Understanding the tuberculosis granuloma: the matrix revolutions
2021; Elsevier BV; Volume: 28; Issue: 2 Linguagem: Inglês
10.1016/j.molmed.2021.11.004
ISSN1471-499X
AutoresPaul Elkington, Marta E. Polak, Michaela T. Reichmann, Alasdair Leslie,
Tópico(s)Diagnosis and treatment of tuberculosis
ResumoClinical observations and data from immunomodulatory biologic therapies highlight the complexity of the host–pathogen relationship in human tuberculosis (TB), with both insufficient and excessive immune responses leading to disease.Multiple lines of evidence, in humans and animal models, indicate that local factors within each TB lesion govern the outcome; progression and regression can occur simultaneously.Unbiased analyses of co-expressed gene networks demonstrate the role of excessive inflammation in driving TB pathology.Degradation of the extracellular matrix, in particular by the collagenase matrix metalloproteinase-1, has emerged as a key pathological event in TB from diverse approaches. Mycobacterium tuberculosis (Mtb) causes the human disease tuberculosis (TB) and remains the top global infectious pandemic after coronavirus disease 2019 (COVID-19). Furthermore, TB has killed many more humans than any other pathogen, after prolonged coevolution to optimise its pathogenic strategies. Full understanding of fundamental disease processes in humans is necessary to successfully combat this highly successful pathogen. While the importance of immunodeficiency has been long recognised, biologic therapies and unbiased approaches are providing unprecedented insights into the intricacy of the host–pathogen interaction. The nature of a protective response is more complex than previously hypothesised. Here, we integrate recent evidence from human studies and unbiased approaches to consider how Mtb causes human TB and highlight the recurring theme of extracellular matrix (ECM) turnover. Mycobacterium tuberculosis (Mtb) causes the human disease tuberculosis (TB) and remains the top global infectious pandemic after coronavirus disease 2019 (COVID-19). Furthermore, TB has killed many more humans than any other pathogen, after prolonged coevolution to optimise its pathogenic strategies. Full understanding of fundamental disease processes in humans is necessary to successfully combat this highly successful pathogen. While the importance of immunodeficiency has been long recognised, biologic therapies and unbiased approaches are providing unprecedented insights into the intricacy of the host–pathogen interaction. The nature of a protective response is more complex than previously hypothesised. Here, we integrate recent evidence from human studies and unbiased approaches to consider how Mtb causes human TB and highlight the recurring theme of extracellular matrix (ECM) turnover. TB is a chronic and persistent human killer, causing more deaths in total over time than any other pathogen and, currently, is the most important infection after COVID-19. Furthermore, the TB pandemic is likely to worsen due to resources being diverted to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) control [1.Cilloni L. et al.The potential impact of the COVID-19 pandemic on the tuberculosis epidemic a modelling analysis.EClinicalMedicine. 2020; 28100603Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. The causative organism, Mtb, has undergone long-term coevolution with humans and is an obligate human pathogen [2.Brites D. Gagneux S. Co-evolution of Mycobacterium tuberculosis and Homo sapiens.Immunol. Rev. 2015; 264: 6-24Crossref PubMed Scopus (152) Google Scholar]. Although there have been significant steps forward, such as new antibiotics for drug-resistant disease, the GeneXpert for rapid diagnosis [3.Walzl G. et al.Tuberculosis: advances and challenges in development of new diagnostics and biomarkers.Lancet Infect. 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The White Plague: Tuberculosis, Man, and Society. Rutgers University Press, 1987Google Scholar]. A recently emerging theme from unbiased analyses is that ECM turnover is a cardinal feature of human TB, which is well described clinically. Here, we consider human TB in light of these emerging phenomena and the accumulating omics data sets, interpreting these findings alongside clinical characteristics of disease. The Mtb human life cycle involves multiple stages and ironically for such a successful pathogen, Mtb usually reaches a dead end in most humans, failing to transmit to a new host (Figure 1) [12.Ernst J.D. The immunological life cycle of tuberculosis.Nat. Rev. Immunol. 2012; 12: 581-591Crossref PubMed Scopus (347) Google Scholar,13.Elkington P.T. Friedland J.S. Permutations of time and place in tuberculosis.Lancet Infect. Dis. 2015; 15: 1357-1360Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. Infection is spread by aerosol from an individual with pulmonary TB, and those with lung cavities (see Glossary) are the most infectious and drive the epidemic [14.Urbanowski M.E. et al.Cavitary tuberculosis: the gateway of disease transmission.Lancet Infect. Dis. 2020; 20: e117-e128Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Therefore, for efficient transmission, Mtb must cause immunopathology and lung matrix destruction at the apices of the lung to exit the host and spread onward [15.Elkington P.T. et al.Tuberculosis immunopathology: the neglected role of extracellular matrix destruction.Sci. Transl. Med. 2011; 3: 71ps6Crossref PubMed Scopus (68) Google Scholar]. In addition, recent PET-CT data suggest that propagation of TB within the lung starts with cavitation, followed by the seeding of new infection foci via bronchial spread [16.Chen R.Y. et al.Radiological and functional evidence of the bronchial spread of tuberculosis: an observational analysis.Lancet Microbe. 2021; 2: e518-e526Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. Therefore, cavitation appears to be central for disease progression within the host as well as onward transmission in the population. In initial infection, Mtb aerosol droplets are typically inhaled to the well-ventilated lower lobes and phagocytosed by alveolar macrophages, although definitive proof in humans is difficult to obtain and not all early lesions are basal. Alveolar macrophages are poor at controlling Mtb [17.Cohen S.B. et al.Alveolar macrophages provide an early Mycobacterium tuberculosis niche and initiate dissemination.Cell Host Microbe. 2018; 24: 439-446 e4Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar], and an initial proliferation generates a large focus of infected cells, often over 5 mm in diameter, as demonstrated by the Ghon focus in the lung base [18.Ghon A. The Primary Lung Focus of Tuberculosis in Children. Churchill, London1916Google Scholar]. During this period, Mtb proliferation is unrestricted by an adaptive host immune response, and it uses a variety of evasion capabilities to proliferate within a range of phagocytes, such as inhibiting phagolysosomal fusion [19.O'Garra A. et al.The immune response in tuberculosis.Annu. Rev. Immunol. 2013; 31: 475-527Crossref PubMed Scopus (824) Google Scholar]. Subsequently, at around 6 weeks, a T cell response develops, which is delayed relative to other respiratory pathogens [20.Ravesloot-Chavez M.M. et al.The innate immune response to Mycobacterium tuberculosis infection.Annu. Rev. Immunol. 2021; 39: 611-637Crossref PubMed Scopus (9) Google Scholar] but ultimately leads to more efficacious control of Mtb. By this stage, Mtb needs to have spread to the lung apex, from where it will exit and restart the infectious cycle [13.Elkington P.T. Friedland J.S. Permutations of time and place in tuberculosis.Lancet Infect. Dis. 2015; 15: 1357-1360Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. How Mtb travels from the lung base to apex is unknown [21.Murray J.F. Bill Dock and the location of pulmonary tuberculosis: how bed rest might have helped consumption.Am. J. Respir. Crit. Care Med. 2003; 168: 1029-1033Crossref PubMed Scopus (24) Google Scholar], although it is likely that infected phagocytes act as Trojan horses carrying the mycobacteria [22.Davis J.M. Ramakrishnan L. The role of the granuloma in expansion and dissemination of early tuberculous infection.Cell. 2009; 136: 37-49Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar,23.Schreiber H.A. et al.Inflammatory dendritic cells migrate in and out of transplanted chronic mycobacterial granulomas in mice.J. Clin. Invest. 2011; 121: 3902-3913Crossref PubMed Scopus (44) Google Scholar]. In patients who never develop an adaptive response, Mtb disseminates throughout the body [24.Dheda K. et al.Tuberculosis.Lancet. 2016; 387: 1211-1226Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar], with miliary TB nodules across the chest X-ray and in other organs, as described as early as 1700 by Manget [11.Dubos R. Dubos J. The White Plague: Tuberculosis, Man, and Society. Rutgers University Press, 1987Google Scholar]. This suggests that Mtb spreads extensively, with the goal of forming a niche in the upper lung, where factors favour persistence over immune eradication. Seminal postmortem studies by Opie confirmed Mtb survival in apical lung lesions in otherwise healthy individuals [25.Opie E.L. Aronson J.D. Tubercle bacilli in latent tuberculous lesions and in lung tissue without tuberculous lesions.Arch. Pathol. Lab. Med. 1927; 4: 1-21Google Scholar]. From this niche, Mtb must then cause inflammation, immunopathology, and cavitation to transmit and, although this can happen at any point, most cases reactivate in the first 2 years after infection [26.Behr M.A. et al.Revisiting the timetable of tuberculosis.BMJ. 2018; 362k2738Crossref PubMed Scopus (172) Google Scholar]. With this time frame, disease evolution is typically a slow process, and changes in the peripheral transcriptome can be detected many months before presentation of active disease [27.Scriba T.J. et al.Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease.PLoS Pathog. 2017; 13e1006687Crossref PubMed Scopus (114) Google Scholar]. As the T cell response develops, Mtb needs to change strategy to reflect the more hostile environment of the host. The recent unpublished identification of changes in Mtb metabolism in response to IFN-γ gives some insight into these events. In sensing host IFN-γ, Mtb is able to change its metabolic rate and transcriptional programme, suggesting that it can respond to host immunological cues [28.Ahmed M. et al.Mycobacterium tuberculosis senses host interferon-γ via the membrane protein MmpL10.bioRxiv. 2021; (Published online November 12, 2021)https://doi.org/10.1101/2021.11.12.468344Google Scholar]. Once into this second phase of the host–pathogen interaction, Mtb must survive on a tightrope, ultimately needing to drive a host immune response that leads to cavitation while avoiding an effective immune response that causes its eradication. The critical structure during this 'post-primary' stage is the granuloma (Figure 2) [29.Pagan A.J. Ramakrishnan L. The formation and function of granulomas.Annu. Rev. Immunol. 2018; 36: 639-665Crossref PubMed Scopus (111) Google Scholar]. This was historically thought to be restrictive to Mtb growth, but such concepts of granuloma function and structure have been questioned recently. For example, key studies in the Mycobacterium marinum/zebrafish model have shown that recruitment of monocytes to the granuloma can favour pathogen proliferation [22.Davis J.M. Ramakrishnan L. The role of the granuloma in expansion and dissemination of early tuberculous infection.Cell. 2009; 136: 37-49Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar,30.Cambier C.J. et al.Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids.Nature. 2014; 505: 218-222Crossref PubMed Scopus (298) Google Scholar]. Indeed, in the same model system, limiting the formation of epithelioid macrophages, which help to wall off the granuloma, in fact helps to limit mycobacterial growth by allowing immune cells access to the granuloma [31.Cronan M.R. et al.Macrophage epithelial reprogramming underlies mycobacterial granuloma formation and promotes infection.Immunity. 2016; 45: 861-876Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar]. In addition, the traditional 'sphere-like' structure of granulomas has been questioned by micro-CT approaches, which suggest a more complex root-like structure of interconnected areas [32.Wells G. et al.Micro-computed tomography analysis of the human tuberculous lung reveals remarkable heterogeneity in 3D granuloma morphology.Am. J. Respir. Crit. Care Med. 2021; 204: 583-595Crossref PubMed Scopus (9) Google Scholar], in which microenvironments may vary. In addition, whether cavities emerge from the middle of caseous necrotic granulomas or from confluent areas of lipoid pneumonia has also been disputed [33.Hunter R.L. Tuberculosis as a three-act play: a new paradigm for the pathogenesis of pulmonary tuberculosis.Tuberculosis (Edinb). 2016; 97: 8-17Crossref PubMed Scopus (92) Google Scholar]. Despite these uncertainties, it is clear that the immune response is both necessary to control infection and essential to drive the tissue destruction that leads to cavitation and spread [15.Elkington P.T. et al.Tuberculosis immunopathology: the neglected role of extracellular matrix destruction.Sci. Transl. Med. 2011; 3: 71ps6Crossref PubMed Scopus (68) Google Scholar]. Multiple types of immunodeficiency can lead to uncontrolled Mtb infection, such as advanced HIV infection, anti-TNF-α treatment, and mutations within the IFN-γ/IL-12/STAT signalling pathway [19.O'Garra A. et al.The immune response in tuberculosis.Annu. Rev. Immunol. 2013; 31: 475-527Crossref PubMed Scopus (824) Google Scholar]. This has led to research that primarily focuses on identifying what is missing from the immune response to Mtb that leads to disease. However, evidence that an absence of an immunological component(s) identified in individuals who progress to active TB disease does not mean that an excess will be beneficial [34.Karp C.L. et al.Tuberculosis vaccines: barriers and prospects on the quest for a transformative tool.Immunol. Rev. 2015; 264: 363-381Crossref PubMed Scopus (44) Google Scholar], and, in fact, diverse evidence shows that inflammation, driven by excessive immunity, is damaging in TB. This debate is not new and dates back to bitter disputes between Koch and Virchow [35.Kaufmann S.H. A short history of Robert Koch's fight against tuberculosis: those who do not remember the past are condemned to repeat it.Tuberculosis (Edinb). 2003; 83: 86-90Crossref PubMed Scopus (24) Google Scholar], over whether Koch's tuberculin vaccine would cure infection or provoke an immune response that degraded the granuloma and enhanced disease. On the one hand, human studies and animal models provide clear evidence that immunological memory from TB exposure is protective [36.Andrews J.R. et al.Risk of progression to active tuberculosis following reinfection with Mycobacterium tuberculosis.Clin. Infect. Dis. 2012; 54: 784-791Crossref PubMed Scopus (226) Google Scholar,37.Cadena A.M. et al.Concurrent infection with Mycobacterium tuberculosis confers robust protection against secondary infection in macaques.PLoS Pathog. 2018; 14e1007305Crossref PubMed Scopus (43) Google Scholar]. On the other hand, in a seminal large-scale epidemiological study, Comstock demonstrated the surprising finding that, among tuberculin reactors, those with the greatest delayed-type hypersensitivity response had the highest risk of subsequent development of TB many years later [38.Comstock G.W. et al.The prognosis of a positive tuberculin reaction in childhood and adolescence.Am. J. 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The demonstration that T cell epitopes of Mtb are hyperconserved compared with nonepitope regions further suggests that the pathogen derives an evolutionary benefit from promoting the host T cell response [40.Coscolla M. et al.M. tuberculosis T cell epitope analysis reveals paucity of antigenic variation and identifies rare variable TB antigens.Cell Host Microbe. 2015; 18: 538-548Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar,41.Comas I. et al.Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved.Nat. Genet. 2010; 42: 498-503Crossref PubMed Scopus (503) Google Scholar]. Most recently, accumulating evidence that anti-PD-1 treatment for cancer can activate latent TB further highlights the danger of an excessive response, with enhanced T cell cytokine production implicated in driving immunopathology [7.Elkington P.T. et al.Implications of tuberculosis reactivation after immune checkpoint inhibition.Am. J. Respir. Crit. 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Taken together, these observations suggest a complex interplay between innate and adaptive responses, along with mycobacterial load, determining a range of outcomes from disseminated and noncavitary disease in the absence of an effective adaptive immune response, control/elimination with an optimal response, and matrix destruction, cavitation, and spread when excessive localised inflammation occurs [9.Tezera L.B. et al.Reconsidering the optimal immune response to Mycobacterium tuberculosis.Am. J. Respir. Crit. Care Med. 2020; 201: 407-413Crossref PubMed Scopus (12) Google Scholar]. Along similar lines, the concept that the optimal strategy for humans might be to sequester and tolerate Mtb has been proposed, and the breakdown of this tolerance leads to active disease [44.Olive A.J. Sassetti C.M. Tolerating the unwelcome guest; how the host withstands persistent Mycobacterium tuberculosis.Front. Immunol. 2018; 9: 2094Crossref PubMed Scopus (11) Google Scholar,45.Divangahi M. et al.Beyond killing Mycobacterium tuberculosis: disease tolerance.Front. Immunol. 2018; 9: 2976Crossref PubMed Scopus (17) Google Scholar]. The fraction of individuals defined as latently infected who in fact harbour viable bacteria is debated [46.Behr M.A. et al.Latent tuberculosis: two centuries of confusion.Am. J. Respir. Crit. Care Med. 2021; 204: 142-148PubMed Google Scholar], but reactivation of Mtb can occur decades after initial infection [47.Lillebaek T. et al.Molecular evidence of endogenous reactivation of Mycobacterium tuberculosis after 33 years of latent infection.J. Infect. Dis. 2002; 185: 401-404Crossref PubMed Scopus (176) Google Scholar], suggesting that this tolerant phenotype can be extremely durable. Adding to the complexity of TB immunology is the fact that TB lesions can have diverse outcomes even in the same individual [11.Dubos R. Dubos J. The White Plague: Tuberculosis, Man, and Society. Rutgers University Press, 1987Google Scholar]. This was summed up neatly by Georges Canetti in 1955, based on examining thousands of tuberculous lungs before the advent of antimicrobial treatment: 'Consider the bacillus in the lesion, experiencing such different fates in various foci of the same patient, and the same fate in widely different patients; destroyed in a certain histologic reaction and thriving in another nearby' [48.Canetti G. The Tubercle Bacillus in the Pulmonary Lesion of Man: Histobacteriology and its Bearing on the Therapy of Pulmonary Tuberculosis.The Tubercle Bacillus in the Pulmonary Lesion of Man: Histobacteriology and Its Bearing on the Therapy of Pulmonary Tuberculosis. Springer, 1955Google Scholar]. Likewise, Dubos wrote in 1952 'all these processes may occur in the same person either at different times or often simultaneously…which is still almost as much a puzzle today'. This concurrent progression and regression of lesions has been elegantly confirmed in modern imaging studies of infected non-human primates (NHPs) [10.Lin P.L. et al.Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing.Nat. Med. 2014; 20: 75-79Crossref PubMed Scopus (325) Google Scholar]. Consequently, it appears that the outcome of infectious foci is determined at a local granuloma level and not systemically, adding to the challenges of dissecting determinants of outcome. One proposed paradigm is that a balance within granulomas is necessary, with both proinflammatory and anti-inflammatory mediators leading to control of infection [49.Cadena A.M. et al.Heterogeneity in tuberculosis.Nat. Rev. Immunol. 2017; 17: 691-702Crossref PubMed Scopus (216) Google Scholar,50.Gideon H.P. et al.Variability in tuberculosis granuloma T cell responses exists, but a balance of pro- and anti-inflammatory cytokines is associated with sterilization.PLoS Pathog. 2015; 11e1004603Crossref PubMed Scopus (190) Google Scholar]. With their pivotal role in orchestrating the immune response, dendritic cells are also likely to have a central role in shaping the immune response and defining outcome [51.Polak M.E. Singh H. Tolerogenic and immunogenic states of Langerhans cells are orchestrated by epidermal signals acting on a core maturation gene module.Bioessays. 2021; 43e2000182Crossref PubMed Scopus (3) Google Scholar]. However, because these events occur within tissue, they are challenging to investigate, and studying the host response in the periphery is unlikely to convey sufficient granularity about individual lesions [52.Cliff J.M. et al.The human immune response to tuberculosis and its treatment: a view from the blood.Immunol. Rev. 2015; 264: 88-102Crossref PubMed Scopus (103) Google Scholar]. Therefore, events determining outcome within individual TB granulomas remain a highly pressing question, and omics analyses should provide a wealth of data to give mechanistic understanding. Recently, several studies reported unbiased analyses aiming to unpick the process. A strategy of comparing TB granulomas with sarcoidosis, a non-infectious granulomatous disease, was utilised to overcome the issue of cell-specific gene expression patterns [53.Reichmann M.T. et al.Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets.J. Clin. Invest. 2021; 131e148136PubMed Google Scholar]. Diverse analytical approaches demonstrated that the collagenase matrix metalloproteinase-1 (MMP1) was highly upregulated in TB and was the most significantly differentially expressed gene between TB and sarcoidosis. Analysis of gene correlations identified a seven-gene TB-specific cluster, comprising MMP1, the monocyte chemoattractants C-C motif chemokine ligand 7 and 8 (CCL7 and CCL8), the divalent transition metal transporter solute carrier family 11 member 1 (SLC11A1; formerly known as NRAMP1), oxidised low-density lipoprotein receptor 1 (OLR1; formerly known as LOX1), family with sequence similarity 124 member A (FAM124A), and galectin 14 pseudogene (LGALS17A). Several of these genes have already been implicated in TB pathogenesis, and consideration of their known functions together informs a putative sequence of events that leads to progression of TB lesions (Figure 3, Key figure). Thus, sequencing of clinical material followed by unbiased analysis generated a hypothesised cascade of disease evolution that can be experimentally investigated. Further bioinformatic analyses in combination with a 3D biomimetic model identified that sphingosine 1 kinase inhibition suppressed Mtb growth, thereby progressing from basic disease understanding to novel therapeutic targets in an unbiased manner [53.Reichmann M.T. et al.Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets.J. Clin. Invest. 2021; 131e148136PubMed Google Scholar]. Using a similar transcriptomic approach, analysis of gene expression was compared in skin stimulated by tuberculin in patients with TB versus healthy controls [54.Pollara G. et al.Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease.Sci. Transl. Med. 2021; 13: eabg7673Crossref PubMed Scopus (8) Google Scholar]. Again, MMP1 emerged as a top divergently upregulated gene, and ingenuity pathway analysis suggested that an excessive IL-17 response was a key regulator. The IL-17/MMP1 profile resolved with treatment of infection, implying that Mtb actively primes an excessive, matrix-destructive immune response that can be replicated by a distal antigenic challenge. The authors highlighted the double-edged sword of IL-17 in TB, with data supporting a protective role [55.Ogongo P. et al.Tissue-resident-like CD4+ T cells secreting IL-17 control Mycobacterium tuberculosis in the human lung.J. Clin. Invest. 2021; 131e142014Crossref PubMed Scopus (11) Google Scholar,56.Dijkman K. et al.Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques.Nat. 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In an early microarray analysis of restimulated macrophages, MMP1 was the most divergently regulated gene in patients with TB, although the authors then focused on a chemokine in validation stages [58.Thuong N.T. et al.Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles.PLoS Pathog. 2008; 4e1000229Crossref PubMed Scopus (111) Google Scholar]. Similarly, m
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