Journal of Bacteriology and Virology 2016. Vol. 46, No. 4 p.312 318 http://dx.doi.org/10.4167/jbv.2016.46.4.312 Research Update (Minireview) Apoptotic Effect of Macrophages against Mycobacterium tuberculosis Lee-Han Kim and Sung Jae Shin * Department of Microbiology, Institute of Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea Mycobacterium tuberculosis (Mtb) causing tuberculosis as an intracellular pathogen initially infects alveolar macrophages following aerosol inhalation. Thus, macrophages play a critical role in the establishment of Mtb infection and macrophage cell death, a common outcome during Mtb infection, may initiate host- or pathogen-favored immune responses, resulting in facilitating protection or pathogenesis, respectively. In addition, virulent Mtb strains are known to inhibit apoptosis and consequently down-regulates immune response using a variety of strategies. In many recent studies have shown that virulent Mtb can either augment or reduce apoptosis by regulating expression of pro-apoptotic and anti-apoptotic proteins belonging to Bcl-2 family proteins. In this review, we will discuss and dissect the apoptotic pathways of Bcl-2 family proteins in Mtb-infected macrophages. Key Words: Mycobacterium tuberculosis, Apoptosis, Bcl-2 family proteins, Anti-apoptotic proteins, Pro-apoptotic proteins INTRODUCTION 결핵 (Tuberculosis) 은주된원인으로결핵균 (Mycobacterium tuberculosis) 에의해전염되는감염성질환이다. 세계인구의 1/3이결핵균에감염된상태로추정되고, 대부분결핵균에감염된자들은약 90% 가활동성결핵이나타나기전까지증상이없는잠복감염상태를보이며, 이중 10% 만이평생동안결핵으로진행될가능성이있다 (1). 세계보건기구 (World Health Organization; WHO) 의 2013년기준, 매년 900만건의신규환자가발생하였고, 약 150 만명이결핵으로인하여사망한다고보고되었으며, 최근 2015년보고된바에의하면 1,004만건의환자가발생하고 180만 ( 후천적면역결핍바이러스 (Human Immunodefi- ciency Virus; HIV) 감염환자중에서 40만명포함 ) 명이결핵으로사망한다고보고되었다 (WHO Report, 2014, 2016). 이처럼결핵및후천성면역결핍과결핵동시감염으로인한환자발생과사망률이매년증가하고있다. 기존에예방과치료방법으로 Bacille Calmette-Guein (BCG) 백신외에여러가지화학적치료제가사용되고있지만, 최근에약제내성 (drug resistance) 을갖는결핵균에의해감염되는환자들이발생됨에따라서결핵퇴치를위한새로운백신및치료제개발을위해서숙주면역반응과의상호작용및다양한병인기전 (pathogenesis) 연구가진행되고있다. 결핵균은호흡을통해서폐에전파되며폐포 (alveolar) 의큰포식세포 (macrophage) 에식세포작용 (phagocytosis) 을통해내부로이입되어, 면역체계 (immune System) 인세포사멸 Received: December 9, 2016/ Revised: December 9, 2016/ Accepted: December 9, 2016 * Corresponding author: Sung Jae Shin. Department of Microbiology and Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Phone: +82-2-2228-1813, Fax: +82-2-392-9310, e-mail: sjshin@yuhs.ac ** This study was supported by the Basic Science Research Program and the International Research & Development Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning of Korea (NRF-2016R1A2A1A05005263 and NRF- 2014K1A3A7A03075054). CC This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/license/by-nc/3.0/). 312
Apoptosis in Macrophages 313 (apoptosis) 를회피하고식포 리소좀 (phagosome-lysosome) 결합을억제시켜서산성화 (acidification) 를막고, 큰포식세포내부환경에서적응하며자신을보호하기위한장소 (niche) 를형성한다 (2). 큰포식세포의내부환경에형성된장소 (niche) 는결핵균의항원들을숙주의주요면역세포와주조직적합성복합체 2형항원제시세포 (MHC class II antigen-processing pathway) 의면역체계로부터보호되고증식 (replication) 또는잠복 (latency) 한다고알려져있다 (2, 3). 결핵균에감염된큰포식세포는결핵균을제어하기위한필수적인 tumor necrosis factor-α (TNF-α) 와 interferon-γ (IFN-γ) 사이토카인을증가시켜염증성면역반응 (inflammatory immune response) 이활성화시키지만, 결핵균은이와같은염증성면역반응을억제하여생존할수있고, 오히려숙주의염증반응을유도하여발생되는조직손상을통하여전파 (dissemination) 된다고보고되었다 (4). 기존보고에의하면, 결핵균의표준균주인, 병원성결핵균 (H37Rv) 과약독화된결핵균 (H37Ra) 을각각감염시킨큰포식세포에서병원성균주에의해세포사멸 (apoptosis) 은억제되고, 세포용해 (cytolysis) 의특징을갖는세포괴사 (cell necrosis) 를유도시켜, 감염을증가시킨다고밝혀졌다 (2, 5). 결핵균은여러가지의표면항원 (surface antigen) 을발현시켜숙주의 pathogen-associated molecular pattern (PAMP) 수용체중에서 Toll-like receptor 2 (TLR2) 에결합하여신호전달되면큰포식세포의 MHC class II의항원제시를억제하고 IFN-γ의반응을억제하는것으로확인되었다 (6, 7). 이는, 결핵균의세포벽 (cell wall) 에존재하는 LprG (Rv1411c) 등의지질단백질 (lipoprotein) 의노출지속시간을조절하면서 TLR2의신호전달 (signaling pathway) 을강제로조절함으로써 CD4+ T cell 인식을회피하기위해서큰포식세포의항원제시기능과염증반응그리고세포사멸을억제시켜숙주의선천면역반응 (innate immune response) 을저해시킨다고보고되었다 (7). 이처럼, 결핵균은숙주와상호작용하여다양한면역반응기작을조절함으로써큰포식세포내부환경에서증식과생존하기위해서진화해왔다. 또한, 결핵균은다양한기전 (mechanism) 을통해세포사멸을억제하고숙주면역세포의면역체계를조절하며숙주의항결핵면역반응을회피한다고알려졌다 (8). 결핵균감염으로인한숙주의방어기전으로선천면역과적응면역반응이필수적이며, 큰포식세포는체내에침입한병원균에대해가장먼저면역반응을유발하는면역세포로서선천면역을담당하고, 활성화된큰포식세포는다양 한세포독성단백질을분비하여세포내에감염된병원균을제거하며, MHC class II 분자를다량발현하여효과적인항원전달세포역할을하고적응면역반응을유도하여병원균에대처한다 (9). 숙주의선천적면역반응으로세포사멸과정이결핵균을제어하는데필수적인기전이라는연구가보고되고있으며 (10), 이와반대로, 숙주큰포식세포의세포사멸기전에필요한분자 (molecule) 들을억제시키고세포괴사기전을유도하기위한분자를증가시켜세포용해를통해서큰포식세포로부터방출되어감염되지않는큰포식세포를감염시키는병인기전이보고되었다 (11). 따라서, 본종설에서는결핵균을제어하기위한큰포식세포의선천면역방어기작으로써필수적인세포사멸에관련된숙주면역세포의유전자또는분자 (molecule) 들의역할과기전에대한연구동향을파악하고, 그중요성을서술하고자한다. 향후, 결핵균을제어하는큰포식세포의세포사멸조절하는유전자및단백질들에대한기능을이해함으로써, 이분자들에대한표적치료를통하여새로운항결핵제의개발에대한연구방향을제시하고자한다. 1. 세포사멸 (apoptosis) 세포사멸은 1997년 Kerr과 Wyllie, 그리고 Currie에의해서처음으로기술되었다 (12). 세포사멸은에너지의존적조절과정으로세포질내부의물질들이자멸소체 (apoptotic body) 라고불리는포낭 (vesicle) 에둘러싸이면서죽어가는세포 (dying cell) 를분해시키며, 이러한자멸소체는포식세포 (phagocytic cell) 에의해서염증반응없이제거된다 (8). 이와같이, 세포사멸은인접하고있는조직에피해를주지않고빠르게세포를죽인다고알려져있다. 세포사멸은세포의생리적인조건과병리학적조건에의해서대표적인두가지외인성경로 (extrinsic-mediated pathway) 와내인성경로 (intrinsic-mediated pathway) 를활성화시켜조절한다 (12). 이러한세포사멸을조절하는대표적인단백질로는 caspases, adaptor proteins, tumor necrosis factor (TNF), tumor necrosis factor receptor (TNF-R) super family, 그리고 Bcl-2 (B-cell lymphoma 2) family 단백질이존재한다 (13). Caspases는세가지로분류되는데, 세포사멸개시자 (initiator) 로 caspase-2, -8, -9, -10과작동자 (effector) 또는집행자 (executioner) 라고불리는 caspase-3, -6, -7, 그리고염증반응에관여하는 caspase-1, -4, -5로분류되어있다 (12). 세포사멸은 caspase라고알려진일련의단백질을분해하는효소에의해수행된다. 세포의정상적인상태에서는 caspase는
314 L-H Kim and SJ Shin pro-caspase라는불활성전구효소형태로존재하지만, 세포사멸신호를받으면 pro-caspase 부류의개시자 (pro-caspase- 2, -8, -9, -10) 그룹이활성화상태인 caspase로전환되고, 이는다른부류의 pro-caspase들을활성화상태인 caspase 로전환하는데촉매역할을하고, caspase에의해활성화된 DNA 가수분해효소 (DNase) 는뉴클레오솜 (nucleosome) 을절단 (cleavage) 하여세포사멸을유도한다 (13). Adaptor protein들은수용체와상호작용하여세포막의특정부분에집합시키는기능을갖는단백질로서 caspase와 tumor necrosis factor (TNF) 수용체를연결시키는기능을가지며, 세포사멸과정동안중요한역할을한다고알려져있다 (11). 또한, Bcl-2 family 단백질들도세포사멸에서다양한역할을수행하는것으로알려져있고, 이 Bcl-2 family 단백질들은크게두가지의항세포사멸단백질 (anti-popototic protein) 들과전세포사멸단백질 (pro-apoptotic protein) 들로분류되며, 아미노산 (amino acid) 구조에존재하는 BH1- BH4 domain 에따라서더욱더분리될수있다. 항세포사멸에관련된단백질은 Bcl-xL, Bcl-2, BFL-1/A1, Mcl-1 등이있으며, 전세포사멸단백질로는 Bax, Bak 등, 그리고 BH3 domain만존재하는 Bid, Bim, Bad, NOXA, PUMA 등이알려져있으며, 이 Bcl-2 family 단백질들이미토콘드리아세포사멸과정 (mitochondria cell death) 을조절한다고밝혀져있다 (14). 1) 외인성경로 (extrinsic-mediated pathway) 외인성세포사멸경로는 TNF-α와 Fas ligand (FasL) 가 TNFR1 (tumor necrosis factor receptor 1) 과 Fas를포함한 TNFR family 단백질수용체에결합하여유도되고, 이로인해 DISC (death-inducing signal complex) 는 Fas-associated death domain과 procaspse-8 또는 procaspase-10과결합함으로써형성된다. 개시자 caspase (caspase-8 또는 caspase-10) 는작동자 caspase-3, -6, 그리고, -7를단백질가수분해과정 (proteolytic processing) 에의해서활성화되고이로인해핵응축 (condensation) 과 DNA 절단 (cleavage), 그리고사멸체 (apoptotic vesicle) 형성을촉진시킨다 (15) (Fig. 1). 2) 내인성경로 (intrinsic-mediated pathway) DNA 손상과영양분고갈과그리고산화적스트레스등과같은내인성스트레스에의해유도되며, 이는미토콘드리아외막투과성 (mitochondrial outer membrane permeability; MOMP) 를증가시켜 cytochrome c가세포질로방출되며, 방출된 cytochrome c는 caspase-9과 Apaf-1과결합하여 apoptosome 을형성하며 (16), 활성화된 caspase-9는하 위 caspase cascade를활성화시킴으로써세포사멸을유도한다. 미토콘드리아투과성은전세포사멸또는항세포사멸 Bcl-2 famlily 단백질에의해조절되며 (17), 전세포사멸단백질인 Bax와 Bak은미토콘드리아외막에구멍 (pore) 을형성하여 cytochrome c를세포질로방출시킨다. 이러한현상은항세포사멸단백질인 Bcl-2와 Bcl-xL, 그리고 Mcl-1 에의해서정반대로작용하여세포사멸을억제한다. Bid는 truncated form (tbid) 으로절단됨으로써활성화되는데, 이것은 Bax와 Bak을활성화시키고 cytochrome c가세포질로방출되게유도한다. Caspase-8이 Bid를절단해서활성화시키며, 이현상을통해외인성과내인성세포사멸경로가 cross-talk 될수있다 (18) (Fig. 1). 2. 결핵균에대응하는큰포식세포의세포사멸세포사멸은숙주의방어기전으로병원균에대응하고선천면역과적응면역을개시하고침입자로부터보호한다고알려져있다 (19). 그러나, 병원균으로알려진 Shigella와 Yersinia, 그리고, Legionella는숙주큰포식세포내에서증식하고전파하기위해서세포사멸을야기시킨다고보고되었다 (20). 몇몇의병원균은 pore 형성독소와단백질합성억제제 (protein synthesis inhibitor) 들을분비하여숙주의세포사멸을유도한다고보고되었으며, 또한바이러스는다양한단백질을숙주에서발현시켜세포사멸을야기시켜증식한다고알려져있다 (21). 다양한병원균들은숙주의큰포식세포의세포사멸기전에필요한구성요소 (component) 들을활성화시킴으로써세포사멸을유도한다고밝혀졌다 (22). 이와같이, 다양한병원균들은숙주의세포사멸을유도하여감염을더욱더진행시킨다고알려져있지만, 결핵균감염에서보고된바에의하면, 숙주세포내의자원 (resources) 들을이용하여생존하고증식하는결핵균에맞서기위한한가지전략으로숙주는세포사멸을활성화시킨다고보고되어있다 (18). 또한, 숙주의큰포식세포에서세포사멸을통해세포내의결핵균성장 (growth) 을억제시키는것으로밝혀졌고 (23), Keane 등의연구에의하면약독화된결핵균또는관련항산균종 (attenuated Mtb strain; Mtb HR7Ra, M. bovis bacillus Callmette-Guerin, and M. kansasii) 은병원성이높은결핵균종 (Mtb H37Rv, Mtb Erdman, Mtb clinical isolate BMC 96.1, and M. bovis wild type) 보다세포사멸이더욱효과적으로일어나고, 결핵균의성장과증식을억제시키고, 이와반대로 virulent Mtb에의해감염된큰포식세포는선천면역인세포사멸이억제되기때
Apoptosis in Macrophages 315 Figure 1. Regulation of apoptosis signaling pathway by Bcl-2 family proteins. The mitochondrial outer membrane permeabilization (MOMP) can be regulated by either extrinsic (death receptor-mediated) and intrinsic (mitochondria-mediated) pathways. MOMP triggers the release of apoptogenic factor such as cytochrome c into cytosol to facilitate activation of caspase 3, resulting in induction of apoptosis. Virulent Mtb promotes the induction and production of Bcl-2 family proteins (①) and eventually inhibits apoptosis pathways (②) to multiplicate inside macrophages. FADD; Fas-associated death domain, Bax; Bcl-2-associated X protein, Bak; Bcl-2-antagonist killer, (t)bid; (truncated) Bax-like BH3 protein, DISC; Death inducing signaling complex, Apaf1; Apoptotic protease activating factor 1, Mtb; Mycobacterium tuberculosis 문이라고 보고하였다 (24). 또한, virulent Mtb는 큰포식세포 근 보고에 따르면 virulent Mtb에 감염된 큰포식세포 또는 에 감염을 일으키고 세포사멸을 억제함으로써 세포 내에 배아 섬유아 세포(embryonic fibroblast)는 세포사멸 유도로 서 증식하고, 세포괴사(necrotic death)를 유도하여 감염을 인한 결핵균 증식과 전파의 원인이 된다고 보고되었다 유발한다고 보고되었다 (25). 여러 문헌에서, Mtb에 감염된 (14, 29). 이는 결핵균에 의해 큰포식세포의 세포사멸이 조 큰포식세포의 세포사멸 조절은 virulent Mtb와 인과관계가 절됨에 따라 발현되는 유전자의 본래의 기능뿐만 아니라 있는 것으로 확인되었다. 예를 들어, virulent Mtb는 숙주의 또 다른 역할을 수행하여, 다른 신호전달 경로에 영향을 큰포식세포의 세포사멸을 억제하고 생존하며, attenuated 줄 수 있기 때문이라고 예상된다. Mtb에 감염된 큰포식세포는 세포사멸을 유도하여 감염을 억제시키는 것으로 확인되었다 (26~28). 이와 반대로, 최
316 L-H Kim and SJ Shin 1) 항세포사멸 Bcl-2 family 단백질에의해조절되는큰포식세포의세포사멸 Bcl-2 family 단백질들은세포사멸에중요한인자 (factor) 로서여러가지의세포와조직의세포사멸과생존 (survival) 을조절하는데중요한역할을한다. Bcl-2 family 단백질에속하는 Myeloid cell leukemia-1 (Mcl-1) 의과발현은다양한세포들에서세포사멸을억제한다고알려져있고 (30), 이전연구에서보고된바에의하면, H37Rv에감염된 THP-1 cells (human monocytic cell derived from an acute monocytic leukemia patient) 에서 Mcl-1의발현이증가됨으로써세포사멸이억제되어결핵균이증식되기때문에, Mcl-1을억제시켜감염된숙주큰포식세포의세포사멸을유도시킴으로써결핵을치료할수있는새로운대안을제시하였다 (10). 암세포사멸연구에서 Mcl-1의 mrna를표적 (target) 하는 small hairpin RNA (shrna) 를이용하여 Mcl-1의발현을감소시킴으로써세포사멸을유도하여다양한암종 (carcinomas) 을치료하는데효과적일것이라고보고되어있다 (31). 최근, 결핵세포사멸연구에서 H37Rv 균주에감염된큰포식세포에서 Mcl-1의발현이증가되어세포사멸이억제되고결핵균이증식하고감염을더욱유발시킨다고보고되었고, Mcl-1 을표적하는 shrna를이용하여 Mcl-1 발현을감소시킴으로써 Bcl-2 발현또한감소되고전세포사멸 (pro-apoptotic protein) 단백질로알려져있는 Bax가증가되어, 감염된큰포식세포의세포사멸이유도되어결핵균증식을억제시킬수있다고밝혀졌다 (32). 이전에, H37Rv 에감염된큰포식세포에서결핵균이증식될수록 Bcl-2의발현이증가되고 Bax의발현이감소됨으로써세포사멸이억제된다고보고되었다 (33). 이밖에도몇몇문헌에서도결핵균에감염된큰포식세포에서 Bfl-1, Bcl-xL 그리고 Mcl-1의발현이증가되고 Bax가감소됨으로인해세포사멸이억제되어결핵균의생존과증식이야기된다고보고되었다 (34, 35). 큰포식세포는선천면역방어로세포사멸을통해결핵균을제어할수있지만, virulent 결핵균에의해 Bcl-2 family 단백질에속하는항세포사멸관련단백질들을조절하여세포사멸로부터회피하여증식하고감염을유발시키는것으로사료된다. 정상의세포내에는전세포사멸단백질과항세포사멸단백질들이항상성 (homeostasis) 을조절하여균형을이루지만, 병원체감염으로인해서두세포사멸에관련된단백질들의균형 (balance) 이깨지면서감염에노출되어질병을야기시킨다. 2) 전세포사멸 Bcl-2 family 단백질에의해조절되는큰포식세포의세포사멸 Bcl-2 family 단백질에속하는전세포사멸단백질들은다양한세포들에서세포사멸을유도한다고알려져있다. Forkhead box O3 (FOXO3) 는세포주기조절 (cell cycle progression), 선천면역반응 (innate immune response), 산화적스트레스에내성 (resistance to oxidative stress), 그리고세포사멸 (apoptosis) 을조절하는전사인자 (transcription factor) 로서전세포사멸에관련된 NOXA와 PUMA 전사를조절하여세포사멸을유도한다 (36). BCG (M. bovis bacillus Callmette- Guerin) 균주에감염된큰포식세포에서 FOXO3가증가되어하위유전자인 PUMA와 NOXA의전사를조절하여, 두유전자를상향조절시킴으로써세포사멸을유도한다고밝혀졌으며, 이는큰포식세포내에서 BCG에유도된세포사멸로인해다양한결핵균의항원이 T 세포 (T cell) 에제시됨으로써적응면역을유도할수있고이로인해기존의백신효능 (efficacy) 을개선시키기위해서중요한표적분자로서이용될수있을것이라고보고되었다 (36). 최근에 virulent Mtb (clinical isolate MT103) 와 MtbVAC (live M. tuberculosis attenuated vaccine) 에각각감염된배아섬유아세포 (embryonic fibroblast) 와큰포식세포에서 virulent Mtb 에의해서만전세포사멸단백질인 Bim의발현이증가되어세포사멸이유도되고결핵균의증식및감염이증가되었고, 더욱이 Bim의 mrna를표적하는 sirna에의해 Bim 의발현이감소되고세포사멸이억제됨에따라서, virulent Mtb의증식과독성을촉진하는원인으로숙주의 Bim이중요하게작용할수도있다고보고되었다 (14). 이는앞서서술한세포사멸의기능과정반대의기능이기에논쟁의여지가있을수있지만, 전세포사멸에관여하는 Bim의역할에관한연구내용이현저히부족하여정확한기능에대해서는논하기어려울것이다. 앞으로결핵균과숙주의큰포식세포간의세포사멸에대한연구가진행되어 Bim의역할에대해서더욱밝혀질것이라고사료된다. CONCLUSION 결핵균의감염에대응하기위해숙주큰포식세포는선천면역반응으로큰포식세포의세포사멸이필수적이다. 그러나, 세포사멸관련된보고들에의하면 virulent Mtb는큰포식세포의세포사멸관련분자들을조절하여, 세포사멸을유도또는억제시킴으로써생존및증식하는것으로
Apoptosis in Macrophages 317 알려졌다. 이와같이, 결핵균은숙주세포의다양한면역반응에서생존하고증식하기위하여오랜시간동안진화를해왔다. 최근결핵제어의문제점은 BCG 백신이듣지않는면역학적내성결핵균과기존약제에내성을보이는약제내성결핵균에의한감염이해마다증가하고있어서, 기존 BCG 백신을대체할수새로운백신이나화학치료제등개발이절실하다. 결핵을제어하기위해많은치료후보물질과백신등이개발되고있으나, 기존 BCG 백신을대체할만큼의효과가없고새로운항생제개발은매우더딘실정이다. 따라서, 결핵에대한이해와숙주의면역반응에대한많은지식을습득함으로써향후, 결핵을제어하기위한새로운전략적연구가필요하다. 결핵의초기감염에대응하여면역반응을시작하는큰포식세포의세포사멸에관련된유전자들의조절과기전을이해함으로써이를바탕으로큰포식세포의세포사멸을통한결핵을제어할수있는신개념의치료제를개발하거나또는결핵에의해조절되는분자를표적치료할수있는약물이나그리고 DNA 백신으로인한, 기능상실유전자의단백질복원 (restoration) 을통하여효과가높은치료제개발이이루어질수있다. 현재종양분야에서세포사멸을유도하는약물이나종양에서특이적으로과발현되는단백질의억제제를사용하여치료제로사용되거나새로운치료제가개발되고있다. 이와같이종양분야에서사용되고있는세포사멸관련단백질억제제들을결핵을제어하는데치료제로서의가능성이있는지검증할필요성이있다고사료된다. 또한, 세포사멸을유도또는억제하는기작및조절유전자에대해서많은지식을얻는다면, 기존의백신을향상시키거나새로운백신및치료제개발을연구하는데중요한밑바탕이될것이다. REFERENCES 1) Wipperman MF, Sampson NS, Thomas ST. Pathogen roid rage: cholesterol utilization by Mycobacterium tuberculosis. Crit Rev Biochem Mol Biol 2014;49:269-93. 2) Chen M, Divangahi M, Gan H, Shin DS, Hong S, Lee DM, et al. Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death. J Exp Med 2008;205:2791-801. 3) Behar SM, Martin CJ, Booty MG, Nishimura T, Zhao X, Gan HX, et al. Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis. Mucosal Immunol 2011;4:279-87. 4) Abebe M, Kim L, Rook G, Aseffa A, Wassie L, Zewdie M, et al. Modulation of cell death by M. tuberculosis as a strategy for pathogen survival. Clin Dev Immunol 2011; 2011:678570. 5) Chen M, Gan H, Remold HG. A mechanism of virulence: virulent Mycobacterium tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis. J Immunol 2006;176:3707-16. 6) Fortune SM, Solache A, Jaeger A, Hill PJ, Belisle JT, Bloom BR, et al. Mycobacterium tuberculosis inhibits macrophage responses to IFN-gamma through myeloid differentiation factor 88-dependent and -independent mechanisms. J Immunol 2004;172:6272-80. 7) Gehring AJ, Dobos KM, Belisle JT, Harding CV, Boom WH. Mycobacterium tuberculosis LprG (Rv1411c): a novel TLR-2 ligand that inhibits human macrophage class II MHC antigen processing. J Immunol 2004;173:2660-8. 8) Parandhaman DK, Narayanan S. Cell death paradigms in the pathogenesis of Mycobacterium tuberculosis infection. Front Cell Infect Microbiol 2014;4:31. 9) Fenton MJ, Vermeulen MW. Immunopathology of tuberculosis: roles of macrophages and monocytes. Infect Immun 1996;64:683-90. 10) Sly LM, Hingley-Wilson SM, Reiner NE, McMaster WR. Survival of Mycobacterium tuberculosis in host macrophages involves resistance to apoptosis dependent upon induction of antiapoptotic Bcl-2 family member Mcl-1. J Immunol 2003;170:430-7. 11) Pedruzzi G, Das PN, Rao KV, Chatterjee S. Understanding PGE2, LXA4 and LTB4 balance during Mycobacterium tuberculosis infection through mathematical model. J Theor Biol 2016;389:159-70. 12) Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007;35:495-516. 13) Strasser A, O'Connor L, Dixit VM. Apoptosis signaling. Annu Rev Biochem 2000;69:217-45. 14) Aguiló N, Uranga S, Marinova D, Martin C, Pardo J. Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis. Cell Death Dis 2014;5:e1343. 15) Creagh EM, Conroy H, Martin SJ. Caspase-activation pathways in apoptosis and immunity. Immunol Rev 2003;193: 10-21.
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