Alvaro A Ordonez1,2, Sudhanshu Abhishek1,2, Alok K Singh1,2,3, Mariah H Klunk1,2, Babak Benham Azad4, Eric O Aboagye5, Laurence Carroll6,7, Sanjay K Jain8,9,10. 1. Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 2. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 3. Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India. 4. Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 5. Comprehensive Cancer Imaging Centre, Department of Surgery & Cancer Hammersmith Campus, Imperial College, London, UK. 6. Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lcarro19@jhmi.edu. 7. Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lcarro19@jhmi.edu. 8. Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhmi.edu. 9. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhmi.edu. 10. Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhmi.edu.
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.
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. Infectedmice 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.
Authors: F M R Perrin; N Woodward; P P J Phillips; T D McHugh; A J Nunn; M C I Lipman; S H Gillespie Journal: Int J Tuberc Lung Dis Date: 2010-12 Impact factor: 2.373
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