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

Abstract

BackgroundDelamanid (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 and secretion of cytokines caused by Dlm on macrophages infected by MDR-MTB strains. Therefore, this article aims to observe the bactericidal activity and secretion of cytokines of the macrophages infected by MDR-MTB strains after Dlm was administered, so as to provide a basis for further perfecting the mechanism of Dlm.MethodsSamples were respectively collected to count the intracellular colony-forming unit (CFU) of macrophages infected by MDR-MTB or H37Rv strains at 4, 8, 24, and 48 h after Dlm at MIC, 10MIC, and 20MIC were administered. Samples were respectively collected to detect the level of IL-12/23 p40, TNF-α, IL-6, and IL-10 in the culture supernatant of macrophages infected by MDR-MTB or H37Rv strains at 4, 24, and 48 h after Dlm at MIC were administered. The levels of four cytokines in the culture supernatant were measured using the Luminex® 200™ (Luminex, USA) according to the manufacturer’s instructions. Data were analyzed by SPSS 25.0 software. The continuous data in normal distribution were expressed as mean ± standard deviation (x¯ ± s) and analyzed by t or F test. P<0.05 was considered statistically significant.Results(1) After Dlm was applied to macrophages infected by MDR-MTB strains:(A) The intracellular CFU gradually decreased, reached the lowest value at 48 h, and was lower than that of Dlm before administration and infection group (P<0.05). (B) The intracellular CFU was further reduced after increasing Dlm dose to 10MIC and 20MIC, and the latter was lower than that of the former (P<0.05). (C) The intracellular CFU of MDR-MTB group was higher than that of H37Rv group at 4~48 h after administration (P<0.05). (2) After Dlm at MIC dose was applied to macrophages infected by MDR-MTB strains: (A) 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 4 h was higher than that of the infection group (P<0.05). The levels of TNF-α at 24 and 48 h were higher than that of Dlm before administration (P<0.05), but were similar to that of the infection group (P>0.05). In addition, the levels of IL-12/23 p40 and TNF-α at any time were similar to that of the H37Rv group after administration (P>0.05). (B) The levels of IL-6 at 24 and 48 h were higher than that of Dlm before administration (P<0.05), but were similar to that of H37Rv group (P>0.05) and were lower than that of infection group (P<0.05). The level of IL-10 at any time didn’t change compared with that of Dlm before administration (P>0.05), but was lower than that of the infection group at 4~48 h and was lower than that of the H37Rv group at 24 h (P<0.05). (C) 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).ConclusionsDlm 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 drug-susceptible tuberculosis strains. Dlm might have immunomodulatory effect, inducing low expression of Th2 cytokines IL-6 and IL-10 at different times after administration.

Factors Associated with Unsuccessful Treatment of Bedaquiline and or Delamanid Based Regimens in Multidrug-Resistant Tuberculosis: A Review

“…Delamanid, a companion drug, has high early bactericidal and sterilization activity to reduce the bacillary load (van Deun et al, 2018). In addition, it has an immunomodulatory activity by modulating Th1 and Th2 cytokines, thus enhances the bactericidal activity of macrophages (Lyu et al, 2021). Delamanid is active against both replicating and dormant TB bacteria.…”