AUTHOR=Lyu Xia-Li , Lin Ting-Ting , Gao Jing-Tao , Jia Hong-Yan , Zhu Chuan-Zhi , Li Zi-Hui , Dong Jing , Sun Qi , Shu Wei , Pan Li-Ping , Zhang Zong-De , Li Qi 

TITLE=The Activities and Secretion of Cytokines Caused by Delamanid on Macrophages Infected by Multidrug-Resistant Mycobacterium tuberculosis Strains

JOURNAL=Frontiers in Immunology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.796677

DOI=10.3389/fimmu.2021.796677

ISSN=1664-3224

ABSTRACT=Background: Delamanid (Dlm) is an effective drug against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains, including Multidrug-resistant Mycobacterium tuberculosis (MDR-MTB). There are few reports on the activity of Dlm on macrophages infected by MDR-MTB strains. Therefore, this article aims to observe the bactericidal activity of Dlm on macrophages infected by MDR-MTB strains and explore the cellular immune mechanism related to its bactericidal effect, so as to provide a basis for further perfecting the mechanism of Dlm.
Methods: Samples were respectively collected to count the intracellular colony-forming unit (CFU) of macrophages infected by MDR-MTB or H37Rv strains at 4h, 8h, 24h and 48h after Dlm at MIC, 10MIC and 20MIC were administered and to detect the level of IL-12/23 p40, TNF-α, IL-6 and IL-10at 4h, 24h and 48h after Dlm at MIC were administered.
Results: (1)After Dlm was applied to macrophages infected by MDR-MTB strains: 
1) The intracellular CFU gradually decreased, reached the lowest value at 48h and was lower than that of Dlm before administration and infection group (P<0.05). 2) The intracellular CFU was further reduced after increasing Dlm dose to 10MIC and 20MIC. (2)  1) The level of IL-12/23 p40 at any time didn't change compared with that of Dlm before administration (P>0.05), while the level of IL-12/23 p40 at 4h was higher than that of the infection group (P<0.05). The level of TNF-α at 24h and 48h were higher than that of Dlm before administration (P<0.05). 2) The level of IL-6 at 24h and 48h were higher than that of Dlm before administration (P<0.05), and were lower than that of infection group (P<0.05).  (3) The level of IL-12/23 p40 and IL-10 didn't change with the change of intracellular CFU (P<0.05), while the level of TNF-α and IL-6 increased with the intracellular CFU decreasing, and the increase level of TNF-α was lower than that of the infection group (P<0.05).
Conclusions: Dlm had strong bactericidal activity against intracellular MDR-MTB which was time-dependent and concentration-dependent. Its bactericidal activity against intracellular MDR-MTB strains was weaker than that against H37Rv. Dlm might have immunomodulatory effect, inducing low expression of Th2 cytokines IL-6 and IL-10.