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Postprimary Tuberculosis and Macrophage Necrosis: Is There a Big ConNECtion?

Postprimary Tuberculosis and Macrophage Necrosis: Is There a Big ConNECtion? PERSPECTIVE crossmark Postprimary Tuberculosis and Macrophage Necrosis: Is There a Big ConNECtion? a b Ka-Wing Wong, William R. Jacobs, Jr. Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China ; Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA ABSTRACT Adult or postprimary tuberculosis (TB) accounts for most TB cases. Its hallmark is pulmonary cavitation, which occurs as a result of necrosis in the lung in individuals with tuberculous pneumonia. Postprimary TB has previously been known to be associated with vascular thrombosis and delayed-type hypersensitivity, but their roles in pulmonary cavitation are unclear. A necrosis-associated extracellular cluster (NEC) refers to a cluster of drug-tolerant Mycobacterium tuberculosis attached to lysed host materials and is proposed to contribute to granulomatous TB. Here we suggest that NECs, perhaps due to big size, produce a distinct host response leading to postprimary TB. We propose that vascular thrombosis and pneumonia arise from NEC and that these processes are promoted by inflammatory cytokines produced from cell-mediated delayed-type hypersensitiv- ity, such as interleukin-17 and gamma interferon, eventually triggering necrosis in the lung and causing cavitation. According to this view, targeting NEC represents a necessary strategy to control adult TB. uberculosis (TB) is one of the most successful pathogens in Hunter et al. (3, 9) and others (10, 11) suggested that vascular humans. The causative agent of TB, Mycobacterium tuberculo- thrombosis and delayed-type hypersensitivity (DTH) are associ- sis, has coexisted with humans since the earliest history of human- ated with tuberculous pneumonia in postprimary TB. Vascular kind (1). It continues to cause appalling morbidity and mortality thrombosis occurs when blood clots due to blood vessel injury. rates (2). Most pulmonary TB cases and almost all transmission of DTH is a T cell-mediated inflammatory response. Lando and Edg- the disease are due to postprimary TB, which is also known as ington identified DTH correlates with induction of macrophage adult or secondary TB (3). Postprimary TB is characterized by procoagulant activity by activated T cells (12). Recent progress on pulmonary cavitation in the upper lobes of lungs. Individuals can understanding the mechanism of thrombosis may shed light on die from an acute pulmonary cavitation, which presents with pro- the underlying mechanism of procoagulant activity induction by found coagulopathy and coughing up large necrotizing pneu- DTH. Here we apply this knowledge to understand how vascular monic materials, or they die from fibrocaseous TB, which is the thrombosis is formed and the role of DTH in the context of most common form of TB and has much less coagulopathy (R. postprimary TB. Our goal is to understand how M. tuberculosis Hunter, personal communication). Fibrocaseous TB takes longer induces tuberculous pneumonia and what host factors contribute to develop and presents with extensive granuloma within pneu- to necrosis. monia that cannot be coughed up (4). Survivors become long- term M. tuberculosis carriers when lung cavities are connected to MACROPHAGE NECROSIS AND THE CONCEPT OF NECROSIS- airways from which M. tuberculosis is coughed out to air. ASSOCIATED EXTRACELLULAR CLUSTER Postprimary TB develops mostly in immunocompetent adults Induction of macrophage necrosis is a key M. tuberculosis viru- who gained immunity earlier in their life from their first M. tuber- lence mechanism. Inhaled M. tuberculosis is first taken up by alve- culosis exposure and primary TB (3). Individuals who have ac- olar macrophages within which it persists or replicates. M. tuber- quired strong cell-mediated immunity to M. tuberculosis proteins, culosis grows when more than 10 of these bacteria infect one as detected by tuberculin (M. tuberculosis extract) skin test, are macrophage (13). If the infected macrophage contains more than more likely to develop and die from cavitary disease (5). This is 25 M. tuberculosis bacteria, the macrophage undergoes necrosis consistent with Koch’s phenomenon, in which TB patients be- and bursts to release M. tuberculosis (14). This process requires the came severely ill or died after receiving tuberculin (6). In contrast, M. tuberculosis ESX-1 protein secretion system (15). The killing of in young individuals, M. tuberculosis induces granulomas charac- macrophages by M. tuberculosis can also occur without ESX-1 terized by local accumulation of immune cells surrounded by ep- when the bacterial burden is high (16). However, such a scenario is ithelioid macrophages, Langerhans giant cells, and a rim of fibrous unlikely to occur if the initial infection dose is low, since ESX-1 is tissue without cavitation. Disseminated tuberculosis in immuno- required for M. tuberculosis to grow intracellularly (17). suppressed individuals is not discussed here. As cavitation is be- Material from necrotic macrophages may be beneficial to M. lieved to be caused by necrosis of granulomas in which M. tuber- Published 12 January 2016 culosis persists or replicates, most TB research has largely been Citation Wong K-W, Jacobs WR, Jr. 2016. Postprimary tuberculosis and macrophage focused on granuloma formation (7). However, in primates, gran- necrosis: is there a big conNECtion? 7(1):e01589-15. doi:10.1128/mBio.01589-15. ulomas are associated with M. tuberculosis killing, whereas pneu- Copyright © 2016 Wong and Jacobs This is an open-access article distributed under the monia is associated with M. tuberculosis replication (8). Histology terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported of postprimary TB in humans indicates that lung necrosis and license, which permits unrestricted noncommercial use, distribution, and reproduction pneumonia, but not granuloma, is associated with pulmonary in any medium, provided the original author and source are credited. cavitation (3). Also, pneumonia and lung necrosis are the leading Address correspondence to Ka-Wing Wong, [email protected], or William R. Jacobs, cause of death among untreated adults with acute TB (3, 9, 10). [email protected]. January/February 2016 Volume 7 Issue 1 e01589-15 mbio.asm.org 1 Perspective tuberculosis. When cultured with lysed leukocytes, M. tuberculosis mary TB also seen in a humanized mouse TB model (34–36). attaches to extracellular matrix materials and enters into a drug- Hunter suggested that bronchial obstruction triggers and exacer- tolerant persistent state (18). Orme suggested that M. tuberculosis bates tuberculous pneumonia, another feature of postprimary TB in this state forms a biofilm-like structure and referred to these (35). Thus, vascular thrombosis arising from ET may lead to tu- structures as necrosis-associated extracellular clusters (NECs) berculous pneumonia. Excessive ETs correlate with inflammation (19). A single NEC likely contains enough M. tuberculosis to kill and severe pneumonia (37). ET has been detected in sputum sam- macrophages upon contact, potentially because big particles make ples from patients experiencing community-based pneumonia phagocytosis difficult to complete and trigger deaths in macro- who were infected with bacterial or viral pathogens (38, 39). Thus, phages and neutrophils (20). Depending on the local environ- ETs may represent a link between TB and thrombotic conditions. ment, M. tuberculosis may remain as a pellicle for years or spread Studies of active TB patients are needed to test the idea. toward oxygen-rich areas such as blood vessels or bronchial air- COMMON DETERMINANTS FOR LIPID PNEUMONIA ways. Along the way, M. tuberculosis can trigger necrotic lesions FORMATION AND MACROPHAGE NECROSIS over time within a larger area of caseous pneumonia (4). The lesions may harden or be healed by fibrosis and calcification. Oth- Postprimary TB is characterized by the presence of tuberculous ers can become soft. When this happens across a bronchus, the pneumonia surrounding alveolar airways, as observed in primate softened materials are coughed out through the bronchus, and a models of TB (8, 40). Cavitation occurs when lung cells in a pa- cavity is formed (4). M. tuberculosis can then grow a massive tient with pneumonia undergo necrosis. The lipid-rich nature of amount by forming a pellicle on the surface of the cavity wall, cells in tuberculous pneumonia was first reported by the pathol- which can be coughed out for transmission (3, 11). ogist R. Virchow in 1860 (R. Hunter, personal communication). NEC was initially proposed in an attempt to understand gran- The lipid accumulation correlates with increased expression of ulomatous TB (19). Here we seek to determine whether the NEC host genes for lipid metabolism (41). Cholesterol crystals in le- model can be extended to understand postprimary TB. We are sions are observed in TB patients and in a humanized mouse particularly interested in applying new findings in the field of model of TB (34). thrombosis in the context of postprimary TB. Tuberculous pneumonia is characterized by the presence of lipid-rich foamy macrophages with few neutrophils (35). Foamy EXTRACELLULAR TRAP: CONNECTING M. TUBERCULOSIS macrophages are induced by at least two M. tuberculosis mecha- INFECTION TO PNEUMONIA? nisms. One involves the interaction between M. tuberculosis keto- Necrotic cells release inflammatory intracellular molecules after mycolic acid and human nuclear receptor 4 (42, 43). Another the plasma membrane collapses. ETosis describes a necrosis in involves interrupting autophagy (44). Autophagy is a recycling which a chromatin structure called an extracellular trap (ET) is pathway critical for lipolysis (45). M. tuberculosis ESX-1 inhibits decondensed and extruded (21). An ET is a stretch of chromo- host lipolysis by disrupting autophagy (46). ESAT-6 perturbs lipid somal DNA and globular protein domains. It traps pathogens and homeostasis and induces foamy macrophages (47). The host fac- prevents their spreading. M. tuberculosis induces ETosis in neu- tor gamma interferon (IFN-) can also promote foamy macro- trophils and macrophages and associates with ETs (22, 23). Ac- phage formation (48). Elevated intracellular lipid levels then cause cordingly, ETosis could generate NECs. macrophage necrosis (49). Since IFN- can promote ESX-1- The discovery of ETs provides a molecular basis of vascular mediated macrophage necrosis (22), it may act in concert with thrombosis (24). An ET induces blood clotting by activating plate- keto-mycolic acid and ESX-1 to induce macrophage necrosis by lets and inducing fibrin and thrombus formation (25). A throm- promoting lipid accumulation. bus contains platelets aggregated within a network of fibrin and Few M. tuberculosis bacteria or a lack of acid-fast mycobacteria chromatin DNA. Infected macrophages in tissues normally do not are found in lipid-rich tuberculous pneumonia (4). Acid fastness encounter blood components, unless blood vessels are damaged. is a physical property of M. tuberculosis’s cell wall. M. tuberculosis In a rabbit model of postprimary TB, tissue-damaging MMP-1 living in a lipid-rich environment loses its acid fastness (50). The activity is responsible for lung damage (26). Such tissue damage mechanism is unclear but may involve dephosphorylation of a key may allow mixing of blood contents with M. tuberculosis-induced enzyme for mycolic acid synthesis (51). Acid-fast-negative M. tu- ETs and trigger thrombosis. At this point, extracellular M. tuber- berculosis is present in sputum of TB patients (19, 52). Acid-fast- culosis can encounter neutrophils and induce necrosis of the in- negative cases account for nearly a third of the ongoing TB trans- fected neutrophils (27). Since M. tuberculosis-infected neutrophils missions in China (53). Half of these TB-transmitting patients do undergo ETosis, this M. tuberculosis-neutrophil interaction may not have cavities (53). We propose that sputum samples from further promote thrombosis and NEC formation (23). these patients contain NECs that originated from tuberculous Thrombosis is associated with TB. Cudkowicz identified pneumonia lesions that are undergoing necrosis and have not yet thrombosis within pulmonary artery branches near tuberculous matured into cavitary lesions. foci in histological autopsy samples of pulmonary TB (28). Vas- TISSUE DAMAGE MEDIATED BY DELAYED-TYPE cular thrombosis has also been observed in patients with postpri- HYPERSENSITIVITY mary TB by Hunter and colleagues (9). Cases of pulmonary TB patients with pulmonary thromboembolism or venous thrombo- Patients with cavitary TB tend to have a stronger reaction to tu- embolism are noted (29–31). Patients with community-based berculin skin test. Canetti indicated that tuberculous lipid pneu- pneumonia also have an elevated risk of thrombosis-related vas- monia is more frequent and more severe in hypersensitive hosts cular diseases (32). Various animal models of TB also show evi- (10). This is a classic example of DTH. Sensitization with repeated dence of vascular thrombosis (33). high doses of heat-killed Mycobacterium bovis generates DTH that Thrombosis can cause airway obstruction, a feature of postpri- triggers cavitation in a postprimary rabbit model of TB (26). M. 2 mbio.asm.org January/February 2016 Volume 7 Issue 1 e01589-15 Perspective tuberculosis trehalose dimycolate and ESAT-6 can induce DTH vage fluid samples (76). M. tuberculosis-specific Th17 cells might (54, 55). DTH is mediated by IFN--producing CD4 T helper localize in tuberculous lesions and escape detection. Alternatively, cell (Th1) cells. IFN- promotes survival of lightly infected mac- heterogeneity of M. tuberculosis strains from different geographic rophages but induces ETosis in heavily infected macrophages (14, regions might generate different Th17 responses. Clinical M. tu- 16, 22). This suggests that infection of lightly infected macro- berculosis isolates secrete different levels of ESAT-6, which induces phages is controlled by IFN--mediated DTH responses, without Th17 differentiation (77). Finally, patients might develop TB which the infection becomes disseminated, as seen in AIDS pa- through a mechanism independent of a DTH response, such as tients. However, the same DTH response in immunocompetent involving Th2 cells that contribute to TB pathogenesis by antago- individuals may help heavily infected macrophages undergo ETo- nizing Th1 responses. sis and help M. tuberculosis persist in a NEC. What is the source of M. tuberculosis that triggers tuberculous The classical view considers IFN- as the sole cytokine medi- lipid pneumonia in postprimary TB? Increasing evidence from ating DTH. The discovery of interleukin-17 (IL-17)-producing T high-burden settings indicates that exogenous reinfection con- (Th17) cells revises this view. Th17 cells develop after initiation of tributes considerably to postprimary TB in adults (78, 79). The DTH mediated by Th1 cells. Excessive and prolonged Th17 re- lymphatic system is a proposed reservoir of latent M. tuberculosis sponses cause tissue damage (56). Th17 cells are implicated in (80, 81) and may provide another source. Either way, deposition human chronic inflammatory lung diseases (57). All these condi- of M. tuberculosis into the upper lobes of lungs can trigger DTH tions are linked to airway obstruction, which can facilitate pneu- pathology toward M. tuberculosis. Skin graft rejection due to DTH monia and cavitation. In mice, Th17 cells play a protective role is associated with neutrophil recruitment and widespread micro- during early M. tuberculosis infection, whereas excessive Th17 re- vascular injury and is mediated by IL-17 and IFN- (82, 83). Im- sponses lead to severe immunopathology and increased M. tuber- munomodulation by mesenchymal stem cells suppresses DTH culosis burden (58–60). This discrepancy may be because, similar and extends skin graft survival (84). This approach shows prom- to IFN-, IL-17’s effect depends on how heavily the macrophages ising results when used as an adjunct therapy to treat drug- are infected. resistant TB (85). It may be possible to treat or prevent postpri- IL-17 is a cytokine that recruits neutrophils. TB patients with mary TB by a host-directed approach that targets DTH. pulmonary cavities have higher neutrophil levels in bronchoal- CONCLUDING REMARKS veolar lavage fluid samples than those without pulmonary cavities Here we present a model of tuberculous pneumonia based on the (61). Inside the pulmonary cavities, there are more neutrophils concept of NEC. Induction of macrophage ETosis by M. tubercu- than macrophages. Also, more than half of the M. tuberculosis losis causes release of intracellular material such as ETs that can bacteria are found associated with neutrophils, compared to less initiate thrombosis. The intracellular material can also interact than a quarter of M. tuberculosis bacteria associated with macro- with M. tuberculosis to form a biofilm-like NEC that is tough to phages (62). If neutrophils encounter an M. tuberculosis NEC, clear by host immunity or antibiotics. The persistent nature of they undergo NETosis (NET stands for neutrophil extracellular NEC might sustain tuberculous pneumonia. DTH responses me- trap) and release more ETs and other extracellular material to diated by IFN- and IL-17 then inflict tissue damage on the lung produce a bigger NEC. NETs have been detected in pulmonary of an individual with pneumonia. Long-term interaction with the cavities and sputum samples from patients with active TB (63). human immune system may have selected for M. tuberculosis bac- This NET contains tissue-degrading MMP-8 that mediates cavi- teria that are efficient at forming NECs for survival and exploiting tation (63). the human DTH for transmission. Accordingly, inhibition of IL-17 stimulates MMP-1 expression from fibroblasts (64, 65). pneumonia and macrophage ETosis caused by M. tuberculosis Sputum MMP-1 activity from patients with TB correlates with should help TB control, as has been shown recently in a mouse lung pathology (66, 67). In the rabbit postprimary TB model, model of pneumonia and TB (86). MMP-1 activity correlates spatially with tissue necrosis and pul- Our NEC model of TB has several implications for developing monary cavitation (26). Transgenic mice expressing human novel therapies for controlling TB. (i) Efforts need to be made to MMP-1 exhibit necrosis of lung tissue and lipid pneumonia upon develop vaccines that prevent the formation of the biofilm caused M. tuberculosis challenge (68). Collectively, Th17 cells may pro- by ET. This might be achieved by developing antibody responses mote cavitation through IL-17-induced MMP-1. that prevent the biofilm formation or target their dissolution. (ii) Th17 differentiation can be promoted by cholesterol crystals We need new chemotherapeutic strategies to kill M. tuberculosis in through NETosis and priming of macrophages for IL-1 produc- a biofilm with drugs that either dissolve the biofilm or kill M. tion (69). Interestingly, diabetes is associated with elevated intra- tuberculosis bacteria that have entered into a persistent state. (iii) cellular cholesterol and primes neutrophils to undergo NETosis Mycobacteriophages may provide attractive therapeutic reagents (70, 71). Diabetes is a risk factor of TB and pulmonary cavitation for killing extracellular M. tuberculosis. (70, 72, 73). ETs are detected in the bronchoalveolar lavage fluid samples from diabetic mice with TB (14). Pulmonary TB patients ACKNOWLEDGMENTS with higher frequencies of Th1 and Th17 cells are more likely to K.-W. Wong was supported by Fudan University, Shanghai Public Health have diabetes (74). It may be possible that M. tuberculosis exploits Clinical Center, and Natural Science Foundation of China grant cholesterol-rich environments to promote NETosis, Th17 differ- 81371777. W. R. Jacobs, Jr., was supported by HHMI and NIH grant entiation, and ultimately, cavitation. AI026170. More Th17 cells were observed in peripheral blood samples We greatly appreciate Douglas Lowrie, Robert Hunter, Hardy Korn- from TB patients than in healthy controls after M. tuberculosis feld, and two anonymous reviewers for their comments and suggestions. antigen stimulation (75). However, similar results were not found We also thank Robert Hunter for bringing our attention to earlier works in another study using peripheral blood and bronchoalveolar la- by R. Virchow, T. Edgington, and H. Dvorak. January/February 2016 Volume 7 Issue 1 e01589-15 mbio.asm.org 3 Perspective 2003. Deletion of RD1 from Mycobacterium tuberculosis mimics bacille FUNDING INFORMATION Calmette-Guerin attenuation. J Infect Dis 187:117–123. http://dx.doi.org/ HHS | National Institutes of Health (NIH) provided funding to William 10.1086/345862. R. Jacobs under grant number AI26170. National Natural Science Foun- 18. Ackart DF, Hascall-Dove L, Caceres SM, Kirk NM, Podell BK, Me- dation of China (NSFC) provided funding to Ka-Wing Wong under grant lander C, Orme IM, Leid JG, Nick JA, Basaraba RJ. 2014. Expression of number 81371777. antimicrobial drug tolerance by attached communities of Mycobacterium tuberculosis. Pathog Dis 70:359 –369. http://dx.doi.org/10.1111/2049 REFERENCES -632X.12144. 1. Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, 19. Orme IM. 2014. A new unifying theory of the pathogenesis of tuberculo- Parkhill J, Malla B, Berg S, Thwaites G, Yeboah-Manu D, Bothamley G, sis. Tuberculosis (Edinb) 94:8 –14. http://dx.doi.org/10.1016/ Mei J, Wei L, Bentley S, Harris SR, Niemann S, Diel R, Aseffa A, Gao j.tube.2013.07.004. Q. 2013. Out-of-Africa migration and Neolithic coexpansion of Mycobac- 20. Branzk N, Lubojemska A, Hardison SE, Wang Q, Gutierrez MG, Brown terium tuberculosis with modern humans. Nat Genet 45:1176 –1182. GD, Papayannopoulos V. 2014. Neutrophils sense microbe size and se- http://dx.doi.org/10.1038/ng.2744. lectively release neutrophil extracellular traps in response to large patho- 2. World Health Organization. 2013. Global tuberculosis report 2013. gens. Nat Immunol 15:1017–1025. http://dx.doi.org/10.1038/ni.2987. World Health Organization, Geneva, Switzerland. 21. Brinkmann V, Zychlinsky A. 2012. Neutrophil extracellular traps: is im- 3. Hunter RL. 2011. Pathology of post primary tuberculosis of the lung: an munity the second function of chromatin? J Cell Biol 198:773–783. http:// illustrated critical review. Tuberculosis (Edinb) 91:497–509. http:// dx.doi.org/10.1083/jcb.201203170. dx.doi.org/10.1016/j.tube.2011.03.007. 22. Wong KW, Jacobs WR, Jr. 2013. Mycobacterium tuberculosis exploits 4. Hunter RL, Actor JK, Hwang SA, Karev V, Jagannath C. 2014. Patho- human interferon gamma to stimulate macrophage extracellular trap for- genesis of post primary tuberculosis: immunity and hypersensitivity in the mation and necrosis. J Infect Dis 208:109 –119. http://dx.doi.org/10.1093/ development of cavities. Ann Clin Lab Sci 44:365–387. infdis/jit097. 5. Auld SC, Click ES, Heilig CM, Miramontes R, Cain KP, Bisson GP, 23. Ramos-Kichik V, Mondragón-Flores R, Mondragón-Castelán M, MacKenzie WR. 2013. Association between tuberculin skin test result and Gonzalez-Pozos S, Muñiz-Hernandez S, Rojas-Espinosa O, Chacón- clinical presentation of tuberculosis disease. BMC Infect Dis 13:460. Salinas R, Estrada-Parra S, Estrada-García I. 2009. Neutrophil extracel- http://dx.doi.org/10.1186/1471-2334-13-460. lular traps are induced by Mycobacterium tuberculosis. Tuberculosis (Ed- 6. Casadevall A, Pirofski LA. 2014. Microbiology: ditch the term pathogen. inb) 89:29 –37. http://dx.doi.org/10.1016/j.tube.2008.09.009. Nature 516:165–166. http://dx.doi.org/10.1038/516165a. 24. Engelmann B, Massberg S. 2013. Thrombosis as an intravascular effector 7. Duque-Correa MA, Kuhl AA, Rodriguez PC, Zedler U, Schommer- of innate immunity. Nat Rev Immunol 13:34 – 45. http://dx.doi.org/ Leitner S, Rao M, Weiner J, Hurwitz R, Qualls JE, Kosmiadi GA, 10.1038/nri3345. Murray PJ, Kaufmann SHE, Reece ST. 2014. Macrophage arginase-1 25. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers controls bacterial growth and pathology in hypoxic tuberculosis granulo- DD, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD. 2010. mas. Proc Natl Acad SciUSA 111:E4024 –E4032. http://dx.doi.org/ Extracellular DNA traps promote thrombosis. Proc Natl Acad SciUSA 10.1073/pnas.1408839111. 107:15880 –15885. http://dx.doi.org/10.1073/pnas.1005743107. 8. Lin PL, Ford CB, Coleman MT, Myers AJ, Gawande R, Ioerger T, 26. Kübler A, Luna B, Larsson C, Ammerman NC, Andrade BB, Orandle Sacchettini J, Fortune SM, Flynn JL. 2014. Sterilization of granulomas is M, Bock KW, Xu Z, Bagci U, Molura DJ, Marshall J, Burns J, Winglee common in active and latent tuberculosis despite within-host variability K, Ahidjo BA, Cheung LS, Klunk M, Jain SK, Kumar NP, Babu S, Sher in bacterial killing. Nat Med 20:75–79. http://dx.doi.org/10.1038/ A. 2015. Mycobacterium tuberculosis dysregulates MMP/TIMP balance nm.3412. to drive rapid cavitation and unrestrained bacterial proliferation. J Pathol 9. Hunter RL, Jagannath C, Actor JK. 2007. Pathology of postprimary 235:431– 444. http://dx.doi.org/10.1002/path.4432. tuberculosis in humans and mice: contradiction of long-held beliefs. 27. Corleis B, Korbel D, Wilson R, Bylund J, Chee R, Schaible UE. 2012. Tuberculosis (Edinb) 87:267–278. http://dx.doi.org/10.1016/ Escape of Mycobacterium tuberculosis from oxidative killing by neutro- j.tube.2006.11.003. phils. Cell Microbiol 14:1109 –1121. http://dx.doi.org/10.1111/j.1462 10. Canetti G. 1955. The tubercle bacillus in the pulmonary lesion of man. -5822.2012.01783.x. Histobacteriology and its bearing on the therapy of pulmonary tubercu- 28. Cudkowicz L. 1952. The blood supply of the lung in pulmonary tubercu- losis. Springer Publishing Company, New York, NY. losis. Thorax 7:270 –276. http://dx.doi.org/10.1136/thx.7.3.270. 11. Rich AR. 1951. The pathogenesis of tuberculosis, 2nd ed. Charles C 29. Goncalves IM, Alves D, Carvalho A, do Ceu Brito M, Calvario F, Thomas, Springfield, IL. http://dx.doi.org/10.1097/00007611-194410000 Duarte R. 2009. Tuberculosis and venous thromboembolism: a case se- -00018. ries. Cases J 2:9333. http://dx.doi.org/10.1186/1757-1626-2-9333. 12. Lando PA, Edgington TS. 1985. An innate host response to the neoplastic 30. Komazaki Y, Sakakibara Y, Sakashita H, Miyazaki Y, Inase N. 2011. cell: syngeneic rat tumor cells can elicit a rapid de novo lymphoid proco- Pulmonary thromboembolism with pulmonary tuberculosis. Kekkaku 86: agulant response. J Immunol 135:3587–3595. 717–722. (In Japanese.) 13. Welin A, Eklund D, Stendahl O, Lerm M. 2011. Human macrophages 31. Sharif-Kashani B, Bikdeli B, Moradi A, Tabarsi P, Chitsaz E, Shemirani infected with a high burden of ESAT-6-expressing M. tuberculosis un- S, Esmaili-Khansari M, Masjedi M. 2010. Coexisting venous thrombo- dergo caspase-1- and cathepsin B-independent necrosis. PLoS One embolism in patients with tuberculosis. Thromb Res 125:478 – 480. http:// 6:e20302. http://dx.doi.org/10.1371/journal.pone.0020302. dx.doi.org/10.1016/j.thromres.2010.01.014. 14. Repasy T, Lee J, Marino S, Martinez N, Kirschner DE, Hendricks G, 32. Violi F, Cangemi R, Calvieri C. 2014. Pneumonia, thrombosis and vas- Baker S, Wilson AA, Kotton DN, Kornfeld H. 2013. Intracellular cular disease. J Thromb Haemost 12:1391–1400. http://dx.doi.org/ bacillary burden reflects a burst size for Mycobacterium tuberculosis in 10.1111/jth.12646. vivo. PLoS Pathog 9:e1003190. http://dx.doi.org/10.1371/ 33. Basaraba RJ. 2008. Experimental tuberculosis: the role of comparative journal.ppat.1003190. pathology in the discovery of improved tuberculosis treatment strategies. 15. Hsu T, Hingley-Wilson SM, Chen B, Chen M, Dai AZ, Morin PM, Tuberculosis (Edinb) 88:S35–S47. http://dx.doi.org/10.1016/S1472 Marks CB, Padiyar J, Goulding C, Gingery M, Eisenberg D, Russell RG, -9792(08)70035-0. Derrick SC, Collins FM, Morris SL, King CH, Jacobs WR. 2003. The 34. Calderon VE, Valbuena G, Goez Y, Judy BM, Huante MB, Sutjita P, primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of Johnston RK, Estes DM, Hunter RL, Actor JK, Cirillo JD, Endsley JJ. secreted lytic function required for invasion of lung interstitial tissue. Proc 2013. A humanized mouse model of tuberculosis. PLoS One 8:e63331. Natl Acad SciUSA 100:12420 –12425. http://dx.doi.org/10.1073/ http://dx.doi.org/10.1371/journal.pone.0063331. pnas.1635213100. 35. Hunter RL. 2011. On the pathogenesis of post primary tuberculosis: the 16. Lee J, Repasy T, Papavinasasundaram K, Sassetti C, Kornfeld H. 2011. Mycobacterium tuberculosis induces an atypical cell death mode to escape role of bronchial obstruction in the pathogenesis of cavities. Tuberculosis from infected macrophages. PLoS One 6:e18367. http://dx.doi.org/ (Edinb) 91(Suppl 1):S6 –S10. http://dx.doi.org/10.1016/ 10.1371/journal.pone.0018367. j.tube.2011.10.003. 17. Lewis K, Liao R, Guinn K, Hickey M, Smith S, Behr M, Sherman D. 36. Arney KL, Judson MA, Sahn SA. 1999. Airway obstruction arising from 4 mbio.asm.org January/February 2016 Volume 7 Issue 1 e01589-15 Perspective blood clot: three reports and a review of the literature. Chest 115:293–300. Mycobacterium tuberculosis. PLoS Pathog 10:e1004115. http:// http://dx.doi.org/10.1378/chest.115.1.293. dx.doi.org/10.1371/journal.ppat.1004115. 37. Narayana Moorthy A, Narasaraju T, Rai P, Perumalsamy R, Tan KB, 52. Garton NJ, Waddell SJ, Sherratt AL, Lee S, Smith RJ, Senner C, Hinds Wang S, Engelward B, Chow VTK. 2013. In vivo and in vitro studies on J, Rajakumar K, Adegbola RA, Besra GS, Butcher PD, Barer MR. 2008. the roles of neutrophil extracellular traps during secondary pneumococcal Cytological and transcript analyses reveal fat and lazy persister-like bacilli pneumonia after primary pulmonary influenza infection. Front Immunol in tuberculous sputum. PLoS Med 5:e75. http://dx.doi.org/10.1371/ 4:56. http://dx.doi.org/10.3389/fimmu.2013.00056. journal.pmed.0050075. 38. Dwyer M, Shan Q, D’Ortona S, Maurer R, Mitchell R, Olesen H, Thiel 53. Yang C, Shen X, Peng Y, Lan R, Zhao Y, Long B, Luo T, Sun G, Li X, S, Huebner J, Gadjeva M. 2014. Cystic fibrosis sputum DNA has NETosis Qiao K, Gui X, Wu J, Xu J, Li F, Li D, Liu F, Shen M, Hong J, Mei J, characteristics and neutrophil extracellular trap release is regulated by DeRiemer K. 2015. Transmission of Mycobacterium tuberculosis in macrophage migration-inhibitory factor. J Innate Immun 6:765–779. China: a population-based molecular epidemiologic study. Clin Infect Dis http://dx.doi.org/10.1159/000363242. 61:219 –227. http://dx.doi.org/10.1093/cid/civ255. 39. Hamaguchi S, Seki M, Yamamoto N, Hirose T, Matsumoto N, Irisawa 54. Pollock JM, McNair J, Bassett H, Cassidy JP, Costello E, Aggerbeck H, T, Takegawa R, Shimazu T, Tomono K. 2012. Case of invasive non- Rosenkrands I, Andersen P. 2003. Specific delayed-type hypersensitivity typable Haemophilus influenzae respiratory tract infection with a large responses to ESAT-6 identify tuberculosis-infected cattle. J Clin Microbiol quantity of neutrophil extracellular traps in sputum. J Inflamm Res 41:1856 –1860. http://dx.doi.org/10.1128/JCM.41.5.1856-1860.2003. 5:137–140. http://dx.doi.org/10.2147/JIR.S39497. 55. Yamagami H, Matsumoto T, Fujiwara N, Arakawa T, Kaneda K, Yano 40. Via LE, Weiner DM, Schimel D, Lin PL, Dayao E, Tankersley SL, Cai I, Kobayashi K. 2001. Trehalose 6,6=-dimycolate (cord factor) of Myco- Y, Coleman MT, Tomko J, Paripati P, Orandle M, Kastenmayer RJ, bacterium tuberculosis induces foreign-body- and hypersensitivity-type Tartakovsky M, Rosenthal A, Portevin D, Eum SY, Lahouar S, Gagneux granulomas in mice. Infect Immun 69:810 – 815. http://dx.doi.org/ S, Young DB, Flynn JL. 2013. Differential virulence and disease progres- 10.1128/IAI.69.2.810-815.2001. sion following Mycobacterium tuberculosis complex infection of the 56. Steinman L. 2007. A brief history of T(H)17, the first major revision in the common marmoset (Callithrix jacchus). Infect Immun 81:2909 –2919. T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 13: http://dx.doi.org/10.1128/IAI.00632-13. 139 –145. http://dx.doi.org/10.1038/nm1551. 41. Kim M, Wainwright HC, Locketz M, Bekker L, Walther GB, Dittrich C, 57. Weaver CT, Elson CO, Fouser LA, Kolls JK. 2013. The Th17 pathway Visser A, Wang W, Hsu F, Wiehart U, Tsenova L, Kaplan G, Russell and inflammatory diseases of the intestines, lungs, and skin. Annu Rev DG. 2010. Caseation of human tuberculosis granulomas correlates with Pathol 8:477–512. http://dx.doi.org/10.1146/annurev-pathol-011110 elevated host lipid metabolism. EMBO Mol Med 2:258 –274. http:// -130318. dx.doi.org/10.1002/emmm.201000079. 58. Kozakiewicz L, Chen Y, Xu J, Wang Y, Dunussi-Joannopoulos K, Ou Q, 42. Dkhar HK, Nanduri R, Mahajan S, Dave S, Saini A, Somavarapu AK, Flynn JL, Porcelli SA, Jacobs WR, Chan J. 2013. B cells regulate neutro- Arora A, Parkesh R, Thakur KG, Mayilraj S, Gupta P. 2014. Mycobac- philia during Mycobacterium tuberculosis infection and BCG vaccination terium tuberculosis keto-mycolic acid and macrophage nuclear receptor by modulating the interleukin-17 response. PLoS Pathog 9:e1003472. TR4 modulate foamy biogenesis in granulomas: a case of a heterologous http://dx.doi.org/10.1371/journal.ppat.1003472. and noncanonical ligand-receptor pair. J Immunol 193:295–305. http:// 59. Cruz A, Fraga AG, Fountain JJ, Rangel-Moreno J, Torrado E, Saraiva dx.doi.org/10.4049/jimmunol.1400092. M, Pereira DR, Randall TD, Pedrosa J, Cooper AM, Castro AG. 2010. 43. Peyron P, Vaubourgeix J, Poquet Y, Levillain F, Botanch C, Bardou F, Pathological role of interleukin 17 in mice subjected to repeated BCG Daffé M, Emile J, Marchou B, Cardona P, de Chastellier C, Altare F. vaccination after infection with Mycobacterium tuberculosis. J Exp Med 2008. Foamy macrophages from tuberculous patients’ granulomas consti- 207:1609 –1616. http://dx.doi.org/10.1084/jem.20100265. tute a nutrient-rich reservoir for M. tuberculosis persistence. PLoS Pathog 60. Desvignes L, Ernst JD. 2009. Interferon-gamma-responsive nonhemato- 4:e1000204. http://dx.doi.org/10.1371/journal.ppat.1000204. poietic cells regulate the immune response to Mycobacterium tuberculo- 44. Podinovskaia M, Lee W, Caldwell S, Russell DG. 2013. Infection of sis. Immunity 31:974 –985. http://dx.doi.org/10.1016/ macrophages with Mycobacterium tuberculosis induces global modifica- j.immuni.2009.10.007. tions to phagosomal function. Cell Microbiol 15:843– 859. http:// 61. Nolan A, Condos R, Huie ML, Dawson R, Dheda K, Bateman E, Rom dx.doi.org/10.1111/cmi.12092. WN, Weiden MD. 2013. Elevated IP-10 and IL-6 from bronchoalveolar 45. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, lavage cells are biomarkers of non-cavitary tuberculosis. Int J Tuberc Lung Cuervo AM, Czaja MJ. 2009. Autophagy regulates lipid metabolism. Dis 17:922–927. http://dx.doi.org/10.5588/ijtld.12.0610. Nature 458:1131–1135. http://dx.doi.org/10.1038/nature07976. 62. Eum S. 2010. Neutrophils are the predominant infected phagocytic cells in 46. Romagnoli A, Etna MP, Giacomini E, Pardini M, Remoli ME, Corazzari the airways of patients with active pulmonary TB. Chest 137:122–128. M, Falasca L, Goletti D, Gafa V, Simeone R, Delogu G, Piacentini M, http://dx.doi.org/10.1378/chest.09-0903. Brosch R, Fimia GM, Coccia EM. 2012. ESX-1 dependent impairment of 63. Ong CWM, Elkington PT, Brilha S, Ugarte-Gil C, Tome-Esteban MT, autophagic flux by Mycobacterium tuberculosis in human dendritic cells. Tezera LB, Pabisiak PJ, Moores RC, Sathyamoorthy T, Patel V, Gilman Autophagy 8:1357–1370. http://dx.doi.org/10.4161/auto.20881. RH, Porter JC, Friedland JS. 2015. Neutrophil-derived MMP-8 drives 47. Singh V, Jamwal S, Jain R, Verma P, Gokhale R, Rao KS. 2012. AMPK-dependent matrix destruction in human pulmonary tuberculosis. Mycobacterium tuberculosis-driven targeted recalibration of macrophage PLoS Pathog 11:e1004917. http://dx.doi.org/10.1371/ lipid homeostasis promotes the foamy phenotype. Cell Host Microbe 12: journal.ppat.1004917. 669 – 681. http://dx.doi.org/10.1016/j.chom.2012.09.012. 64. Wu Y, Zhu L, Liu L, Zhang J, Peng B. 2014. Interleukin-17A stimulates 48. Michael DR, Ashlin TG, Davies CS, Gallagher H, Stoneman TW, migration of periodontal ligament fibroblasts via p38 MAPK/NF-kappaB- Buckley ML, Ramji DP. 2013. Differential regulation of macropinocyto- dependent MMP-1 expression. J Cell Physiol 229:292–299. http:// sis in macrophages by cytokines: implications for foam cell formation and dx.doi.org/10.1002/jcp.24444. atherosclerosis. Cytokine 64:357–361. http://dx.doi.org/10.1016/ 65. Cortez DM, Feldman MD, Mummidi S, Valente AJ, Steffensen B, j.cyto.2013.05.016. Vincenti M, Barnes JL, Chandrasekar B. 2007. IL-17 stimulates MMP-1 49. Tabas I. 2002. Consequences of cellular cholesterol accumulation: basic expression in primary human cardiac fibroblasts via p38 MAPK- and concepts and physiological implications. J Clin Invest 110:905–911. http:// ERK1/2-dependent C/EBP-beta, NF-kappaB, and AP-1 activation. Am J dx.doi.org/10.1172/JCI0216452. Physiol Heart Circ Physiol 293:H3356 –H3365. 50. Daniel J, Maamar H, Deb C, Sirakova TD, Kolattukudy PE. 2011. 66. Nayak L, Tunga H, De RK. 2013. Disease co-morbidity and the human Mycobacterium tuberculosis uses host triacylglycerol to accumulate lipid Wnt signaling pathway: a network-wise study. Omics 17:318 –337. http:// droplets and acquires a dormancy-like phenotype in lipid-loaded macro- dx.doi.org/10.1089/omi.2012.0053. phages. PLoS Pathog 7:e1002093. http://dx.doi.org/10.1371/ 67. Seddon J, Kasprowicz V, Walker NF, Yuen HM, Sunpath H, Tezera L, journal.ppat.1002093. Meintjes G, Wilkinson RJ, Bishai WR, Friedland JS, Elkington PT. 2013. 51. Vilchèze C, Molle V, Carrère-Kremer S, Leiba J, Mourey L, Shenai S, Procollagen III N-terminal propeptide and desmosine are released by ma- Baronian G, Tufariello J, Hartman T, Veyron-Churlet R, Trivelli X, trix destruction in pulmonary tuberculosis. J Infect Dis 208:1571–1579. Tiwari S, Weinrick B, Alland D, Guérardel Y, Jacobs WR, Kremer L. http://dx.doi.org/10.1093/infdis/jit343. 2014. Phosphorylation of KasB regulates virulence and acid-fastness in 68. Elkington P, Shiomi T, Breen R, Nuttall RK, Ugarte-Gil CA, Walker January/February 2016 Volume 7 Issue 1 e01589-15 mbio.asm.org 5 Perspective NF, Saraiva L, Pedersen B, Mauri F, Lipman M, Edwards DR, Robert- 78. Marx FM, Dunbar R, Enarson DA, Williams BG, Warren RM, van der son BD, D’Armiento J, Friedland JS. 2011. MMP-1 drives immunopa- Spuy GD, van Helden PD, Beyers N. 2014. The temporal dynamics of thology in human tuberculosis and transgenic mice. J Clin Invest 121: relapse and reinfection tuberculosis after successful treatment: a retro- 1827–1833. http://dx.doi.org/10.1172/JCI45666. spective cohort study. Clin Infect Dis 58:1676 –1683. http://dx.doi.org/ 69. Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. 2015. Inflam- 10.1093/cid/ciu186. mation. Neutrophil extracellular traps license macrophages for cytokine 79. Shen G, Xue Z, Shen X, Sun B, Gui X, Shen M, Mei J, Gao Q. 2006. production in atherosclerosis. Science 349:316 –320. http://dx.doi.org/ Recurrent tuberculosis and exogenous reinfection, Shanghai, China. 10.1126/science.aaa8064. Emerg Infect Dis 12:1776 –1778. http://dx.doi.org/10.3201/ 70. Martinez N, Kornfeld H. 2014. Diabetes and immunity to tuberculosis. eid1211.051207. Eur J Immunol 44:617– 626. http://dx.doi.org/10.1002/eji.201344301. 80. Behr MA, Waters WR. 2014. Is tuberculosis a lymphatic disease with a 71. Wong SL, Demers M, Martinod K, Gallant M, Wang Y, Goldfine AB, pulmonary portal? Lancet Infect Dis 14:250 –255. http://dx.doi.org/ Kahn CR, Wagner DD. 2015. Diabetes primes neutrophils to undergo 10.1016/S1473-3099(13)70253-6. NETosis, which impairs wound healing. Nat Med 21:815– 819. http:// 81. Das B, Kashino SS, Pulu I, Kalita D, Swami V, Yeger H, Felsher DW, dx.doi.org/10.1038/nm.3887. Campos-Neto A. 2013. CD271() bone marrow mesenchymal stem cells 72. Chen H, Liu M, Jiang S, Gu F, Huang S, Gao T, Zhang Z. 2014. Impact may provide a niche for dormant Mycobacterium tuberculosis. Sci Transl of diabetes on diagnostic delay for pulmonary tuberculosis in Beijing. Int Med 5:170ra13. http://dx.doi.org/10.1126/scitranslmed.3004912. J Tuberc Lung Dis 18:267–271. http://dx.doi.org/10.5588/ijtld.13.0140. 82. Dvorak HF. 1979. Rejection of first-set skin allografts in man. The micro- 73. Park SW, Shin JW, Kim JY, Park IW, Choi BW, Choi JC, Kim YS. 2012. The effect of diabetic control status on the clinical features of pulmonary vasculature is the critical target of the immune response. J Exp Med 150: tuberculosis. Eur J Clin Microbiol Infect Dis 31:1305–1310. http:// 322–337. http://dx.doi.org/10.1084/jem.150.2.322. dx.doi.org/10.1007/s10096-011-1443-3. 83. Rajesh D, Zhou Y, Jankowska-Gan E, Roenneburg DA, Dart ML, 74. Kumar NP, Sridhar R, Banurekha VV, Jawahar MS, Nutman TB, Babu Torrealba J, Burlingham WJ. 2010. Th1 and Th17 immunocompetence S. 2013. Expansion of pathogen-specific T-helper 1 and T-helper 17 cells in humanized NOD/SCID/IL2rgammanull mice. Hum Immunol 71: in pulmonary tuberculosis with coincident type 2 diabetes mellitus. J In- 551–559. http://dx.doi.org/10.1016/j.humimm.2010.02.019. fect Dis 208:739 –748. http://dx.doi.org/10.1093/infdis/jit241. 84. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, 75. Cowan J, Pandey S, Filion LG, Angel JB, Kumar A, Cameron DW. Hardy W, Devine S, Ucker D, Deans R, Moseley A, Hoffman R. 2002. 2012. Comparison of interferon-gamma-, interleukin (IL)-17- and IL- Mesenchymal stem cells suppress lymphocyte proliferation in vitro and 22-expressing CD4 T cells, IL-22-expressing granulocytes and proin- prolong skin graft survival in vivo. Exp Hematol 30:42– 48. http:// flammatory cytokines during latent and active tuberculosis infection. dx.doi.org/10.1016/S0301-472X(01)00769-X. Clin Exp Immunol 167:317–329. http://dx.doi.org/10.1111/j.1365 85. Skrahin A, Ahmed RK, Ferrara G, Rane L, Poiret T, Isaikina Y, Skrahina -2249.2011.04520.x. A, Zumla A, Maeurer MJ. 2014. Autologous mesenchymal stromal cell 76. Perreau M, Rozot V, Welles HC, Belluti-Enders F, Vigano S, Maillard infusion as adjunct treatment in patients with multidrug and extensively M, Dorta G, Mazza-Stalder J, Bart P, Roger T, Calandra T, Nicod L, drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Re- Harari A. 2013. Lack of Mycobacterium tuberculosis-specific interleukin- spir Med 2:108 –122. http://dx.doi.org/10.1016/S2213-2600(13)70234-0. 17A-producing CD4 T cells in active disease. Eur J Immunol 43: 86. Amaral EP, Ribeiro SCM, Lanes VR, Almeida FM, de Andrade MRM, 939 –948. http://dx.doi.org/10.1002/eji.201243090. Bomfim CCB, Salles ÉM, Bortoluci KR, Coutinho-Silva R, Hirata MH, 77. Solans L, Aguilo N, Samper S, Pawlik A, Frigui W, Martin C, Brosch R, Alvarez JM, Lasunskaia EB, D’Império-Lima MR. 2014. Pulmonary Gonzalo-Asensio J. 2014. A specific polymorphism in Mycobacterium tuberculosis H37Rv causes differential ESAT-6 expression and identifies infection with hypervirulent mycobacteria reveals a crucial role for the WhiB6 as a novel ESX-1 component. Infect Immun 82:3446 –3456. http:// P2X7 receptor in aggressive forms of tuberculosis. PLoS Pathog 10: dx.doi.org/10.1128/IAI.01824-14. e1004188. http://dx.doi.org/10.1371/journal.ppat.1004188. 6 mbio.asm.org January/February 2016 Volume 7 Issue 1 e01589-15 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png mBio Pubmed Central

Postprimary Tuberculosis and Macrophage Necrosis: Is There a Big ConNECtion?

Wong, Ka-Wing; Jacobs, William R.
mBio , Volume 7 (1) – Jan 12, 2016
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Abstract

PERSPECTIVE crossmark Postprimary Tuberculosis and Macrophage Necrosis: Is There a Big ConNECtion? a b Ka-Wing Wong, William R. Jacobs, Jr. Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China ; Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA ABSTRACT Adult or postprimary tuberculosis (TB) accounts for most TB cases. Its hallmark is pulmonary cavitation, which occurs as a result of necrosis in the lung in individuals with tuberculous pneumonia. Postprimary TB has previously been known to be associated with vascular thrombosis and delayed-type hypersensitivity, but their roles in pulmonary cavitation are unclear. A necrosis-associated extracellular cluster (NEC) refers to a cluster of drug-tolerant Mycobacterium tuberculosis attached to lysed host materials and is proposed to contribute to granulomatous TB. Here we suggest that NECs, perhaps due to big size, produce a distinct host response leading to postprimary TB. We propose that vascular thrombosis and pneumonia arise from NEC and that these processes are promoted by inflammatory cytokines produced from cell-mediated delayed-type hypersensitiv- ity, such as interleukin-17 and gamma interferon, eventually triggering necrosis in the lung and causing cavitation. According to this view, targeting NEC represents a necessary strategy to control adult TB. uberculosis (TB) is one of the most successful pathogens in Hunter et al. (3, 9) and others (10, 11) suggested that vascular humans. The causative agent of TB, Mycobacterium tuberculo- thrombosis and delayed-type hypersensitivity (DTH) are associ- sis, has coexisted with humans since the earliest history of human- ated with tuberculous pneumonia in postprimary TB. Vascular kind (1). It continues to cause appalling morbidity and mortality thrombosis occurs when blood clots due to blood vessel injury. rates (2). Most pulmonary TB cases and almost all transmission of DTH is a T cell-mediated inflammatory response. Lando and Edg- the disease are due to postprimary TB, which is also known as ington identified DTH correlates with induction of macrophage adult or secondary TB (3). Postprimary TB is characterized by procoagulant activity by activated T cells (12). Recent progress on pulmonary cavitation in the upper lobes of lungs. Individuals can understanding the mechanism of thrombosis may shed light on die from an acute pulmonary cavitation, which presents with pro- the underlying mechanism of procoagulant activity induction by found coagulopathy and coughing up large necrotizing pneu- DTH. Here we apply this knowledge to understand how vascular monic materials, or they die from fibrocaseous TB, which is the thrombosis is formed and the role of DTH in the context of most common form of TB and has much less coagulopathy (R. postprimary TB. Our goal is to understand how M. tuberculosis Hunter, personal communication). Fibrocaseous TB takes longer induces tuberculous pneumonia and what host factors contribute to develop and presents with extensive granuloma within pneu- to necrosis. monia that cannot be coughed up (4). Survivors become long- term M. tuberculosis carriers when lung cavities are connected to MACROPHAGE NECROSIS AND THE CONCEPT OF NECROSIS- airways from which M. tuberculosis is coughed out to air. ASSOCIATED EXTRACELLULAR CLUSTER Postprimary TB develops mostly in immunocompetent adults Induction of macrophage necrosis is a key M. tuberculosis viru- who gained immunity earlier in their life from their first M. tuber- lence mechanism. Inhaled M. tuberculosis is first taken up by alve- culosis exposure and primary TB (3). Individuals who have ac- olar macrophages within which it persists or replicates. M. tuber- quired strong cell-mediated immunity to M. tuberculosis proteins, culosis grows when more than 10 of these bacteria infect one as detected by tuberculin (M. tuberculosis extract) skin test, are macrophage (13). If the infected macrophage contains more than more likely to develop and die from cavitary disease (5). This is 25 M. tuberculosis bacteria, the macrophage undergoes necrosis consistent with Koch’s phenomenon, in which TB patients be- and bursts to release M. tuberculosis (14). This process requires the came severely ill or died after receiving tuberculin (6). In contrast, M. tuberculosis ESX-1 protein secretion system (15). The killing of in young individuals, M. tuberculosis induces granulomas charac- macrophages by M. tuberculosis can also occur without ESX-1 terized by local accumulation of immune cells surrounded by ep- when the bacterial burden is high (16). However, such a scenario is ithelioid macrophages, Langerhans giant cells, and a rim of fibrous unlikely to occur if the initial infection dose is low, since ESX-1 is tissue without cavitation. Disseminated tuberculosis in immuno- required for M. tuberculosis to grow intracellularly (17). suppressed individuals is not discussed here. As cavitation is be- Material from necrotic macrophages may be beneficial to M. lieved to be caused by necrosis of granulomas in which M. tuber- Published 12 January 2016 culosis persists or replicates, most TB research has largely been Citation Wong K-W, Jacobs WR, Jr. 2016. Postprimary tuberculosis and macrophage focused on granuloma formation (7). However, in primates, gran- necrosis: is there a big conNECtion? 7(1):e01589-15. doi:10.1128/mBio.01589-15. ulomas are associated with M. tuberculosis killing, whereas pneu- Copyright © 2016 Wong and Jacobs This is an open-access article distributed under the monia is associated with M. tuberculosis replication (8). Histology terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported of postprimary TB in humans indicates that lung necrosis and license, which permits unrestricted noncommercial use, distribution, and reproduction pneumonia, but not granuloma, is associated with pulmonary in any medium, provided the original author and source are credited. cavitation (3). Also, pneumonia and lung necrosis are the leading Address correspondence to Ka-Wing Wong, [email protected], or William R. Jacobs, cause of death among untreated adults with acute TB (3, 9, 10). [email protected]. January/February 2016 Volume 7 Issue 1 e01589-15 mbio.asm.org 1 Perspective tuberculosis. When cultured with lysed leukocytes, M. tuberculosis mary TB also seen in a humanized mouse TB model (34–36). attaches to extracellular matrix materials and enters into a drug- Hunter suggested that bronchial obstruction triggers and exacer- tolerant persistent state (18). Orme suggested that M. tuberculosis bates tuberculous pneumonia, another feature of postprimary TB in this state forms a biofilm-like structure and referred to these (35). Thus, vascular thrombosis arising from ET may lead to tu- structures as necrosis-associated extracellular clusters (NECs) berculous pneumonia. Excessive ETs correlate with inflammation (19). A single NEC likely contains enough M. tuberculosis to kill and severe pneumonia (37). ET has been detected in sputum sam- macrophages upon contact, potentially because big particles make ples from patients experiencing community-based pneumonia phagocytosis difficult to complete and trigger deaths in macro- who were infected with bacterial or viral pathogens (38, 39). Thus, phages and neutrophils (20). Depending on the local environ- ETs may represent a link between TB and thrombotic conditions. ment, M. tuberculosis may remain as a pellicle for years or spread Studies of active TB patients are needed to test the idea. toward oxygen-rich areas such as blood vessels or bronchial air- COMMON DETERMINANTS FOR LIPID PNEUMONIA ways. Along the way, M. tuberculosis can trigger necrotic lesions FORMATION AND MACROPHAGE NECROSIS over time within a larger area of caseous pneumonia (4). The lesions may harden or be healed by fibrosis and calcification. Oth- Postprimary TB is characterized by the presence of tuberculous ers can become soft. When this happens across a bronchus, the pneumonia surrounding alveolar airways, as observed in primate softened materials are coughed out through the bronchus, and a models of TB (8, 40). Cavitation occurs when lung cells in a pa- cavity is formed (4). M. tuberculosis can then grow a massive tient with pneumonia undergo necrosis. The lipid-rich nature of amount by forming a pellicle on the surface of the cavity wall, cells in tuberculous pneumonia was first reported by the pathol- which can be coughed out for transmission (3, 11). ogist R. Virchow in 1860 (R. Hunter, personal communication). NEC was initially proposed in an attempt to understand gran- The lipid accumulation correlates with increased expression of ulomatous TB (19). Here we seek to determine whether the NEC host genes for lipid metabolism (41). Cholesterol crystals in le- model can be extended to understand postprimary TB. We are sions are observed in TB patients and in a humanized mouse particularly interested in applying new findings in the field of model of TB (34). thrombosis in the context of postprimary TB. Tuberculous pneumonia is characterized by the presence of lipid-rich foamy macrophages with few neutrophils (35). Foamy EXTRACELLULAR TRAP: CONNECTING M. TUBERCULOSIS macrophages are induced by at least two M. tuberculosis mecha- INFECTION TO PNEUMONIA? nisms. One involves the interaction between M. tuberculosis keto- Necrotic cells release inflammatory intracellular molecules after mycolic acid and human nuclear receptor 4 (42, 43). Another the plasma membrane collapses. ETosis describes a necrosis in involves interrupting autophagy (44). Autophagy is a recycling which a chromatin structure called an extracellular trap (ET) is pathway critical for lipolysis (45). M. tuberculosis ESX-1 inhibits decondensed and extruded (21). An ET is a stretch of chromo- host lipolysis by disrupting autophagy (46). ESAT-6 perturbs lipid somal DNA and globular protein domains. It traps pathogens and homeostasis and induces foamy macrophages (47). The host fac- prevents their spreading. M. tuberculosis induces ETosis in neu- tor gamma interferon (IFN-) can also promote foamy macro- trophils and macrophages and associates with ETs (22, 23). Ac- phage formation (48). Elevated intracellular lipid levels then cause cordingly, ETosis could generate NECs. macrophage necrosis (49). Since IFN- can promote ESX-1- The discovery of ETs provides a molecular basis of vascular mediated macrophage necrosis (22), it may act in concert with thrombosis (24). An ET induces blood clotting by activating plate- keto-mycolic acid and ESX-1 to induce macrophage necrosis by lets and inducing fibrin and thrombus formation (25). A throm- promoting lipid accumulation. bus contains platelets aggregated within a network of fibrin and Few M. tuberculosis bacteria or a lack of acid-fast mycobacteria chromatin DNA. Infected macrophages in tissues normally do not are found in lipid-rich tuberculous pneumonia (4). Acid fastness encounter blood components, unless blood vessels are damaged. is a physical property of M. tuberculosis’s cell wall. M. tuberculosis In a rabbit model of postprimary TB, tissue-damaging MMP-1 living in a lipid-rich environment loses its acid fastness (50). The activity is responsible for lung damage (26). Such tissue damage mechanism is unclear but may involve dephosphorylation of a key may allow mixing of blood contents with M. tuberculosis-induced enzyme for mycolic acid synthesis (51). Acid-fast-negative M. tu- ETs and trigger thrombosis. At this point, extracellular M. tuber- berculosis is present in sputum of TB patients (19, 52). Acid-fast- culosis can encounter neutrophils and induce necrosis of the in- negative cases account for nearly a third of the ongoing TB trans- fected neutrophils (27). Since M. tuberculosis-infected neutrophils missions in China (53). Half of these TB-transmitting patients do undergo ETosis, this M. tuberculosis-neutrophil interaction may not have cavities (53). We propose that sputum samples from further promote thrombosis and NEC formation (23). these patients contain NECs that originated from tuberculous Thrombosis is associated with TB. Cudkowicz identified pneumonia lesions that are undergoing necrosis and have not yet thrombosis within pulmonary artery branches near tuberculous matured into cavitary lesions. foci in histological autopsy samples of pulmonary TB (28). Vas- TISSUE DAMAGE MEDIATED BY DELAYED-TYPE cular thrombosis has also been observed in patients with postpri- HYPERSENSITIVITY mary TB by Hunter and colleagues (9). Cases of pulmonary TB patients with pulmonary thromboembolism or venous thrombo- Patients with cavitary TB tend to have a stronger reaction to tu- embolism are noted (29–31). Patients with community-based berculin skin test. Canetti indicated that tuberculous lipid pneu- pneumonia also have an elevated risk of thrombosis-related vas- monia is more frequent and more severe in hypersensitive hosts cular diseases (32). Various animal models of TB also show evi- (10). This is a classic example of DTH. Sensitization with repeated dence of vascular thrombosis (33). high doses of heat-killed Mycobacterium bovis generates DTH that Thrombosis can cause airway obstruction, a feature of postpri- triggers cavitation in a postprimary rabbit model of TB (26). M. 2 mbio.asm.org January/February 2016 Volume 7 Issue 1 e01589-15 Perspective tuberculosis trehalose dimycolate and ESAT-6 can induce DTH vage fluid samples (76). M. tuberculosis-specific Th17 cells might (54, 55). DTH is mediated by IFN--producing CD4 T helper localize in tuberculous lesions and escape detection. Alternatively, cell (Th1) cells. IFN- promotes survival of lightly infected mac- heterogeneity of M. tuberculosis strains from different geographic rophages but induces ETosis in heavily infected macrophages (14, regions might generate different Th17 responses. Clinical M. tu- 16, 22). This suggests that infection of lightly infected macro- berculosis isolates secrete different levels of ESAT-6, which induces phages is controlled by IFN--mediated DTH responses, without Th17 differentiation (77). Finally, patients might develop TB which the infection becomes disseminated, as seen in AIDS pa- through a mechanism independent of a DTH response, such as tients. However, the same DTH response in immunocompetent involving Th2 cells that contribute to TB pathogenesis by antago- individuals may help heavily infected macrophages undergo ETo- nizing Th1 responses. sis and help M. tuberculosis persist in a NEC. What is the source of M. tuberculosis that triggers tuberculous The classical view considers IFN- as the sole cytokine medi- lipid pneumonia in postprimary TB? Increasing evidence from ating DTH. The discovery of interleukin-17 (IL-17)-producing T high-burden settings indicates that exogenous reinfection con- (Th17) cells revises this view. Th17 cells develop after initiation of tributes considerably to postprimary TB in adults (78, 79). The DTH mediated by Th1 cells. Excessive and prolonged Th17 re- lymphatic system is a proposed reservoir of latent M. tuberculosis sponses cause tissue damage (56). Th17 cells are implicated in (80, 81) and may provide another source. Either way, deposition human chronic inflammatory lung diseases (57). All these condi- of M. tuberculosis into the upper lobes of lungs can trigger DTH tions are linked to airway obstruction, which can facilitate pneu- pathology toward M. tuberculosis. Skin graft rejection due to DTH monia and cavitation. In mice, Th17 cells play a protective role is associated with neutrophil recruitment and widespread micro- during early M. tuberculosis infection, whereas excessive Th17 re- vascular injury and is mediated by IL-17 and IFN- (82, 83). Im- sponses lead to severe immunopathology and increased M. tuber- munomodulation by mesenchymal stem cells suppresses DTH culosis burden (58–60). This discrepancy may be because, similar and extends skin graft survival (84). This approach shows prom- to IFN-, IL-17’s effect depends on how heavily the macrophages ising results when used as an adjunct therapy to treat drug- are infected. resistant TB (85). It may be possible to treat or prevent postpri- IL-17 is a cytokine that recruits neutrophils. TB patients with mary TB by a host-directed approach that targets DTH. pulmonary cavities have higher neutrophil levels in bronchoal- CONCLUDING REMARKS veolar lavage fluid samples than those without pulmonary cavities Here we present a model of tuberculous pneumonia based on the (61). Inside the pulmonary cavities, there are more neutrophils concept of NEC. Induction of macrophage ETosis by M. tubercu- than macrophages. Also, more than half of the M. tuberculosis losis causes release of intracellular material such as ETs that can bacteria are found associated with neutrophils, compared to less initiate thrombosis. The intracellular material can also interact than a quarter of M. tuberculosis bacteria associated with macro- with M. tuberculosis to form a biofilm-like NEC that is tough to phages (62). If neutrophils encounter an M. tuberculosis NEC, clear by host immunity or antibiotics. The persistent nature of they undergo NETosis (NET stands for neutrophil extracellular NEC might sustain tuberculous pneumonia. DTH responses me- trap) and release more ETs and other extracellular material to diated by IFN- and IL-17 then inflict tissue damage on the lung produce a bigger NEC. NETs have been detected in pulmonary of an individual with pneumonia. Long-term interaction with the cavities and sputum samples from patients with active TB (63). human immune system may have selected for M. tuberculosis bac- This NET contains tissue-degrading MMP-8 that mediates cavi- teria that are efficient at forming NECs for survival and exploiting tation (63). the human DTH for transmission. Accordingly, inhibition of IL-17 stimulates MMP-1 expression from fibroblasts (64, 65). pneumonia and macrophage ETosis caused by M. tuberculosis Sputum MMP-1 activity from patients with TB correlates with should help TB control, as has been shown recently in a mouse lung pathology (66, 67). In the rabbit postprimary TB model, model of pneumonia and TB (86). MMP-1 activity correlates spatially with tissue necrosis and pul- Our NEC model of TB has several implications for developing monary cavitation (26). Transgenic mice expressing human novel therapies for controlling TB. (i) Efforts need to be made to MMP-1 exhibit necrosis of lung tissue and lipid pneumonia upon develop vaccines that prevent the formation of the biofilm caused M. tuberculosis challenge (68). Collectively, Th17 cells may pro- by ET. This might be achieved by developing antibody responses mote cavitation through IL-17-induced MMP-1. that prevent the biofilm formation or target their dissolution. (ii) Th17 differentiation can be promoted by cholesterol crystals We need new chemotherapeutic strategies to kill M. tuberculosis in through NETosis and priming of macrophages for IL-1 produc- a biofilm with drugs that either dissolve the biofilm or kill M. tion (69). Interestingly, diabetes is associated with elevated intra- tuberculosis bacteria that have entered into a persistent state. (iii) cellular cholesterol and primes neutrophils to undergo NETosis Mycobacteriophages may provide attractive therapeutic reagents (70, 71). Diabetes is a risk factor of TB and pulmonary cavitation for killing extracellular M. tuberculosis. (70, 72, 73). ETs are detected in the bronchoalveolar lavage fluid samples from diabetic mice with TB (14). Pulmonary TB patients ACKNOWLEDGMENTS with higher frequencies of Th1 and Th17 cells are more likely to K.-W. Wong was supported by Fudan University, Shanghai Public Health have diabetes (74). It may be possible that M. tuberculosis exploits Clinical Center, and Natural Science Foundation of China grant cholesterol-rich environments to promote NETosis, Th17 differ- 81371777. W. R. Jacobs, Jr., was supported by HHMI and NIH grant entiation, and ultimately, cavitation. AI026170. More Th17 cells were observed in peripheral blood samples We greatly appreciate Douglas Lowrie, Robert Hunter, Hardy Korn- from TB patients than in healthy controls after M. tuberculosis feld, and two anonymous reviewers for their comments and suggestions. antigen stimulation (75). However, similar results were not found We also thank Robert Hunter for bringing our attention to earlier works in another study using peripheral blood and bronchoalveolar la- by R. Virchow, T. Edgington, and H. Dvorak. January/February 2016 Volume 7 Issue 1 e01589-15 mbio.asm.org 3 Perspective 2003. Deletion of RD1 from Mycobacterium tuberculosis mimics bacille FUNDING INFORMATION Calmette-Guerin attenuation. J Infect Dis 187:117–123. http://dx.doi.org/ HHS | National Institutes of Health (NIH) provided funding to William 10.1086/345862. R. Jacobs under grant number AI26170. National Natural Science Foun- 18. Ackart DF, Hascall-Dove L, Caceres SM, Kirk NM, Podell BK, Me- dation of China (NSFC) provided funding to Ka-Wing Wong under grant lander C, Orme IM, Leid JG, Nick JA, Basaraba RJ. 2014. Expression of number 81371777. antimicrobial drug tolerance by attached communities of Mycobacterium tuberculosis. Pathog Dis 70:359 –369. http://dx.doi.org/10.1111/2049 REFERENCES -632X.12144. 1. Comas I, Coscolla M, Luo T, Borrell S, Holt KE, Kato-Maeda M, 19. Orme IM. 2014. A new unifying theory of the pathogenesis of tuberculo- Parkhill J, Malla B, Berg S, Thwaites G, Yeboah-Manu D, Bothamley G, sis. Tuberculosis (Edinb) 94:8 –14. http://dx.doi.org/10.1016/ Mei J, Wei L, Bentley S, Harris SR, Niemann S, Diel R, Aseffa A, Gao j.tube.2013.07.004. Q. 2013. Out-of-Africa migration and Neolithic coexpansion of Mycobac- 20. Branzk N, Lubojemska A, Hardison SE, Wang Q, Gutierrez MG, Brown terium tuberculosis with modern humans. Nat Genet 45:1176 –1182. GD, Papayannopoulos V. 2014. Neutrophils sense microbe size and se- http://dx.doi.org/10.1038/ng.2744. lectively release neutrophil extracellular traps in response to large patho- 2. World Health Organization. 2013. Global tuberculosis report 2013. gens. Nat Immunol 15:1017–1025. http://dx.doi.org/10.1038/ni.2987. World Health Organization, Geneva, Switzerland. 21. Brinkmann V, Zychlinsky A. 2012. Neutrophil extracellular traps: is im- 3. Hunter RL. 2011. Pathology of post primary tuberculosis of the lung: an munity the second function of chromatin? J Cell Biol 198:773–783. http:// illustrated critical review. Tuberculosis (Edinb) 91:497–509. http:// dx.doi.org/10.1083/jcb.201203170. dx.doi.org/10.1016/j.tube.2011.03.007. 22. Wong KW, Jacobs WR, Jr. 2013. Mycobacterium tuberculosis exploits 4. Hunter RL, Actor JK, Hwang SA, Karev V, Jagannath C. 2014. Patho- human interferon gamma to stimulate macrophage extracellular trap for- genesis of post primary tuberculosis: immunity and hypersensitivity in the mation and necrosis. J Infect Dis 208:109 –119. http://dx.doi.org/10.1093/ development of cavities. Ann Clin Lab Sci 44:365–387. infdis/jit097. 5. Auld SC, Click ES, Heilig CM, Miramontes R, Cain KP, Bisson GP, 23. Ramos-Kichik V, Mondragón-Flores R, Mondragón-Castelán M, MacKenzie WR. 2013. Association between tuberculin skin test result and Gonzalez-Pozos S, Muñiz-Hernandez S, Rojas-Espinosa O, Chacón- clinical presentation of tuberculosis disease. BMC Infect Dis 13:460. Salinas R, Estrada-Parra S, Estrada-García I. 2009. Neutrophil extracel- http://dx.doi.org/10.1186/1471-2334-13-460. lular traps are induced by Mycobacterium tuberculosis. Tuberculosis (Ed- 6. Casadevall A, Pirofski LA. 2014. Microbiology: ditch the term pathogen. inb) 89:29 –37. http://dx.doi.org/10.1016/j.tube.2008.09.009. Nature 516:165–166. http://dx.doi.org/10.1038/516165a. 24. Engelmann B, Massberg S. 2013. Thrombosis as an intravascular effector 7. Duque-Correa MA, Kuhl AA, Rodriguez PC, Zedler U, Schommer- of innate immunity. Nat Rev Immunol 13:34 – 45. http://dx.doi.org/ Leitner S, Rao M, Weiner J, Hurwitz R, Qualls JE, Kosmiadi GA, 10.1038/nri3345. Murray PJ, Kaufmann SHE, Reece ST. 2014. Macrophage arginase-1 25. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers controls bacterial growth and pathology in hypoxic tuberculosis granulo- DD, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD. 2010. mas. Proc Natl Acad SciUSA 111:E4024 –E4032. http://dx.doi.org/ Extracellular DNA traps promote thrombosis. Proc Natl Acad SciUSA 10.1073/pnas.1408839111. 107:15880 –15885. http://dx.doi.org/10.1073/pnas.1005743107. 8. Lin PL, Ford CB, Coleman MT, Myers AJ, Gawande R, Ioerger T, 26. Kübler A, Luna B, Larsson C, Ammerman NC, Andrade BB, Orandle Sacchettini J, Fortune SM, Flynn JL. 2014. Sterilization of granulomas is M, Bock KW, Xu Z, Bagci U, Molura DJ, Marshall J, Burns J, Winglee common in active and latent tuberculosis despite within-host variability K, Ahidjo BA, Cheung LS, Klunk M, Jain SK, Kumar NP, Babu S, Sher in bacterial killing. Nat Med 20:75–79. http://dx.doi.org/10.1038/ A. 2015. Mycobacterium tuberculosis dysregulates MMP/TIMP balance nm.3412. to drive rapid cavitation and unrestrained bacterial proliferation. J Pathol 9. Hunter RL, Jagannath C, Actor JK. 2007. Pathology of postprimary 235:431– 444. http://dx.doi.org/10.1002/path.4432. tuberculosis in humans and mice: contradiction of long-held beliefs. 27. Corleis B, Korbel D, Wilson R, Bylund J, Chee R, Schaible UE. 2012. Tuberculosis (Edinb) 87:267–278. http://dx.doi.org/10.1016/ Escape of Mycobacterium tuberculosis from oxidative killing by neutro- j.tube.2006.11.003. phils. Cell Microbiol 14:1109 –1121. http://dx.doi.org/10.1111/j.1462 10. Canetti G. 1955. The tubercle bacillus in the pulmonary lesion of man. -5822.2012.01783.x. Histobacteriology and its bearing on the therapy of pulmonary tubercu- 28. Cudkowicz L. 1952. The blood supply of the lung in pulmonary tubercu- losis. Springer Publishing Company, New York, NY. losis. Thorax 7:270 –276. http://dx.doi.org/10.1136/thx.7.3.270. 11. Rich AR. 1951. The pathogenesis of tuberculosis, 2nd ed. Charles C 29. Goncalves IM, Alves D, Carvalho A, do Ceu Brito M, Calvario F, Thomas, Springfield, IL. http://dx.doi.org/10.1097/00007611-194410000 Duarte R. 2009. Tuberculosis and venous thromboembolism: a case se- -00018. ries. Cases J 2:9333. http://dx.doi.org/10.1186/1757-1626-2-9333. 12. Lando PA, Edgington TS. 1985. An innate host response to the neoplastic 30. Komazaki Y, Sakakibara Y, Sakashita H, Miyazaki Y, Inase N. 2011. cell: syngeneic rat tumor cells can elicit a rapid de novo lymphoid proco- Pulmonary thromboembolism with pulmonary tuberculosis. Kekkaku 86: agulant response. J Immunol 135:3587–3595. 717–722. (In Japanese.) 13. Welin A, Eklund D, Stendahl O, Lerm M. 2011. Human macrophages 31. Sharif-Kashani B, Bikdeli B, Moradi A, Tabarsi P, Chitsaz E, Shemirani infected with a high burden of ESAT-6-expressing M. tuberculosis un- S, Esmaili-Khansari M, Masjedi M. 2010. Coexisting venous thrombo- dergo caspase-1- and cathepsin B-independent necrosis. PLoS One embolism in patients with tuberculosis. Thromb Res 125:478 – 480. http:// 6:e20302. http://dx.doi.org/10.1371/journal.pone.0020302. dx.doi.org/10.1016/j.thromres.2010.01.014. 14. Repasy T, Lee J, Marino S, Martinez N, Kirschner DE, Hendricks G, 32. Violi F, Cangemi R, Calvieri C. 2014. Pneumonia, thrombosis and vas- Baker S, Wilson AA, Kotton DN, Kornfeld H. 2013. Intracellular cular disease. J Thromb Haemost 12:1391–1400. http://dx.doi.org/ bacillary burden reflects a burst size for Mycobacterium tuberculosis in 10.1111/jth.12646. vivo. PLoS Pathog 9:e1003190. http://dx.doi.org/10.1371/ 33. Basaraba RJ. 2008. Experimental tuberculosis: the role of comparative journal.ppat.1003190. pathology in the discovery of improved tuberculosis treatment strategies. 15. Hsu T, Hingley-Wilson SM, Chen B, Chen M, Dai AZ, Morin PM, Tuberculosis (Edinb) 88:S35–S47. http://dx.doi.org/10.1016/S1472 Marks CB, Padiyar J, Goulding C, Gingery M, Eisenberg D, Russell RG, -9792(08)70035-0. Derrick SC, Collins FM, Morris SL, King CH, Jacobs WR. 2003. The 34. Calderon VE, Valbuena G, Goez Y, Judy BM, Huante MB, Sutjita P, primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of Johnston RK, Estes DM, Hunter RL, Actor JK, Cirillo JD, Endsley JJ. secreted lytic function required for invasion of lung interstitial tissue. Proc 2013. A humanized mouse model of tuberculosis. PLoS One 8:e63331. Natl Acad SciUSA 100:12420 –12425. http://dx.doi.org/10.1073/ http://dx.doi.org/10.1371/journal.pone.0063331. pnas.1635213100. 35. Hunter RL. 2011. On the pathogenesis of post primary tuberculosis: the 16. Lee J, Repasy T, Papavinasasundaram K, Sassetti C, Kornfeld H. 2011. Mycobacterium tuberculosis induces an atypical cell death mode to escape role of bronchial obstruction in the pathogenesis of cavities. Tuberculosis from infected macrophages. PLoS One 6:e18367. http://dx.doi.org/ (Edinb) 91(Suppl 1):S6 –S10. http://dx.doi.org/10.1016/ 10.1371/journal.pone.0018367. j.tube.2011.10.003. 17. Lewis K, Liao R, Guinn K, Hickey M, Smith S, Behr M, Sherman D. 36. Arney KL, Judson MA, Sahn SA. 1999. Airway obstruction arising from 4 mbio.asm.org January/February 2016 Volume 7 Issue 1 e01589-15 Perspective blood clot: three reports and a review of the literature. Chest 115:293–300. Mycobacterium tuberculosis. PLoS Pathog 10:e1004115. http:// http://dx.doi.org/10.1378/chest.115.1.293. dx.doi.org/10.1371/journal.ppat.1004115. 37. Narayana Moorthy A, Narasaraju T, Rai P, Perumalsamy R, Tan KB, 52. Garton NJ, Waddell SJ, Sherratt AL, Lee S, Smith RJ, Senner C, Hinds Wang S, Engelward B, Chow VTK. 2013. In vivo and in vitro studies on J, Rajakumar K, Adegbola RA, Besra GS, Butcher PD, Barer MR. 2008. the roles of neutrophil extracellular traps during secondary pneumococcal Cytological and transcript analyses reveal fat and lazy persister-like bacilli pneumonia after primary pulmonary influenza infection. Front Immunol in tuberculous sputum. PLoS Med 5:e75. http://dx.doi.org/10.1371/ 4:56. http://dx.doi.org/10.3389/fimmu.2013.00056. journal.pmed.0050075. 38. Dwyer M, Shan Q, D’Ortona S, Maurer R, Mitchell R, Olesen H, Thiel 53. Yang C, Shen X, Peng Y, Lan R, Zhao Y, Long B, Luo T, Sun G, Li X, S, Huebner J, Gadjeva M. 2014. Cystic fibrosis sputum DNA has NETosis Qiao K, Gui X, Wu J, Xu J, Li F, Li D, Liu F, Shen M, Hong J, Mei J, characteristics and neutrophil extracellular trap release is regulated by DeRiemer K. 2015. Transmission of Mycobacterium tuberculosis in macrophage migration-inhibitory factor. J Innate Immun 6:765–779. China: a population-based molecular epidemiologic study. Clin Infect Dis http://dx.doi.org/10.1159/000363242. 61:219 –227. http://dx.doi.org/10.1093/cid/civ255. 39. Hamaguchi S, Seki M, Yamamoto N, Hirose T, Matsumoto N, Irisawa 54. Pollock JM, McNair J, Bassett H, Cassidy JP, Costello E, Aggerbeck H, T, Takegawa R, Shimazu T, Tomono K. 2012. Case of invasive non- Rosenkrands I, Andersen P. 2003. Specific delayed-type hypersensitivity typable Haemophilus influenzae respiratory tract infection with a large responses to ESAT-6 identify tuberculosis-infected cattle. J Clin Microbiol quantity of neutrophil extracellular traps in sputum. J Inflamm Res 41:1856 –1860. http://dx.doi.org/10.1128/JCM.41.5.1856-1860.2003. 5:137–140. http://dx.doi.org/10.2147/JIR.S39497. 55. Yamagami H, Matsumoto T, Fujiwara N, Arakawa T, Kaneda K, Yano 40. Via LE, Weiner DM, Schimel D, Lin PL, Dayao E, Tankersley SL, Cai I, Kobayashi K. 2001. Trehalose 6,6=-dimycolate (cord factor) of Myco- Y, Coleman MT, Tomko J, Paripati P, Orandle M, Kastenmayer RJ, bacterium tuberculosis induces foreign-body- and hypersensitivity-type Tartakovsky M, Rosenthal A, Portevin D, Eum SY, Lahouar S, Gagneux granulomas in mice. Infect Immun 69:810 – 815. http://dx.doi.org/ S, Young DB, Flynn JL. 2013. Differential virulence and disease progres- 10.1128/IAI.69.2.810-815.2001. sion following Mycobacterium tuberculosis complex infection of the 56. Steinman L. 2007. A brief history of T(H)17, the first major revision in the common marmoset (Callithrix jacchus). Infect Immun 81:2909 –2919. T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 13: http://dx.doi.org/10.1128/IAI.00632-13. 139 –145. http://dx.doi.org/10.1038/nm1551. 41. Kim M, Wainwright HC, Locketz M, Bekker L, Walther GB, Dittrich C, 57. Weaver CT, Elson CO, Fouser LA, Kolls JK. 2013. The Th17 pathway Visser A, Wang W, Hsu F, Wiehart U, Tsenova L, Kaplan G, Russell and inflammatory diseases of the intestines, lungs, and skin. Annu Rev DG. 2010. Caseation of human tuberculosis granulomas correlates with Pathol 8:477–512. http://dx.doi.org/10.1146/annurev-pathol-011110 elevated host lipid metabolism. EMBO Mol Med 2:258 –274. http:// -130318. dx.doi.org/10.1002/emmm.201000079. 58. Kozakiewicz L, Chen Y, Xu J, Wang Y, Dunussi-Joannopoulos K, Ou Q, 42. Dkhar HK, Nanduri R, Mahajan S, Dave S, Saini A, Somavarapu AK, Flynn JL, Porcelli SA, Jacobs WR, Chan J. 2013. B cells regulate neutro- Arora A, Parkesh R, Thakur KG, Mayilraj S, Gupta P. 2014. Mycobac- philia during Mycobacterium tuberculosis infection and BCG vaccination terium tuberculosis keto-mycolic acid and macrophage nuclear receptor by modulating the interleukin-17 response. PLoS Pathog 9:e1003472. TR4 modulate foamy biogenesis in granulomas: a case of a heterologous http://dx.doi.org/10.1371/journal.ppat.1003472. and noncanonical ligand-receptor pair. J Immunol 193:295–305. http:// 59. Cruz A, Fraga AG, Fountain JJ, Rangel-Moreno J, Torrado E, Saraiva dx.doi.org/10.4049/jimmunol.1400092. M, Pereira DR, Randall TD, Pedrosa J, Cooper AM, Castro AG. 2010. 43. Peyron P, Vaubourgeix J, Poquet Y, Levillain F, Botanch C, Bardou F, Pathological role of interleukin 17 in mice subjected to repeated BCG Daffé M, Emile J, Marchou B, Cardona P, de Chastellier C, Altare F. vaccination after infection with Mycobacterium tuberculosis. J Exp Med 2008. Foamy macrophages from tuberculous patients’ granulomas consti- 207:1609 –1616. http://dx.doi.org/10.1084/jem.20100265. tute a nutrient-rich reservoir for M. tuberculosis persistence. PLoS Pathog 60. Desvignes L, Ernst JD. 2009. Interferon-gamma-responsive nonhemato- 4:e1000204. http://dx.doi.org/10.1371/journal.ppat.1000204. poietic cells regulate the immune response to Mycobacterium tuberculo- 44. Podinovskaia M, Lee W, Caldwell S, Russell DG. 2013. Infection of sis. Immunity 31:974 –985. http://dx.doi.org/10.1016/ macrophages with Mycobacterium tuberculosis induces global modifica- j.immuni.2009.10.007. tions to phagosomal function. Cell Microbiol 15:843– 859. http:// 61. Nolan A, Condos R, Huie ML, Dawson R, Dheda K, Bateman E, Rom dx.doi.org/10.1111/cmi.12092. WN, Weiden MD. 2013. Elevated IP-10 and IL-6 from bronchoalveolar 45. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, lavage cells are biomarkers of non-cavitary tuberculosis. Int J Tuberc Lung Cuervo AM, Czaja MJ. 2009. Autophagy regulates lipid metabolism. Dis 17:922–927. http://dx.doi.org/10.5588/ijtld.12.0610. Nature 458:1131–1135. http://dx.doi.org/10.1038/nature07976. 62. Eum S. 2010. Neutrophils are the predominant infected phagocytic cells in 46. Romagnoli A, Etna MP, Giacomini E, Pardini M, Remoli ME, Corazzari the airways of patients with active pulmonary TB. Chest 137:122–128. M, Falasca L, Goletti D, Gafa V, Simeone R, Delogu G, Piacentini M, http://dx.doi.org/10.1378/chest.09-0903. Brosch R, Fimia GM, Coccia EM. 2012. ESX-1 dependent impairment of 63. Ong CWM, Elkington PT, Brilha S, Ugarte-Gil C, Tome-Esteban MT, autophagic flux by Mycobacterium tuberculosis in human dendritic cells. Tezera LB, Pabisiak PJ, Moores RC, Sathyamoorthy T, Patel V, Gilman Autophagy 8:1357–1370. http://dx.doi.org/10.4161/auto.20881. RH, Porter JC, Friedland JS. 2015. Neutrophil-derived MMP-8 drives 47. Singh V, Jamwal S, Jain R, Verma P, Gokhale R, Rao KS. 2012. AMPK-dependent matrix destruction in human pulmonary tuberculosis. Mycobacterium tuberculosis-driven targeted recalibration of macrophage PLoS Pathog 11:e1004917. http://dx.doi.org/10.1371/ lipid homeostasis promotes the foamy phenotype. Cell Host Microbe 12: journal.ppat.1004917. 669 – 681. http://dx.doi.org/10.1016/j.chom.2012.09.012. 64. Wu Y, Zhu L, Liu L, Zhang J, Peng B. 2014. Interleukin-17A stimulates 48. Michael DR, Ashlin TG, Davies CS, Gallagher H, Stoneman TW, migration of periodontal ligament fibroblasts via p38 MAPK/NF-kappaB- Buckley ML, Ramji DP. 2013. Differential regulation of macropinocyto- dependent MMP-1 expression. J Cell Physiol 229:292–299. http:// sis in macrophages by cytokines: implications for foam cell formation and dx.doi.org/10.1002/jcp.24444. atherosclerosis. Cytokine 64:357–361. http://dx.doi.org/10.1016/ 65. Cortez DM, Feldman MD, Mummidi S, Valente AJ, Steffensen B, j.cyto.2013.05.016. Vincenti M, Barnes JL, Chandrasekar B. 2007. IL-17 stimulates MMP-1 49. Tabas I. 2002. Consequences of cellular cholesterol accumulation: basic expression in primary human cardiac fibroblasts via p38 MAPK- and concepts and physiological implications. J Clin Invest 110:905–911. http:// ERK1/2-dependent C/EBP-beta, NF-kappaB, and AP-1 activation. Am J dx.doi.org/10.1172/JCI0216452. Physiol Heart Circ Physiol 293:H3356 –H3365. 50. Daniel J, Maamar H, Deb C, Sirakova TD, Kolattukudy PE. 2011. 66. Nayak L, Tunga H, De RK. 2013. Disease co-morbidity and the human Mycobacterium tuberculosis uses host triacylglycerol to accumulate lipid Wnt signaling pathway: a network-wise study. Omics 17:318 –337. http:// droplets and acquires a dormancy-like phenotype in lipid-loaded macro- dx.doi.org/10.1089/omi.2012.0053. phages. PLoS Pathog 7:e1002093. http://dx.doi.org/10.1371/ 67. Seddon J, Kasprowicz V, Walker NF, Yuen HM, Sunpath H, Tezera L, journal.ppat.1002093. Meintjes G, Wilkinson RJ, Bishai WR, Friedland JS, Elkington PT. 2013. 51. Vilchèze C, Molle V, Carrère-Kremer S, Leiba J, Mourey L, Shenai S, Procollagen III N-terminal propeptide and desmosine are released by ma- Baronian G, Tufariello J, Hartman T, Veyron-Churlet R, Trivelli X, trix destruction in pulmonary tuberculosis. J Infect Dis 208:1571–1579. Tiwari S, Weinrick B, Alland D, Guérardel Y, Jacobs WR, Kremer L. http://dx.doi.org/10.1093/infdis/jit343. 2014. Phosphorylation of KasB regulates virulence and acid-fastness in 68. Elkington P, Shiomi T, Breen R, Nuttall RK, Ugarte-Gil CA, Walker January/February 2016 Volume 7 Issue 1 e01589-15 mbio.asm.org 5 Perspective NF, Saraiva L, Pedersen B, Mauri F, Lipman M, Edwards DR, Robert- 78. Marx FM, Dunbar R, Enarson DA, Williams BG, Warren RM, van der son BD, D’Armiento J, Friedland JS. 2011. MMP-1 drives immunopa- Spuy GD, van Helden PD, Beyers N. 2014. The temporal dynamics of thology in human tuberculosis and transgenic mice. J Clin Invest 121: relapse and reinfection tuberculosis after successful treatment: a retro- 1827–1833. http://dx.doi.org/10.1172/JCI45666. spective cohort study. Clin Infect Dis 58:1676 –1683. http://dx.doi.org/ 69. Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. 2015. Inflam- 10.1093/cid/ciu186. mation. Neutrophil extracellular traps license macrophages for cytokine 79. Shen G, Xue Z, Shen X, Sun B, Gui X, Shen M, Mei J, Gao Q. 2006. production in atherosclerosis. Science 349:316 –320. http://dx.doi.org/ Recurrent tuberculosis and exogenous reinfection, Shanghai, China. 10.1126/science.aaa8064. Emerg Infect Dis 12:1776 –1778. http://dx.doi.org/10.3201/ 70. Martinez N, Kornfeld H. 2014. Diabetes and immunity to tuberculosis. eid1211.051207. Eur J Immunol 44:617– 626. http://dx.doi.org/10.1002/eji.201344301. 80. Behr MA, Waters WR. 2014. Is tuberculosis a lymphatic disease with a 71. Wong SL, Demers M, Martinod K, Gallant M, Wang Y, Goldfine AB, pulmonary portal? Lancet Infect Dis 14:250 –255. http://dx.doi.org/ Kahn CR, Wagner DD. 2015. Diabetes primes neutrophils to undergo 10.1016/S1473-3099(13)70253-6. NETosis, which impairs wound healing. Nat Med 21:815– 819. http:// 81. Das B, Kashino SS, Pulu I, Kalita D, Swami V, Yeger H, Felsher DW, dx.doi.org/10.1038/nm.3887. Campos-Neto A. 2013. CD271() bone marrow mesenchymal stem cells 72. Chen H, Liu M, Jiang S, Gu F, Huang S, Gao T, Zhang Z. 2014. Impact may provide a niche for dormant Mycobacterium tuberculosis. Sci Transl of diabetes on diagnostic delay for pulmonary tuberculosis in Beijing. Int Med 5:170ra13. http://dx.doi.org/10.1126/scitranslmed.3004912. J Tuberc Lung Dis 18:267–271. http://dx.doi.org/10.5588/ijtld.13.0140. 82. Dvorak HF. 1979. Rejection of first-set skin allografts in man. The micro- 73. Park SW, Shin JW, Kim JY, Park IW, Choi BW, Choi JC, Kim YS. 2012. The effect of diabetic control status on the clinical features of pulmonary vasculature is the critical target of the immune response. J Exp Med 150: tuberculosis. Eur J Clin Microbiol Infect Dis 31:1305–1310. http:// 322–337. http://dx.doi.org/10.1084/jem.150.2.322. dx.doi.org/10.1007/s10096-011-1443-3. 83. Rajesh D, Zhou Y, Jankowska-Gan E, Roenneburg DA, Dart ML, 74. Kumar NP, Sridhar R, Banurekha VV, Jawahar MS, Nutman TB, Babu Torrealba J, Burlingham WJ. 2010. Th1 and Th17 immunocompetence S. 2013. Expansion of pathogen-specific T-helper 1 and T-helper 17 cells in humanized NOD/SCID/IL2rgammanull mice. Hum Immunol 71: in pulmonary tuberculosis with coincident type 2 diabetes mellitus. J In- 551–559. http://dx.doi.org/10.1016/j.humimm.2010.02.019. fect Dis 208:739 –748. http://dx.doi.org/10.1093/infdis/jit241. 84. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, 75. Cowan J, Pandey S, Filion LG, Angel JB, Kumar A, Cameron DW. Hardy W, Devine S, Ucker D, Deans R, Moseley A, Hoffman R. 2002. 2012. Comparison of interferon-gamma-, interleukin (IL)-17- and IL- Mesenchymal stem cells suppress lymphocyte proliferation in vitro and 22-expressing CD4 T cells, IL-22-expressing granulocytes and proin- prolong skin graft survival in vivo. Exp Hematol 30:42– 48. http:// flammatory cytokines during latent and active tuberculosis infection. dx.doi.org/10.1016/S0301-472X(01)00769-X. Clin Exp Immunol 167:317–329. http://dx.doi.org/10.1111/j.1365 85. Skrahin A, Ahmed RK, Ferrara G, Rane L, Poiret T, Isaikina Y, Skrahina -2249.2011.04520.x. A, Zumla A, Maeurer MJ. 2014. Autologous mesenchymal stromal cell 76. Perreau M, Rozot V, Welles HC, Belluti-Enders F, Vigano S, Maillard infusion as adjunct treatment in patients with multidrug and extensively M, Dorta G, Mazza-Stalder J, Bart P, Roger T, Calandra T, Nicod L, drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Re- Harari A. 2013. Lack of Mycobacterium tuberculosis-specific interleukin- spir Med 2:108 –122. http://dx.doi.org/10.1016/S2213-2600(13)70234-0. 17A-producing CD4 T cells in active disease. Eur J Immunol 43: 86. Amaral EP, Ribeiro SCM, Lanes VR, Almeida FM, de Andrade MRM, 939 –948. http://dx.doi.org/10.1002/eji.201243090. Bomfim CCB, Salles ÉM, Bortoluci KR, Coutinho-Silva R, Hirata MH, 77. Solans L, Aguilo N, Samper S, Pawlik A, Frigui W, Martin C, Brosch R, Alvarez JM, Lasunskaia EB, D’Império-Lima MR. 2014. Pulmonary Gonzalo-Asensio J. 2014. A specific polymorphism in Mycobacterium tuberculosis H37Rv causes differential ESAT-6 expression and identifies infection with hypervirulent mycobacteria reveals a crucial role for the WhiB6 as a novel ESX-1 component. Infect Immun 82:3446 –3456. http:// P2X7 receptor in aggressive forms of tuberculosis. 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