陳偉偉，張冉冉，曹 雯，陳 晉

結(jié)核分枝桿菌免疫逃避機(jī)制研究進(jìn)展

陳偉偉，張冉冉，曹 雯，陳 晉

結(jié)核病(Tuberculosis TB)主要由結(jié)核分枝桿菌(Mycobacteriumtuberculosis，Mtb)感染引起，結(jié)核分枝桿菌在機(jī)體中長(zhǎng)期存在與其逃避機(jī)體免疫殺傷機(jī)制密切相關(guān)。已發(fā)現(xiàn)的結(jié)核分枝桿菌免疫逃避機(jī)制包括阻止巨噬細(xì)胞吞噬溶酶體的成熟及酸化，抑制氧化應(yīng)激反應(yīng)，抑制細(xì)胞凋亡及自噬等。結(jié)核分枝桿菌逃避宿主免疫殺傷的機(jī)制錯(cuò)綜復(fù)雜，目前尚未完全明了，本文就結(jié)核分枝桿菌免疫逃避機(jī)制做一綜述，為其深入研究提供參考。

結(jié)核分枝桿菌；逃逸機(jī)制；免疫殺傷

結(jié)核分枝桿菌在與宿主長(zhǎng)期相互作用下，有些能逃避宿主的免疫殺傷從而在宿主細(xì)胞中長(zhǎng)期存在，即形成一系列免疫逃避機(jī)制，這給結(jié)核病的防治帶來極大的阻礙。結(jié)核分枝桿菌是胞內(nèi)寄生菌，主要通過飛沫經(jīng)呼吸道傳播，感染人體后，先經(jīng)巨噬細(xì)胞內(nèi)化吞噬，隨后與溶酶體結(jié)合酸化細(xì)菌寄存的吞噬體，通過一系列蛋白水解酶和脂肪酶活動(dòng)殺傷病原菌[1]，近幾年研究證明，凋亡對(duì)抑制胞內(nèi)結(jié)核分枝桿菌繁殖有一定的影響，同時(shí)巨噬細(xì)胞的自噬也被證明是重要的病原體清除途徑[2-4]。為抵抗機(jī)體廣泛的殺菌作用，結(jié)核分枝桿菌通過一系列應(yīng)對(duì)措施得以在細(xì)胞內(nèi)環(huán)境生存，應(yīng)對(duì)措施包括阻止吞噬溶酶體的成熟及酸化，抑制氧化應(yīng)激反應(yīng)，抑制細(xì)胞凋亡及自噬[5]。研究表明，結(jié)核分枝桿菌多年來之所以成為第二大致死性疾病的病原體，不僅在于其結(jié)構(gòu)的復(fù)雜性，也與其能夠調(diào)節(jié)宿主的免疫應(yīng)答機(jī)制、逃避宿主的免疫防御及殺傷密切相關(guān)[6]，因此，有必要對(duì)結(jié)核分枝桿菌免疫逃避機(jī)制進(jìn)行更深入的研究。先前已有大量關(guān)于結(jié)核分枝桿菌免疫逃避綜述，本文在王飛雨等[7]撰寫的綜述的基礎(chǔ)上就該內(nèi)容近年研究成果作一概括。

1 阻止巨噬細(xì)胞吞噬溶酶體的成熟及酸化

結(jié)核分枝桿菌感染巨噬細(xì)胞后，為其能長(zhǎng)期存在機(jī)體并保持其自身的毒力，可通過阻礙巨噬細(xì)胞吞噬體成熟、酸化以及抑制自噬溶酶體的形成[8-11]。結(jié)核分枝桿菌在與宿主長(zhǎng)期作用進(jìn)化過程中，自身結(jié)構(gòu)及其菌體成分即可一定程度阻止吞噬溶酶體成熟及酸化的功能。已有的研究表明，結(jié)核分枝桿菌細(xì)胞壁的物理結(jié)構(gòu)及其分子組成的特殊性，可通過調(diào)節(jié)自身的pH發(fā)揮抵制巨噬細(xì)胞吞噬小體酸化的作用，從而逃避吞噬體的酸化殺傷。此外，也有研究表明，結(jié)核分枝桿菌菌體蛋白及脂類成分能通過抑制吞噬體的成熟提高自身的生存率。先前已有報(bào)道表明結(jié)核分枝桿菌的部分分泌蛋白，如LpdC、NdkA、PknG、SapM 等，其維持結(jié)核分枝桿菌在宿主細(xì)胞內(nèi)的生長(zhǎng)主要通過不同的路徑來發(fā)揮其抑制巨噬細(xì)胞吞噬體成熟的功能[6]。SecA2[10]和PtpA[8]是結(jié)核分枝桿菌分泌的兩種蛋白質(zhì)，均能通過影響V-ATPase從而抑制吞噬體的酸化過程，阻止吞噬溶酶體的成熟。近期研究表明，促炎癥轉(zhuǎn)錄因子NF-κB可通過調(diào)控溶酶體酶釋放到吞噬體的轉(zhuǎn)運(yùn)過程，從而導(dǎo)致病原體殺傷能力的減低，而阻斷NF-κB激活途徑可以導(dǎo)致溶酶體和巨噬細(xì)胞吞噬體正常融合現(xiàn)象的減少[12]。組織蛋白酶Cathepsins是一種蛋白水解酶，在內(nèi)吞過程中發(fā)揮重要的作用，通過參與抗原提呈途徑直接或間接殺傷病原菌。Pires D.研究表明[13]結(jié)核分枝桿菌感染機(jī)體后，會(huì)導(dǎo)致大部分組織蛋白酶表達(dá)量下降，尤其是Cathepsins B，L和S，同時(shí)抑制IFNγ調(diào)控組織蛋白酶mRNA，因此減少相應(yīng)的組織蛋白酶產(chǎn)生，從而減少其對(duì)病原菌的殺傷增加病原菌在細(xì)胞內(nèi)的存活。ESX-3分泌的由EsxG 和EsxH組成的二聚體已經(jīng)證實(shí)能通過阻止巨噬細(xì)胞吞噬體成熟從而保持結(jié)核分枝桿菌的毒力。鋅離子和鐵離子能通過調(diào)節(jié)ESX-3的分泌從而對(duì)結(jié)核分枝桿菌在機(jī)體內(nèi)的生存產(chǎn)生影響，在無鋅離子和鐵離子的條件下，EsxG 和EsxH生成增加，進(jìn)一步阻止吞噬溶酶體的成熟，增加結(jié)核分枝桿菌生存率[14]。

2 抑制氧化應(yīng)激反應(yīng)

氧化應(yīng)激(Oxidative Stress，OS)在機(jī)體抵抗外來細(xì)菌入侵時(shí)發(fā)揮重要的作用。結(jié)核分枝桿菌感染巨噬細(xì)胞后，活化的宿主可通過呼吸暴發(fā)從而生成大量的代謝性自由基，借助強(qiáng)氧化作用和細(xì)胞毒作用有效地清除結(jié)核分枝桿菌[6]。巨噬細(xì)胞產(chǎn)生的殺傷結(jié)核分枝桿菌的物質(zhì)包括活性氧中間物(ROI)以及活性氮介質(zhì)(RNI)，這些ROI和RNI可以通過與各種分子，包括核酸、蛋白質(zhì)、脂類和碳水化合物廣泛作用從而達(dá)到殺菌的作用[15]。結(jié)核分枝桿菌可以通過降低磷酯酶D的活性, 減少活性氧中間體和活性氮中間體的產(chǎn)生從而逃避病原菌在機(jī)體內(nèi)的氧化殺傷。已有的研究表明，結(jié)核分枝桿菌自身結(jié)構(gòu)的物理特性就具有一定的抗氧化作用，其細(xì)胞壁上富含的特殊成分已經(jīng)證實(shí)可以有效的減少自由基的生成[16]。Dong Min[17]等人通過敲除結(jié)核分枝桿菌EIS基因，檢測(cè)其促炎癥細(xì)胞因子與氧自由基的產(chǎn)生情況，發(fā)現(xiàn)EIS基因敲除的結(jié)核分枝桿菌感染機(jī)體后能導(dǎo)致機(jī)體大量產(chǎn)生促炎癥細(xì)胞因子TNF-a，IL-6以及氧自由基，表明EIS基因在調(diào)節(jié)宿主氧化應(yīng)激應(yīng)答方面發(fā)揮重要的作用。EIS基因?qū)Y(jié)核分枝桿菌在機(jī)體內(nèi)的生存調(diào)節(jié)主要是通過JNK信號(hào)通路調(diào)節(jié)ROS的產(chǎn)生，而其調(diào)節(jié)ROS的主要是N-乙酰轉(zhuǎn)移酶結(jié)構(gòu)域。結(jié)核分枝桿菌分泌的蛋白CFP-10,ESAT-6以及CFP-10和ESAT-6的復(fù)合物能夠有效抑制氧自由基的產(chǎn)生，在蛋白質(zhì)治療5 min后即可觀察到氧自由基明顯的下降。Niladri Ganguly等[18]實(shí)驗(yàn)結(jié)果表明，CFP-10和ESAT-6的復(fù)合物相比于CFP-10或ESAT-6單一成分具有更高效的抑制氧自由基的作用，其主要是通過抑制脂多糖誘導(dǎo)的NF-κB激活，從而下調(diào)ROS的產(chǎn)生。結(jié)核分枝桿菌的KatG酶，trxB2酶相應(yīng)的編碼基因在H2O2和NO作用的條件下表達(dá)量明顯增加，表明這兩種酶對(duì)氧化環(huán)境有一定的抵抗作用[19]。結(jié)核分枝桿菌rv0431基因編碼的具有特殊折疊結(jié)構(gòu)的胞質(zhì)膜連接蛋白已經(jīng)證實(shí)能夠減少結(jié)核分枝桿菌膜囊泡的生成，而囊泡中含有豐富的巨噬細(xì)胞Toll樣受體2(TLR2)激動(dòng)劑LpqH，因此結(jié)核分枝桿菌rv0431基因能通過減少與巨噬細(xì)胞受體相互作用從而減少免疫刺激因子產(chǎn)生，減少結(jié)核分枝桿菌在機(jī)體的免疫殺傷[20]。

3 抑制細(xì)胞凋亡及自噬

凋亡是指為維護(hù)細(xì)胞內(nèi)環(huán)境的穩(wěn)定，由基因控制的細(xì)胞主動(dòng)有序的死亡。凋亡在結(jié)核分枝桿菌感染初期是巨噬細(xì)胞對(duì)抗病原菌非常重要的先天性防御機(jī)制[21]，能有效控制細(xì)菌的繁殖，降低其在細(xì)胞內(nèi)的生存能力，從而維持機(jī)體正常結(jié)構(gòu)和功能。已有的研究表明，巨噬細(xì)胞凋亡程度與結(jié)核分枝桿菌毒力相關(guān)，無毒或減毒菌株相比于毒力菌株引起的巨噬細(xì)胞凋亡數(shù)目明顯增多，表明毒力菌株能顯著下調(diào)宿主細(xì)胞的凋亡[22]。巨噬細(xì)胞有多種凋亡途徑，已有的研究表明，結(jié)核分枝桿菌能干擾巨噬細(xì)胞凋亡的Caspase酶途徑[23]，JAK2/STAT1途徑[24]，TNF-α途徑[25]和Bcl-2途徑[26]，從而減少巨噬細(xì)胞的凋亡，增加病原菌的生存。結(jié)核分枝桿菌分泌的一些蛋白已經(jīng)證實(shí)會(huì)抑制細(xì)胞的凋亡，如SecA2和超氧化物歧化酶SodA、過氧化氫/過氧化物酶KatG、Ⅰ型NADH 脫氫酶NuoG、絲氨酸/蘇氨酸蛋白激酶PknE、Rv3655c等[27-29]。董江濤等人研究發(fā)現(xiàn)，在結(jié)核分枝桿菌感染的早期和晚期，結(jié)核分枝桿菌小分子熱休克蛋白 Hsp16.3可能是通過促進(jìn) Bcl-2蛋白的表達(dá)以及抑制凋亡蛋白酶 Caspase-3的表達(dá)等機(jī)制從而能夠有效抑制小鼠肺泡巨噬細(xì)胞的凋亡[30]。Neeraj Kumar Sainid等的研究表明，結(jié)核分枝桿菌的Mce4A與結(jié)核分枝桿菌的免疫逃逸相關(guān)，實(shí)驗(yàn)結(jié)果發(fā)現(xiàn)Mce4刺激THP-1細(xì)胞后，可以促進(jìn)細(xì)胞因子TNF-α和IFNγ等的產(chǎn)生。Mce4A對(duì)THP-1凋亡的影響機(jī)制與TNF-α相關(guān)，在抗TNF-α抗體存在的條件下，THP-1細(xì)胞的凋亡比例與單獨(dú)Mce4A作用相比明顯下降[31]。

自噬是在自噬相關(guān)基因的調(diào)控下，細(xì)胞利用溶酶體降解自身受損的細(xì)胞器以及大分子物質(zhì)的過程，能殺傷胞內(nèi)病原菌從而有助于維持細(xì)胞的穩(wěn)態(tài)[32]。同時(shí)，自噬還是一種重要的免疫防御機(jī)制，參與機(jī)體固有免疫和適應(yīng)性免疫應(yīng)答[33]。研究表明，自噬在巨噬細(xì)胞抗分枝桿菌過程中至關(guān)重要，且結(jié)核分枝桿菌抑制自噬的能力與其細(xì)菌毒力相關(guān)[5-7]，毒力菌株相比于無毒菌株或者減毒菌株更能抑制巨噬細(xì)胞的自噬能力，毒力菌株能上調(diào)Th2細(xì)胞因子水平，同時(shí)抑制Th1型細(xì)胞免疫應(yīng)答，從而減少巨噬細(xì)胞的自噬。Shilpa V. Jamwal等研究發(fā)現(xiàn)，結(jié)核分枝桿菌在感染機(jī)體初期的胞質(zhì)定位能增強(qiáng)細(xì)菌抑制巨噬細(xì)胞自噬激活的能力，同時(shí)，激活胞質(zhì)磷脂酶A2(cPLA2)能增強(qiáng)Mtb逃逸到胞質(zhì)的能力，恢復(fù)結(jié)核分枝桿菌的毒力，因此能抑制細(xì)胞的自噬[34]。cPLA2抑制對(duì)胞內(nèi)定位的細(xì)菌生存無影響，卻能降低胞質(zhì)定位的細(xì)菌的生存率，表明cPLA2對(duì)胞質(zhì)定位的結(jié)核分枝桿菌在機(jī)體內(nèi)生存繁殖有重要作用。Mtb EIS蛋白已經(jīng)證實(shí)可以增強(qiáng)結(jié)核分枝桿菌在巨噬細(xì)胞內(nèi)的存活，其中一個(gè)機(jī)制即負(fù)向調(diào)節(jié)細(xì)胞自噬[17]，EIS基因敲除的結(jié)核分枝桿菌能促使自噬囊泡的積聚以及促炎癥因子的產(chǎn)生，從而增加細(xì)胞自噬。而Liang Duan, Min Yi等的研究認(rèn)為，Mtb EIS蛋白可能是通過H3乙?；险{(diào)IL-10，因此激活A(yù)kt/mTOR/p70S6K通路從而抑制巨噬細(xì)胞自噬[35]。ESAT-6也證實(shí)能通過雷帕霉素蛋白(MTOR)激活途徑調(diào)節(jié)自噬吞噬溶酶體融合，導(dǎo)致溶酶體功能障礙，從而抑制細(xì)胞的自噬[36]。Dong Hu等人研究發(fā)現(xiàn)，酸性磷酸酶SapM也能通過阻斷自噬吞噬體與溶酶體融合而抑制細(xì)胞的自噬，其機(jī)制可能與RAB7抑制相關(guān)[37]。已有的研究表明，miR30-A能抑制宿主殺傷結(jié)核分枝桿菌的能力。在結(jié)核分枝感染機(jī)體后，miR30-A表達(dá)上調(diào)，且miR30-A表達(dá)量與細(xì)菌菌量呈正相關(guān)，實(shí)驗(yàn)結(jié)果表明，miR30-A增強(qiáng)細(xì)菌在機(jī)體的生存率主要通過miR30-A抑制宿主細(xì)胞的自噬，其主要是通過選擇性抑制ATG5和beclin-1[38]。

4 小結(jié)與展望

結(jié)核分枝桿菌在與宿主長(zhǎng)期相互作用的過程中, 為其能在宿主體內(nèi)存活并增殖從而逐漸形成多種逃避免疫殺傷策略。盡管先前已有大量關(guān)于結(jié)核分枝桿菌免疫逃避的研究，但是結(jié)核分枝桿菌逃避宿主免疫殺傷的機(jī)制錯(cuò)綜復(fù)雜，目前尚未完全明了。結(jié)核分枝桿菌免疫逃避機(jī)制與結(jié)核病發(fā)生，發(fā)展密切相關(guān)，因此了解宿主在抗結(jié)核免疫過程中的作用以及深入探討其與結(jié)核分枝桿菌免疫逃逸有關(guān)的殺傷機(jī)制，將有助于結(jié)核病的預(yù)防及治療。

[1] Russell DG, Vanderven BC, Glennie S, et al. The macrophage marches on its phagosome: dynamic assays of phagosome function[J]. Nat Rev Immunol, 2009, 9(8): 594-600.

[2] Nath L, Kumar D, Varshney A，et al. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation[J].PNAS，2012，10：168-176.

[3] Deretic V, Delgado M, Vergne I, et al. Autophagy in immunity against mycobacterium tuberculosis: a model system to dissect immunological roles of autophagy[J]. Curr Top Microbiol Immunol, 2009, 335: 169-188.

[4] Kumar D, Nath L, Kamal MA, et al. Genome-wide analysis of the host intracellular network that regulates survival ofMycobacteriumtuberculosis[J]. Cell, 2010, 140(5): 731-743.

[5] Geluk A, van Meijgaarden KE, Joosten SA, et al. Innovative strategies to identifyM.tuberculosisantigens and epitopes using genome-wide analyses[J]. Front Immunol, 2014, 5: 256.

[6] Ehrt S, Schnappinger D. Mycobacterial survival strategies in the phagosome: defence against host stresses[J]. Cellular Microbiol, 2009, 11(8): 1170-1178.

[7] Wang FY,Zhang L.Progress in the mechanism ofMycobacteriumtuberculosisevasion from the immune killing[J].Chin J Zoonoses,2015,31(6):579-582.DOI:10.3969/cjz.j.issn.1002-2694.2015.06.018

王飛雨, 章樂.結(jié)核分枝桿菌逃逸免疫殺傷機(jī)制的研究進(jìn)展[J]. 中國(guó)人獸共患病學(xué)報(bào)，2015，31(6)：579-582.

[8] Li W, Xie J. Role of mycobacteria effectors in phagosome maturation blockage and new drug targets discovery[J]. J Cell Biochem, 2011, 112(10): 2688-2693.

[9] Ni Cheallaigh C, Keane J, Lavelle EC, et al. Autophagy in the immune response to tuberculosis: clinical perspectives[J]. Clin Exp Immunol, 2011, 164(3): 291-300.

[10] Sullivan JT, Young EF, McCann JR, et al. TheMycobacteriumtuberculosisSecA2system subverts phagosome maturation to promote growth in macrophages[J]. Infect Immun, 2012, 80(3): 996-1006.

[11] Wong D, Bach H, Sun J, et al.Mycobacteriumtuberculosisprotein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification[J]. Proc Natl Acad Sci USA, 2011, 108(48): 19371-19376.

[12] Gutierrez MC. NF-kappa B activation controls phagolysosome fusion-mediated killing of mycobacteria by macrophages[J]. Immunology, 2008, 181: 2651-2663.

[13] Pires D, Marques J, Pombo JP, et al. Role of cathepsins inMycobacteriumtuberculosissurvival in human macrophages[J]. Sci Rep, 2016, 6: 32247.

[14] Tinaztepe E, Wei JR, Raynowska J, et al. Role of metal-dependent regulation of ESX-3 secretion in intracellular survival ofMycobacteriumtuberculosis[J]. Infect Immun, 2016, 84(8): 2255-2263.

[15] Saikolappan S, Das K, Sasindran SJ, et al. OsmC proteins ofMycobacteriumtuberculosisandMycobacteriumsmegmatisprotect against organic hydroperoxide stress[J]. Tuberculosis (Edinb), 2011, 91(Suppl 1): S119-127.

[16] Flynn JL, Chan J. Immune evasion byMycobacteriumtuberculosis: living with the enemy[J]. Curr Opin Immunol, 2003, 15(4): 450-455.

[17] Shin DM, Jeon BY, Lee HM, et al.Mycobacteriumtuberculosiseis regulates autophagy, inflammation, and cell death through redox-dependent signaling[J]. PLoS Pathog, 2010, 6(12): e1001230.

[18] Ganguly N, Giang PH, Gupta C, et al.Mycobacteriumtuberculosissecretory proteins CFP-10, ESAT-6 and the CFP10:ESAT6 complex inhibit lipopolysaccharide-induced NF-κB transactivation by downregulation of reactive oxidative species (ROS) production[J]. Immunol Cell Biol, 2007, 86(1): 98-106.[19] Voskuil MI, Bartek IL, Visconti K, et al. The response ofMycobacteriumtuberculosisto reactive oxygen and nitrogen species[J]. Front Microbiol, 2011, 2: 105.

[20] Poonam Rath CH, Wang T, Wang TZ, et al. Genetic regulation of vesiculogenesis and immunomodulation inMycobacteriumtuberculosis[J]. Natl Acad Sci, 2013, 110(79): E4790-E4797.

[21] Behar SM, Martin CJ, Booty MG, et al. Apoptosis is an innate defense function of macrophages againstMycobacteriumtuberculosis[J]. Mucosal Immunol, 2011, 4(3): 279-287.

[22] Gan H, Lee J, Ren F, et al.Mycobacteriumtuberculosisblocks crosslinking of annexin-1 and apoptotic envelope formation on infected macrophages to maintain virulence[J]. Nat Immunol, 2008, 9(10): 1189-1197.

[23] Derrick SC, Morris SL. The ESAT6 protein ofMycobacteriumtuberculosisinduces apoptosis of macrophages by activating caspase expression[J]. Cellular Microbiol, 2007, 9(6): 1547-1555.

[24] Rojas M, Olivier M, Garcia LF. Activation of JAK2/STAT1-α-dependent signaling events duringMycobacteriumtuberculosis-induced macrophage apoptosis[J]. Cellular Immunol, 2002, 217(1-2): 58-66.

[25] Clay H, Volkman HE, Ramakrishnan L. Tumor necrosis factor signaling mediates resistance toMycobacteriabyinhibitingbacterial growth and macrophage death[J]. Immunity, 2008, 29(2): 283-294.

[26] Mogga SJ，Mustafa T,Sviland L,et al. Increased Bcl-2 and reduced Bax expression in infected macrophages in slowly progressive primary murineMycobacteriumtuberculosisinfection[J].Scandinavian J Immunology,2002, 56: 383-391.

[27] Goletti D, Danelishvili L, Yamazaki Y, et al. SecretedMycobacteriumtuberculosisRv3654c and Rv3655c proteins participate in the suppression of macrophage apoptosis[J]. PLoS One, 2010, 5(5): e10474.

[28] Kumar D, Narayanan S. PknE, a serine/threonine kinase ofMycobacteriumtuberculosismodulates multiple apoptotic paradigms[J]. Infect Genet Evol, 2012, 12(4): 737-747.

[29] Miller JL, Velmurugan K, Cowan MJ, et al. The type I NADH dehydrogenase ofMycobacteriumtuberculosiscounters phagosomal NOX2 activity to inhibit TNF-alpha-mediated host cell apoptosis[J]. PLoS Pathog, 2010, 6(4): e1000864.

[30] Tuo QZ,Dong JT,Tian XZ,et al.Relation between expression ofMycobacteriumtuberculosisHsp16.3 and apoptosis of infected mouse alveolar macrophages[J].2014,35(3):300-35.

庹清章,董江濤, 田璽擇. 結(jié)核分枝桿菌Hsp16.3表達(dá)與感染小鼠肺泡巨噬細(xì)胞凋亡的關(guān)系[J]. 西安交通大學(xué)學(xué)報(bào)，2014,35(3)：300-305.

[31] Saini NK, Sinha R, Singh P, et al. Mce4A protein ofMycobacteriumtuberculosisinduces pro inflammatory cytokine response leading to macrophage apoptosis in a TNF-α dependent manner[J]. Microbial Pathogenesis, 2016, 100: 43-50.

[32] Deretic V. Autophagy in immunity and cell-autonomous defense against intracellular microbes[J]. Immunological Rev, 2011, 240(1): 92-104.

[33] Deretic V. Multiple regulatory and effector roles of autophagy in immunity[J]. Curr Opin Immunol, 2009, 21(1): 53-62.

[34] Jamwal SV, Mehrotra P, Singh A, et al. Mycobacterial escape from macrophage phagosomes to the cytoplasm represents an alternate adaptation mechanism[J]. Sci Rep, 2016, 6: 23089.

[35] Duan L, Yi M, Chen J, et al.MycobacteriumtuberculosisEIS gene inhibits macrophage autophagy through up-regulation of IL-10 by increasing the acetylation of histone H3[J]. Biochem Biophys Res Commun, 2016, 473(4): 1229-1234.

[36] Dong H, Jing W, Runpeng Z, et al. ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR[J]. Biochem Biophys Res Commun, 2016, 477(2): 195-201.

[37] Hu D, Wu J, Wang W, et al. Autophagy regulation revealed by SapM-induced block of autophagosome-lysosome fusion via binding RAB7[J]. Biochem Biophys Res Commun, 2015, 461(2): 401-407.

[38] Chen Z, Wang T, Liu Z, et al. Inhibition of autophagy by MiR-30A induced byMycobacteriatuberculosisas a possible mechanism of immune escape in human macrophages[J]. Jpn J Infect Dis, 2015, 68(5): 420-424.

Chen Jin, Email: chenjindor@126.com

ProgressinimmuneescapemechanismsofMycobacteriumtuberculosis

CHEN Wei-wei, ZHANG Ran-ran, CAO Wen, CHEN Jin

(DepartmentofClinicalLaboratory,ShanghaiPulmonaryHospital,SchoolofMedicine,TongjiUniversity,Shanghai200433,China)

Tuberculosis(TB) is mainly caused byMycobacteriumtuberculosis (Mtb), which in the body long-term existence is closely related to the immune escape mechanism. Mtb’s immune escape mechanisms have been found to include prevention of phagosomal maturation and acidification of lysosomes, suppression of oxidative stress, inhibition of apoptosis and autophagy. Mtb immune escape mechanism to avoid the host is complex, not yet fully understood. This article focuses on Mtb immune escape mechanism as a review, is an in-depth study to provide a reference.

Mycobacteriumtuberculosis; escape mechanism; immune killing

10.3969/j.issn.1002-2694.2017.08.013

國(guó)家自然科學(xué)基金(No.81371775)

陳 晉，Email：chenjindor@126.com

同濟(jì)大學(xué)附屬上海市肺科醫(yī)院檢驗(yàn)科，上海 200433

Funded by the National Natural Science Foundation of China (No. 81371775)

R378.91

：A

：1002-2694(2017)08-0730-04

2017-02-08編輯：張智芳