The Deconstructed Granuloma: A Complex High-Throughput Drug Screening Platform for the Discovery of Host-Directed Therapeutics Against Tuberculosis
Mycobacterium tuberculosis (Mtb) continues to be a threat to Global Public Health, and its control will require an array of therapeutic strategies. It has been appreciated that high-throughput screens using cell-based assays to identify compounds targeting Mtb within macrophages represent a valuable...
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doaj-b7e17853d3d9438abea37fe30b8b5caa2020-11-24T22:19:46ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882018-08-01810.3389/fcimb.2018.00275392876The Deconstructed Granuloma: A Complex High-Throughput Drug Screening Platform for the Discovery of Host-Directed Therapeutics Against TuberculosisLu Huang0Nicole L. Kushner1Monique E. Theriault2Davide Pisu3Shumin Tan4Case W. McNamara5H. Mike Petrassi6David G. Russell7Amanda C. Brown8Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, United StatesCalifornia Institute for Biomedical Research (Calibr), La Jolla, CA, United StatesCalifornia Institute for Biomedical Research (Calibr), La Jolla, CA, United StatesDepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesMycobacterium tuberculosis (Mtb) continues to be a threat to Global Public Health, and its control will require an array of therapeutic strategies. It has been appreciated that high-throughput screens using cell-based assays to identify compounds targeting Mtb within macrophages represent a valuable tool for drug discovery. However, the host immune environment, in the form of lymphocytes and cytokines, is completely absent in a chemical screening platform based on infected macrophages alone. The absence of these players unnecessarily limits the breadth of novel host target pathways to be interrogated. In this study, we detail a new drug screening platform based on dissociated murine TB granulomas, named the Deconstructed Granuloma (DGr), that utilizes fluorescent Mtb reporter strains screened in the host immune environment of the infection site. The platform has been used to screen a collection of known drug candidates. Data from a representative 384-well plate containing known anti-bacterial compounds are shown, illustrating the robustness of the screening platform. The novel deconstructed granuloma platform represents an accessible, sensitive and robust high-throughput screen suitable for the inclusive interrogation of immune targets for Host-Directed Therapeutics.https://www.frontiersin.org/article/10.3389/fcimb.2018.00275/fulltuberculosispulmonaryMycobacterium tuberculosishigh-throughput screening assayshost-directed therapeuticsmacrophages |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lu Huang Nicole L. Kushner Monique E. Theriault Davide Pisu Shumin Tan Case W. McNamara H. Mike Petrassi David G. Russell Amanda C. Brown |
spellingShingle |
Lu Huang Nicole L. Kushner Monique E. Theriault Davide Pisu Shumin Tan Case W. McNamara H. Mike Petrassi David G. Russell Amanda C. Brown The Deconstructed Granuloma: A Complex High-Throughput Drug Screening Platform for the Discovery of Host-Directed Therapeutics Against Tuberculosis Frontiers in Cellular and Infection Microbiology tuberculosis pulmonary Mycobacterium tuberculosis high-throughput screening assays host-directed therapeutics macrophages |
author_facet |
Lu Huang Nicole L. Kushner Monique E. Theriault Davide Pisu Shumin Tan Case W. McNamara H. Mike Petrassi David G. Russell Amanda C. Brown |
author_sort |
Lu Huang |
title |
The Deconstructed Granuloma: A Complex High-Throughput Drug Screening Platform for the Discovery of Host-Directed Therapeutics Against Tuberculosis |
title_short |
The Deconstructed Granuloma: A Complex High-Throughput Drug Screening Platform for the Discovery of Host-Directed Therapeutics Against Tuberculosis |
title_full |
The Deconstructed Granuloma: A Complex High-Throughput Drug Screening Platform for the Discovery of Host-Directed Therapeutics Against Tuberculosis |
title_fullStr |
The Deconstructed Granuloma: A Complex High-Throughput Drug Screening Platform for the Discovery of Host-Directed Therapeutics Against Tuberculosis |
title_full_unstemmed |
The Deconstructed Granuloma: A Complex High-Throughput Drug Screening Platform for the Discovery of Host-Directed Therapeutics Against Tuberculosis |
title_sort |
deconstructed granuloma: a complex high-throughput drug screening platform for the discovery of host-directed therapeutics against tuberculosis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cellular and Infection Microbiology |
issn |
2235-2988 |
publishDate |
2018-08-01 |
description |
Mycobacterium tuberculosis (Mtb) continues to be a threat to Global Public Health, and its control will require an array of therapeutic strategies. It has been appreciated that high-throughput screens using cell-based assays to identify compounds targeting Mtb within macrophages represent a valuable tool for drug discovery. However, the host immune environment, in the form of lymphocytes and cytokines, is completely absent in a chemical screening platform based on infected macrophages alone. The absence of these players unnecessarily limits the breadth of novel host target pathways to be interrogated. In this study, we detail a new drug screening platform based on dissociated murine TB granulomas, named the Deconstructed Granuloma (DGr), that utilizes fluorescent Mtb reporter strains screened in the host immune environment of the infection site. The platform has been used to screen a collection of known drug candidates. Data from a representative 384-well plate containing known anti-bacterial compounds are shown, illustrating the robustness of the screening platform. The novel deconstructed granuloma platform represents an accessible, sensitive and robust high-throughput screen suitable for the inclusive interrogation of immune targets for Host-Directed Therapeutics. |
topic |
tuberculosis pulmonary Mycobacterium tuberculosis high-throughput screening assays host-directed therapeutics macrophages |
url |
https://www.frontiersin.org/article/10.3389/fcimb.2018.00275/full |
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