)抑制IFIT3的表達(dá),然后再用熱滅活白念珠菌對THP-1細(xì)胞進(jìn)行刺激。結(jié)果發(fā)現(xiàn)IFIT3表達(dá)下調(diào)后,細(xì)胞的凋亡增加。這說明IFIT3具有抗凋亡作用。綜上,這部分結(jié)果說明了miR-146a具有促凋亡作用,其促凋亡的作用可能是通過下調(diào)IFIT3的表達(dá)來實(shí)現(xiàn)的。結(jié)論綜上,本研究的主要發(fā)現(xiàn)是:白念珠菌可以通過活化NF-κB的方式上調(diào)THP-1細(xì)胞內(nèi)miR-146a的表達(dá),這種上調(diào)作用與參與白念珠菌識別的模式識別受體Dectin-1無關(guān)。MiR-146表達(dá)上調(diào)具有兩個(gè)生物學(xué)意義:第一,負(fù)向調(diào)節(jié)IFN-β的產(chǎn)生,并由此調(diào)節(jié)了多個(gè)ISG的表達(dá),且我們的研究證實(shí)miR-146a的這種生物學(xué)功能與其理論靶點(diǎn)IRF5無關(guān);第二,miR-146a通過IFN-β→IFIT3軸調(diào)節(jié)細(xì)胞的凋亡。
[Abstract]:Candida albicans is a conditional pathogen parasitic on the surface of the mucous membrane and skin of the human body. Under normal circumstances, it does not cause infectious diseases, but when the body's immunity is reduced or suppressed, Candida albicans takes the advantage of the disease and causes systemic candidal infection. Systemic Candida infection is a dangerous and dangerous disease. The common APC includes macrophages, monocytes, dendritic cells and so on, which express the high level of pattern recognition receptor (PRR) on the surface, which is responsible for the first time to perceive the invasion of APC. The molecular basis of Candida albicans.PRR perceiving Candida albicans is the pathogen associated molecular pattern (PAMP) on the surface of the recognizer. According to the molecular structure and function, PRR is divided into many species, including Toll like receptor (TLR), retinoic acid induced gene like receptor (RLRs) and NOD like receptor (NLR). Because of the larger volume of Candida albicans, the variety of PAMP is more, and the cause is more. PRR is involved in its immune recognition. Previous studies have shown that the TLR2, TLR4 and TLR6 of the TLR family are involved in the immune recognition of Candida. In addition, the Dectin-1, Dectin-2, etc. of the NLR family are also involved in the immune recognition of Candida albicans. When Candida albicans are combined with PRR of the APC surface, multiple intracellular signaling pathways are rapidly activated and ultimately guided. APC rapidly releases various inflammatory factors at the infected site, such as interleukin 1 (IL-1), tumor necrosis factor alpha (TNF- alpha) and type I interferon and so on. In the first time, the immune clearance of Candida albicans is promoted. On the other hand, APC phagocytosis of Candida albicans, the antigen is eliminated, and the antigen fragments are delivered to T cells and secreted at the same time. The cytokine, such as IL-12, transforming growth factor beta (TGF- beta) and so on, forms a specific cytokine pattern in the region to guide the subsequent acquired immune response. The immune response to Candida albicans must be in fine control. On the one hand, the excessive inflammatory response can lead to the immune pathological damage of the body. On the other hand, if inflammation is affected. It is impossible to clear the pathogenic bacteria of the invading organism and eventually lead to the spread of.MicroRNA, a class of short chain non coded RNA. with 18-25 bases, which showed that it was widely involved in the differentiation and development of immune cells and the regulation of immune response. Multiple studies showed that miR-1 46a is a very active immunomodulatory molecule, which has been widely involved in the negative regulation of the TLR signaling pathway and the RIG-I signaling pathway. In the previous study, we used microRNA chips to analyze the microRNA expression profiles of thermally inactivated Candida albicans stimulated human mononuclear dendritic cells (Mo-DCs), and found that the expression of miR-146a was up-regulated, but the conclusion was that the expression of miR-146a was up-regulated. The fruit has not been confirmed by PCR, and the biological significance of the increased expression of miR-146a is still not clear. In this study, we explored the role of miR-146a in the intrinsic immune response induced by Candida albicans. The first part of the heat inactivated Candida albicans, through the NF- kappa B dependent manner, the expression of miR-146a in the cell modulation, we first heat the cells. Inactivated Candida albicans stimulated THP-1 cells, RAW 264.3, mononuclear dendritic cells and PMA induced macrophages. Then RT-PCR was used to detect the changes in the expression of miR-146a. It was found that Candida albicans stimulated the expression of miR-146a in cells. We used NF- kappa B inhibitor PDTC to pretreat the cells and then use Candida albicans for Candida albicans. Stimulated, the expression changes of miR-146a after the inhibition of NF- kappa B were observed. The results showed that PDTC could partly down regulate the expression of miR-146a. It was suggested that the expression of miR-146a was partly dependent on NF- kappa B.. Since previous studies showed that Dectin-1 was one of the PRR of Candida albicans immune recognition, we used Kunming. When the polysaccharide was closed to Dectin-1, the expression of miR-146a was observed with Candida albicans. The results showed that the expression of miR-146a had no effect on the expression of miR-146a. We also used the Dectin-1 agonist Curdlan to activate THP-1 cells, and also found that the expression abundance of miR-146a in the cells was not affected. These results suggest that Candida albicans can pass through NF- kappa B up-regulated the expression of miR-146a in the cell, but the function of the up regulation of miR-146a was not related to Dectin-1. Second part miR-146a negatively regulated the ability of Candida albicans to induce the release of interferon beta in THP-1 cells. We further analyzed the biological significance of albicans albicans up regulation of miR-146a surface. We use heat to inactivate Candida albicans. ELISA assay was used to detect the expression level of interferon beta (IFN- beta) in cultured THP-1 cells and the expression of IFN- beta, IFN- beta, ISG gene (ISG) gene 2-5- oligoadenylate synthetase (OAS-1) and anti visco protein 1 (MX1). The results showed that thermally inactivated Candida albicans could promote the release of IFN- beta in THP-1 cells, up regulation of OAS-1 and impurities. 1, we transfected miR-146a mimic and inhibitor into THP-1 cells, stimulated the Candida albicans with heat inactivation, and cultured the IFN- beta level in the base with ELISA strategy. The expression of OAS-1 and MX1 m RNA was detected by RT-PCR method. Or can enhance the ability of Candida albicans to induce the release of IFN- beta in THP-1 cells, indicating that miR-146a is a negative regulator of IFN- beta. In addition, we also found that miR-146a mimic inhibits the ability of Candida albicans to increase OAS-1 and MX1, while miR-146a inhibitor plays the opposite role. These results suggest that the activation of Candida albicans in heat inactivated Candida albicans. In the THP-1 cells, the biological significance of the up regulation of miR-146a expression may lie in the negative regulation of the release of IFN- beta, and thus negatively regulates the expression of ISG. The third part of the target analysis of miR-146a is due to the previous study that the expression of IFN- beta in Monal derived dendritic cells expressed by Candida albicans was related to the interferon regulator 5 (IRF5). It is also found that IRF5 is the target of miR-146a. Therefore, we will further analyze whether IRF5 is the target of miR-146a. We found that the expression of IRF5 at m RNA and protein levels has not changed significantly after the use of thermally inactivated Candida albicans to stimulate the expression of M RNA and protein. The expression of IRF5 was not affected by the activation of Candida albicans with heat inactivation. So we determined that IRF5 was not the target of miR-146a. Then, we predicted that a ISG named IFIT3 was the target of miR-146a with bioinformatics software. We found m RNA of IFIT3 by using the thermal inactivated Candida albicans to stimulate the THP-1 cells. And the protein showed a tendency to increase first and then decrease, suggesting that miR-146a could regulate the expression of IFIT3. We transfected miR-146a mimic or inhibitor into THP-1 cells and stimulated by exogenous IFN- beta. It was found that miR-146a could downregulate the expression of IFIT3. We further used the report gene technique to verify miR-146a and IFIT3 M. If 3 'UTR has interaction, it is found that there is no interaction between the two. Therefore, miR-146a regulation may regulate the expression of IFIT3 by indirect action. In conclusion, we think that miR-146a does not regulate the expression of IFN- beta through IRF5 in the THP-1 cells stimulated by Candida albicans, although it can regulate the expression of IFIT3, but it is not direct. The fourth part mi-146a regulates the apoptosis of THP-1 cells through IFIT3, which regulates the apoptosis of THP-1 cells through IFIT3, considering that miR-146a can regulate the expression of IFIT3, while previous studies have shown that IFIT3 is associated with apoptosis. The analysis of whether the apoptosis of THP-1 cells by miR-146a is related to IFIT3. We first transfect miR-146ainhibitor or mimic into THP-1 cells, then use Candida albicans to stimulate them, and detect the cell apoptosis using Annexin V-PI method. We found that miR-146a mimic can promote cell apoptosis and miR-146a inhibitor is fine. The effect of apoptosis is not significant. These results suggest that miR-146a is a factor promoting apoptosis. Then, we use siRNA technique to inhibit the expression of IFIT3, and then use heat inactivated Candida albicans to stimulate the THP-1 cells. The results showed that the apoptosis of the cells increased after the down regulation of IFIT3 expression. This shows that IFIT3 has anti apoptosis effect. The results show that miR-146a has the role of promoting apoptosis, and its role in promoting apoptosis may be achieved by down regulating the expression of IFIT3. Conclusion the main discovery of this study is that Candida albicans can increase the expression of miR-146a in THP-1 cells by activating NF- kappa B, the up regulation and the pattern recognition of Candida albicans. The up-regulated expression of the other receptor Dectin-1 has two biological significance: first, the negative regulation of the production of IFN- beta and thereby regulating the expression of multiple ISG, and our study confirms that this biological function of miR-146a is independent of its theoretical target IRF5; second, miR-146a regulates cell apoptosis through the IFN- beta - IFIT3 axis.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R519.3

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7 趙敬軍;;白念珠菌分泌型天冬氨酸蛋白酶的研究近況[J];國外醫(yī)學(xué)(微生物學(xué)分冊);2000年02期

8 牛云彤,李少平;白念珠菌毒力因子研究進(jìn)展[J];中國微生態(tài)學(xué)雜志;2000年01期

9 王魯,刁慶春,蔣戈,劉榮卿,鐘白玉;白念珠菌保護(hù)性單抗的研究[J];中華皮膚科雜志;2001年05期

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3 黃廣華;;白念珠菌有性生殖、形態(tài)發(fā)生及毒性的進(jìn)化[A];中國菌物學(xué)會(huì)第五屆會(huì)員代表大會(huì)暨2011年學(xué)術(shù)年會(huì)論文摘要集[C];2011年

4 王慧;徐寧;喻其林;程欣欣;邢來君;李明春;;鈣細(xì)胞存活途徑與白念珠菌的致病性[A];中國菌物學(xué)會(huì)第五屆會(huì)員代表大會(huì)暨2011年學(xué)術(shù)年會(huì)論文摘要集[C];2011年

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8 曾躍斌;;白念珠菌全基因組表達(dá)譜芯片在抗真菌藥物研究中的應(yīng)用[A];中國藥理學(xué)會(huì)第十一屆全國化療藥理學(xué)術(shù)研討會(huì)論文集[C];2012年

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10 景偉芳;王惠平;;白念珠菌對唑類藥物耐藥機(jī)制的研究進(jìn)展[A];中華醫(yī)學(xué)會(huì)第十五次全國皮膚性病學(xué)術(shù)會(huì)議論文集[C];2009年

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8 王平;陰道念珠菌菌種及香蓮方逆轉(zhuǎn)白念珠菌耐藥基因組學(xué)研究[D];廣州中醫(yī)藥大學(xué);2013年

9 許懿;小檗堿與氟康唑協(xié)同抗耐藥白念珠菌的作用機(jī)制研究[D];第二軍醫(yī)大學(xué);2010年

10 李彩霞;陰道細(xì)菌群落多樣性及外陰陰道念珠菌病相關(guān)白念珠菌基因多態(tài)性研究[D];北京協(xié)和醫(yī)學(xué)院;2013年

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9 劉樂;不同培養(yǎng)條件對白念珠菌芽管形成的影響[D];蘭州大學(xué);2008年

10 閻瀾;白念珠菌耐藥株的蛋白質(zhì)組與基因表達(dá)譜分析及差異蛋白質(zhì)與差異基因的識別鑒定[D];第二軍醫(yī)大學(xué);2006年

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