@article{8694fdcbe3f645f5aac1bd63505cba6a,
title = "Cotreatment With Clofazimine and Rapamycin Eliminates Drug-Resistant Tuberculosis by Inducing Polyfunctional Central Memory T-Cell Responses",
abstract = "Mycobacterium tuberculosis, the causative agent of tuberculosis, is acquiring drug resistance at a faster rate than the discovery of new antibiotics. Therefore, alternate therapies that can limit the drug resistance and disease recurrence are urgently needed. Emerging evidence indicates that combined treatment with antibiotics and an immunomodulator provides superior treatment efficacy. Clofazimine (CFZ) enhances the generation of T central memory (TCM) cells by blocking the Kv1.3+ potassium channels. Rapamycin (RAPA) facilitates M. tuberculosis clearance by inducing autophagy. In this study, we observed that cotreatment with CFZ and RAPA potently eliminates both multiple and extensively drug-resistant (MDR and XDR) clinical isolates of M. tuberculosis in a mouse model by inducing robust T-cell memory and polyfunctional TCM responses. Furthermore, cotreatment reduces the expression of latency-associated genes of M. tuberculosis in human macrophages. Therefore, CFZ and RAPA cotherapy holds promise for treating patients infected with MDR and XDR strains of M. tuberculosis.",
keywords = "central memory T cells, clofazimine, extensively drug-resistant tuberculosis, helper T cells, immunotherapy, multidrug-resistance, rapamycin, tuberculosis",
author = "Singh, {Dhiraj Kumar} and Ashima Bhaskar and Isha Pahuja and Aishwarya Shaji and Barnani Moitra and Yufang Shi and Dwivedi, {Ved Prakash} and Gobardhan Das",
note = "Funding Information: Financial support. This work was support by Science and Engineering Research Board (SERB), Department of Biotechnology (DBT), Department of Science and Technology, Government of India; and International Centre for Genetic Engineering and Biotechnology, New Delhi, India. A. V. is the recipient of a Junior Research Fellowship from DBT. A. B. is the recipient of a Fellowship from DBT (grant number HGK-IYBA); and a Women Excellence Award from SERB. V. P. D. is the recipient of an Early Career Research Award from SERB. Y. S. is supported by the Jiangsu Province International Science and Technology Cooperation Program (grant number BZ2019017). Funding Information: We acknowledge the support of the Department of Biotechnology-supported Tuberculosis Aerosol Challenge Facility at the International Centre for Genetic Engineering and Biotechnology, New Delhi, India, and their staff in accomplishing this work. This work was support by Science and Engineering Research Board (SERB), Department of Biotechnology (DBT), Department of Science and Technology, Government of India; and International Centre for Genetic Engineering and Biotechnology, New Delhi, India. A. V. is the recipient of a Junior Research Fellowship from DBT. A. B. is the recipient of a Fellowship from DBT (grant number HGK-IYBA); and a Women Excellence Award from SERB. V. P. D. is the recipient of an Early Career Research Award from SERB. Y. S. is supported by the Jiangsu Province International Science and Technology Cooperation Program (grant number BZ2019017). Publisher Copyright: {\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved.",
year = "2023",
month = nov,
day = "1",
doi = "10.1093/infdis/jiad214",
language = "English (US)",
volume = "228",
pages = "1166--1178",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
number = "9",
}