Abstract
Purpose
Despite recent advances in antimicrobial treatments, tuberculosis (TB) remains a major global health threat. Mycobacterium tuberculosis proliferates in macrophages, preventing apoptosis by inducing anti-apoptotic proteins leading to necrosis of the infected cells. Necrosis then leads to increased tissue destruction, reducing the penetration of antimicrobials and immune cells to the areas where they are needed most. Pro-apoptotic drugs could be used as host-directed therapies in TB to improve antimicrobial treatments and patient outcomes.
Procedure
We evaluated [18F]-ICMT-11, a caspase-3/7-specific positron emission tomography (PET) radiotracer, in macrophage cell cultures and in an animal model of pulmonary TB that closely resembles human disease.
Results
Cells infected with M. tuberculosis and treated with cisplatin accumulated [18F]-ICMT-11 at significantly higher levels compared with that of controls, which correlated with levels of caspase-3/7 activity. Infected mice treated with cisplatin with increased caspase-3/7 activity also had a higher [18F]-ICMT-11 PET signal compared with that of untreated infected animals.
Conclusions
[18F]-ICMT-11 PET could be used as a noninvasive approach to measure intralesional pro-apoptotic responses in situ in pulmonary TB models and support the development of pro-apoptotic host-directed therapies for TB.
Similar content being viewed by others
References
World Health Organization (2019) Global Tuberculosis Report. WHO, Geneva
Sly LM, Hingley-Wilson SM, Reiner NE, McMaster WR (2003) Survival of Mycobacterium tuberculosis in host macrophages involves resistance to apoptosis dependent upon induction of antiapoptotic Bcl-2 family member Mcl-1. J Immunol 170:430–437
Gan H, Lee J, Ren F, Chen M, Kornfeld H, Remold HG (2008) Mycobacterium tuberculosis blocks crosslinking of annexin-1 and apoptotic envelope formation on infected macrophages to maintain virulence. Nat Immunol 9:1189–1197
Ordonez AA, Wang H, Magombedze G, Ruiz-Bedoya CA, Srivastava S, Chen A, Tucker EW, Urbanowski ME, Pieterse L, Cardozo EF, Lodge MA, Shah MR, Holt DP, Mathews WB, Dannals RF, Gobburu JVS, Peloquin CA, Rowe SP, Gumbo T, Ivaturi VD, Jain SK (2020) Dynamic imaging in tuberculosis patients reveals heterogeneous drug exposures in pulmonary lesions. Nat Med:1–6. https://doi.org/10.1038/s41591-020-0770-2
Wang Q, Liu S, Tang Y, Liu Q, Yao Y (2014) MPT64 protein from Mycobacterium tuberculosis inhibits apoptosis of macrophages through NF-kB-miRNA21-Bcl-2 pathway. PLoS One 9:e100949
Zhao X, Khan N, Gan H, Tzelepis F, Nishimura T, Park SY, Divangahi M, Remold HG (2017) Bcl-xL mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages. Mucosal Immunol 10:1553–1568
Ordonez AA, Maiga M, Gupta S, Weinstein E, Bishai WR, Jain SK (2014) Novel adjunctive therapies for the treatment of tuberculosis. Curr Mol Med 14:385–395
Ordonez AA, Pokkali S, Kim S et al (2018) Adjunct antibody administration with standard treatment reduces relapse rates in a murine tuberculosis model of necrotic granulomas. PLoS One 13:e0197474
Ordonez AA, Pokkali S, Sanchez-Bautista J, Klunk MH, Urbanowski ME, Kübler A, Bishai WR, Elkington PT, Jain SK (2019) Matrix metalloproteinase inhibition in a murine model of cavitary tuberculosis paradoxically worsens pathology. J Infect Dis 219:633–636
Singh R, Letai A, Sarosiek K (2019) Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol 20:175–193
Ordonez AA, Pokkali S, DeMarco VP, Klunk M, Mease RC, Foss CA, Pomper MG, Jain SK (2015) Radioiodinated DPA-713 imaging correlates with bactericidal activity of tuberculosis treatments in mice. Antimicrob Agents Chemother 59:642–649
Ordonez AA, Tasneen R, Pokkali S, Xu Z, Converse PJ, Klunk MH, Mollura DJ, Nuermberger EL, Jain SK (2016) Mouse model of pulmonary cavitary tuberculosis and expression of matrix metalloproteinase-9. Dis Model Mech 9:779–788
Nguyen Q-D, Smith G, Glaser M, Perumal M, Årstad E, Aboagye EO (2009) Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [18F]-labeled isatin sulfonamide. Proc Natl Acad Sci U S A 106:16375–16380
Dubash SR, Merchant S, Heinzmann K, Mauri F, Lavdas I, Inglese M, Kozlowski K, Rama N, Masrour N, Steel JF, Thornton A, Lim AK, Lewanski C, Cleator S, Coombes RC, Kenny L, Aboagye EO (2018) Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer. Eur J Nucl Med Mol Imaging 45:2285–2299
Fortt R, Smith G, Awais RO, Luthra SK, Aboagye EO (2012) Automated GMP synthesis of [18F] ICMT-11 for in vivo imaging of caspase-3 activity. Nucl Med Biol 39:1000–1005
Witney TH, Fortt RR, Aboagye EO (2014) Preclinical assessment of carboplatin treatment efficacy in lung cancer by 18F-ICMT-11-positron emission tomography. PLoS One 9:e91694
Yang M, Chen P, Liu J et al (2019) Clockophagy is a novel selective autophagy process favoring ferroptosis. Sci Adv 5:eaaw2238
Weinstein E, Liu L, Ordonez A, Wang H, Hooker JM, Tonge PJ, Jain SK (2012) Noninvasive determination of 2-[18F]-fluoroisonicotinic acid hydrazide pharmacokinetics by positron emission tomography in Mycobacterium tuberculosis-infected mice. Antimicrob Agents Chemother 56:6284–6290
Prideaux B, Via LE, Zimmerman MD, Eum S, Sarathy J, O'Brien P, Chen C, Kaya F, Weiner DM, Chen PY, Song T, Lee M, Shim TS, Cho JS, Kim W, Cho SN, Olivier KN, Barry CE 3rd, Dartois V (2015) The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med 21:1223–1227
Kaczmarek A, Vandenabeele P, Krysko DV (2013) Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38:209–223
Ernst JD (2012) The immunological life cycle of tuberculosis. Nat Rev Immunol 12:581–591
Perrin FM, Woodward N, Phillips PP, McHugh T, Nunn AJ, Lipman MC, Gillespie SH (2010) Radiological cavitation, sputum mycobacterial load and treatment response in pulmonary tuberculosis. Int J Tuberc Lung Dis 14:1596–1602
Torrado E, Robinson RT, Cooper AM (2011) Cellular response to mycobacteria: balancing protection and pathology. Trends Immunol 32:66–72
Nguyen Q-D, Challapalli A, Smith G, Fortt R, Aboagye EO (2012) Imaging apoptosis with positron emission tomography: ‘bench to bedside’ development of the caspase-3/7 specific radiotracer [18F] ICMT-11. Eur J Cancer 48:432–440
Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241
Nguyen Q-D, Lavdas I, Gubbins J, Smith G, Fortt R, Carroll LS, Graham MA, Aboagye EO (2013) Temporal and spatial evolution of therapy-induced tumor apoptosis detected by caspase-3–selective molecular imaging. Clin Cancer Res 19:3914–3924
Smith G, Glaser M, Perumal M, Nguyen QD, Shan B, Arstad E, Aboagye EO (2008) Design, synthesis, and biological characterization of a caspase 3/7 selective isatin labeled with 2-[18F]fluoroethylazide. J Med Chem 51:8057–8067
Vassileva V, Stribbling SM, Barnes C, Carroll L, Braga M, Abrahams J, Heinzmann K, Haegeman C, MacFarlane M, Simpson KL, Dive C, Honeychurch J, Illidge TM, Aboagye EO (2019) Evaluation of apoptosis imaging biomarkers in a genetic model of cell death. EJNMMI Res 9:18
Challapalli A, Kenny LM, Hallett WA, Kozlowski K, Tomasi G, Gudi M, al-Nahhas A, Coombes RC, Aboagye EO (2013) 18F-ICMT-11, a caspase-3–specific PET tracer for apoptosis: biodistribution and radiation dosimetry. J Nucl Med 54:1551–1556
Fisher DE (1994) Apoptosis in cancer therapy: crossing the threshold. Cell 78:539–542
Acknowledgments
This study was funded by the National Institutes of Health Director’s Transformative Research Award R01-EB020539 (SKJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Ordonez, A.A., Abhishek, S., Singh, A.K. et al. Caspase-Based PET for Evaluating Pro-Apoptotic Treatments in a Tuberculosis Mouse Model. Mol Imaging Biol 22, 1489–1494 (2020). https://doi.org/10.1007/s11307-020-01494-9
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11307-020-01494-9