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Tackling tissue destruction in tuberculosis
Transactions of the Royal Society of Tropical Medicine and Hygiene (2008) 102, 953—954
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
MINI-REVIEW
Tackling tissue destruction in tuberculosis Jon S. Friedland ∗ Department of Infectious Diseases and Immunity, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK Available online 3 July 2008
KEYWORDS Tuberculosis; Matrix metalloproteinases; Inflammation; Tissue destruction; Treatment
Summary Drug-resistant tuberculosis (TB) is a major worldwide problem. The immune system usually controls TB, but once active disease develops, the inflammatory immune response drives tissue destruction. Tissue damage is a result of enzymatic activity, and matrix metalloproteinases (MMPs) have a key role. There are a few new anti-mycobacterial drugs in trial and some vaccine candidates in development but options for control of TB are limited. A novel approach may be to combine antibiotic therapy with limiting the activity of the key mediators of tissue damage, such as MMPs, by inhibiting either the enzymes directly or the pathways that regulate them. © 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
There are many reasons why tuberculosis (TB) is difficult to treat. Multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) are grabbing the headlines, producing concerns about potentially untreatable disease (Gandhi et al., 2006). At a routine level, normal short-course chemotherapy takes at least 6 months, which may lead to non-compliance, as for much of the treatment time the patient may feel quite well. There is considerable research into strategies that may one day eliminate disease. A large effort concentrates on developing pre-emptive vaccines, although some are investigating post-exposure and therapeutic vaccines (Baumann et al., 2006). However, previous infection with TB does not prevent re-infection. Furthermore, patients with active TB are infected with the organism for many years but have been unable to prime their immune system sufficiently to prevent the emergence of clinical disease. There is a relatively limited understanding of immune responses in active disease compared to dormant infection. Such facts indicate that developing an effective vaccine may be difficult. In addition, unless a vaccine works against those
∗
Tel.: +44 20 8383 8521; fax: +44 20 8383 3394. E-mail address: [email protected]
already infected, it is going to take a long time to clear the current level of TB carriage. So despite some excellent progress in the field of vaccination, there is a need to focus on issues around treatment; a 2 week therapy for TB would radically change global infection. It is encouraging to see a small number of new drugs for TB at a relatively advanced stage in development (Sacchettini et al., 2008). However, we know from experience with Salmonella typhi and other organisms that keeping ahead of drug resistance is a difficult business. New antibacterials alone may not be enough. One of the most striking observations in TB is that there are over 1.7 billion infected people, of whom less than 1% have active disease at any one time. In the majority of cases, the human immune system copes well to control infection. However, the immune system is equally important in pathology. The inflammatory immune response rather than the pathogen itself is responsible for much of the clinically apparent tissue damage and subsequent fibrosis, scarring and long-term morbidity in those patients who survive active infection. So what drives tissue destruction in TB? Tissue damage is the result of enzymes secreted by inflammatory leucocytes and cells at the site of active infection. This is often the lung, where the main structural proteins are collagens. The only enzymes able to destroy
0035-9203/$ — see front matter © 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2008.05.008
954 collagen at neutral pH are the matrix metalloproteinases (MMPs). The MMP family are able to degrade all components of the extracellular matrix (Parks et al., 2004). There is increasing evidence that active TB is characterised by the development of a matrix-degrading phenotype in which MMP activity is relatively unopposed by the specific tissue inhibitors of metalloproteinases. MMPs are released from a broad range of cells at sites of infection, including leucocytes (monocytes, macrophages, lymphocytes and neutrophils), fibroblasts and epithelial cells. It is apparent from MMP screens of different infected cell types that only a limited number of these enzymes are particularly involved in the response to TB. Among these, MMP-1, a collagenase, seems particularly important (Elkington et al., 2005). Inhibiting these molecules may decrease leucocyte recruitment and reduce tissue destruction without abolishing necessary host defence mechanisms. Reducing inflammatory tissue damage may have many consequences. Firstly, there would be the immediate benefit of reduced local tissue destruction. Secondly, smaller areas of hypoxic tissue damage may allow better penetration and function of anti-mycobacterial drugs. Thirdly, the immune system may start to switch from a pro-inflammatory to a resolving phenotype. Is it realistic to expect to selectively block MMP activity? In fact, MMP inhibitors have been trialled in patients with other diseases. Further research aims to identify switch points upstream that may be targets for small molecules. Inhibitors of the p38 mitogen-activated protein kinase pathway, a key signalling pathway regulating MMP activity, have already been studied in humans. In TB, obtaining the proof that blocking MMPs would be beneficial is hampered by the fact that there is no good model of the tissue destruction seen in patients. However, considerable effort is being focused on trying to improve current models, and it seems likely that this will be achieved in the near future. Cynics may say that even if inflammatory tissue destruction is important and can be inhibited, this will not improve outcome as the strategy does not target the pathogen. This is true. It will be necessary to combine immunological and pharmacological therapies to develop a true short-course treatment to tackle TB. The cynic pops up again, saying that those with TB will be unable to afford immunotherapy. Currently, biologicals are expensive, but this is unlikely to stay the case once such compounds are in
J.S. Friedland widespread use. There are other examples where advances in technology and manufacturing that have seemed highly complex ultimately resulted in something that is eminently affordable. If drug resistance continues to rise, there will be no choice but to explore alternative options. Developing anti-inflammatory therapies may not be easy, but neither will be developing new vaccines. One thing is clear, the time to investigate novel approaches to treatment is now. Acknowledgements: The author thanks Drs Paul T. Elkington, Justin A. Green and Joanna C. Porter for their helpful comments on the manuscript. Funding: The author’s work is supported by grant funding from The Wellcome Trust and The Medical Research Council (UK). The author acknowledges support from the NIHR Biomedical Research Centre Funding Scheme at Imperial College. Conflicts of interest: None declared. Ethical approval: Not required.
References Baumann, S., Nasser Eddine, A., Kaufmann, S.H., 2006. Progress in tuberculosis vaccine development. Curr. Opin. Immunol. 18, 438—448. Elkington, P.T., Nuttall, R.K., Boyle, J.J., O’Kane, C.M., Horncastle, D.E., Edwards, D.R., Friedland, J.S., 2005. Mycobacterium tuberculosis, but not vaccine BCG, specifically upregulates matrix metalloproteinase-1. Am. J. Respir. Crit. Care Med. 172, 1596—1604. Gandhi, N.R., Moll, A., Sturm, A.W., Pawinski, R., Govender, T., Lalloo, U., Zeller, K., Andrews, J., Friedland, G., 2006. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 368, 1575—1580. Parks, W.C., Wilson, C.L., Lopez-Boado, Y.S., 2004. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 4, 617—629. Sacchettini, J.C., Rubin, E.J., Freundlich, J.S., 2008. Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis. Nat. Rev. Microbiol. 6, 41—52.
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
MINI-REVIEW
Tackling tissue destruction in tuberculosis Jon S. Friedland ∗ Department of Infectious Diseases and Immunity, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK Available online 3 July 2008
KEYWORDS Tuberculosis; Matrix metalloproteinases; Inflammation; Tissue destruction; Treatment
Summary Drug-resistant tuberculosis (TB) is a major worldwide problem. The immune system usually controls TB, but once active disease develops, the inflammatory immune response drives tissue destruction. Tissue damage is a result of enzymatic activity, and matrix metalloproteinases (MMPs) have a key role. There are a few new anti-mycobacterial drugs in trial and some vaccine candidates in development but options for control of TB are limited. A novel approach may be to combine antibiotic therapy with limiting the activity of the key mediators of tissue damage, such as MMPs, by inhibiting either the enzymes directly or the pathways that regulate them. © 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
There are many reasons why tuberculosis (TB) is difficult to treat. Multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) are grabbing the headlines, producing concerns about potentially untreatable disease (Gandhi et al., 2006). At a routine level, normal short-course chemotherapy takes at least 6 months, which may lead to non-compliance, as for much of the treatment time the patient may feel quite well. There is considerable research into strategies that may one day eliminate disease. A large effort concentrates on developing pre-emptive vaccines, although some are investigating post-exposure and therapeutic vaccines (Baumann et al., 2006). However, previous infection with TB does not prevent re-infection. Furthermore, patients with active TB are infected with the organism for many years but have been unable to prime their immune system sufficiently to prevent the emergence of clinical disease. There is a relatively limited understanding of immune responses in active disease compared to dormant infection. Such facts indicate that developing an effective vaccine may be difficult. In addition, unless a vaccine works against those
∗
Tel.: +44 20 8383 8521; fax: +44 20 8383 3394. E-mail address: [email protected]
already infected, it is going to take a long time to clear the current level of TB carriage. So despite some excellent progress in the field of vaccination, there is a need to focus on issues around treatment; a 2 week therapy for TB would radically change global infection. It is encouraging to see a small number of new drugs for TB at a relatively advanced stage in development (Sacchettini et al., 2008). However, we know from experience with Salmonella typhi and other organisms that keeping ahead of drug resistance is a difficult business. New antibacterials alone may not be enough. One of the most striking observations in TB is that there are over 1.7 billion infected people, of whom less than 1% have active disease at any one time. In the majority of cases, the human immune system copes well to control infection. However, the immune system is equally important in pathology. The inflammatory immune response rather than the pathogen itself is responsible for much of the clinically apparent tissue damage and subsequent fibrosis, scarring and long-term morbidity in those patients who survive active infection. So what drives tissue destruction in TB? Tissue damage is the result of enzymes secreted by inflammatory leucocytes and cells at the site of active infection. This is often the lung, where the main structural proteins are collagens. The only enzymes able to destroy
0035-9203/$ — see front matter © 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2008.05.008
954 collagen at neutral pH are the matrix metalloproteinases (MMPs). The MMP family are able to degrade all components of the extracellular matrix (Parks et al., 2004). There is increasing evidence that active TB is characterised by the development of a matrix-degrading phenotype in which MMP activity is relatively unopposed by the specific tissue inhibitors of metalloproteinases. MMPs are released from a broad range of cells at sites of infection, including leucocytes (monocytes, macrophages, lymphocytes and neutrophils), fibroblasts and epithelial cells. It is apparent from MMP screens of different infected cell types that only a limited number of these enzymes are particularly involved in the response to TB. Among these, MMP-1, a collagenase, seems particularly important (Elkington et al., 2005). Inhibiting these molecules may decrease leucocyte recruitment and reduce tissue destruction without abolishing necessary host defence mechanisms. Reducing inflammatory tissue damage may have many consequences. Firstly, there would be the immediate benefit of reduced local tissue destruction. Secondly, smaller areas of hypoxic tissue damage may allow better penetration and function of anti-mycobacterial drugs. Thirdly, the immune system may start to switch from a pro-inflammatory to a resolving phenotype. Is it realistic to expect to selectively block MMP activity? In fact, MMP inhibitors have been trialled in patients with other diseases. Further research aims to identify switch points upstream that may be targets for small molecules. Inhibitors of the p38 mitogen-activated protein kinase pathway, a key signalling pathway regulating MMP activity, have already been studied in humans. In TB, obtaining the proof that blocking MMPs would be beneficial is hampered by the fact that there is no good model of the tissue destruction seen in patients. However, considerable effort is being focused on trying to improve current models, and it seems likely that this will be achieved in the near future. Cynics may say that even if inflammatory tissue destruction is important and can be inhibited, this will not improve outcome as the strategy does not target the pathogen. This is true. It will be necessary to combine immunological and pharmacological therapies to develop a true short-course treatment to tackle TB. The cynic pops up again, saying that those with TB will be unable to afford immunotherapy. Currently, biologicals are expensive, but this is unlikely to stay the case once such compounds are in
J.S. Friedland widespread use. There are other examples where advances in technology and manufacturing that have seemed highly complex ultimately resulted in something that is eminently affordable. If drug resistance continues to rise, there will be no choice but to explore alternative options. Developing anti-inflammatory therapies may not be easy, but neither will be developing new vaccines. One thing is clear, the time to investigate novel approaches to treatment is now. Acknowledgements: The author thanks Drs Paul T. Elkington, Justin A. Green and Joanna C. Porter for their helpful comments on the manuscript. Funding: The author’s work is supported by grant funding from The Wellcome Trust and The Medical Research Council (UK). The author acknowledges support from the NIHR Biomedical Research Centre Funding Scheme at Imperial College. Conflicts of interest: None declared. Ethical approval: Not required.
References Baumann, S., Nasser Eddine, A., Kaufmann, S.H., 2006. Progress in tuberculosis vaccine development. Curr. Opin. Immunol. 18, 438—448. Elkington, P.T., Nuttall, R.K., Boyle, J.J., O’Kane, C.M., Horncastle, D.E., Edwards, D.R., Friedland, J.S., 2005. Mycobacterium tuberculosis, but not vaccine BCG, specifically upregulates matrix metalloproteinase-1. Am. J. Respir. Crit. Care Med. 172, 1596—1604. Gandhi, N.R., Moll, A., Sturm, A.W., Pawinski, R., Govender, T., Lalloo, U., Zeller, K., Andrews, J., Friedland, G., 2006. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 368, 1575—1580. Parks, W.C., Wilson, C.L., Lopez-Boado, Y.S., 2004. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 4, 617—629. Sacchettini, J.C., Rubin, E.J., Freundlich, J.S., 2008. Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis. Nat. Rev. Microbiol. 6, 41—52.