Histone deacetylase inhibitors impair the host immune response against Mycobacterium tuberculosis infection

Functional Inhibition of Host Histone Deacetylases (HDACs) Enhances in vitro and in vivo Anti-mycobacterial Activity in Human Macrophages and in Zebrafish

“…Demonstration of synergistic effects of TSA and PKA/PKB inhibitors is in line with results by Zhu et al (81), who demonstrated upregulation of the PI3K-AKT1 signaling pathway in Mtb-infected THP-1 cells treated with TSA. Of note, Zhu et al (81) reported TSA to promote Mtb survival but this discrepancy is likely explained by the use of the THP-1 cell line which requires stimulation with phorbol 12-myristate 13-acetate (PMA) as opposed to primary macrophages, as well as the higher concentration (625 nM) of TSA they used, which was highly toxic in our model. Our work is one of the first demonstrations of synergism (82) between different HDT compounds in the control of bacterial pathogens and provides an important avenue for further studies in this area.…”

“…Moreover, PKA inhibition might also have impaired class IIa HDAC function by interfering with nucleocytoplasmic trafficking since PKA activation promotes nuclear import of HDAC4 by phosphorylation and inhibits class IIa HDAC nuclear export via the LKB1-SIK2/3 axis (79,80). Demonstration of synergistic effects of TSA and PKA/PKB inhibitors is in line with results by Zhu et al (81), who demonstrated upregulation of the PI3K-AKT1 signaling pathway in Mtb-infected THP-1 cells treated with TSA. Of note, Zhu et al (81) reported TSA to promote Mtb survival but this discrepancy is likely explained by the use of the THP-1 cell line which requires stimulation with phorbol 12-myristate 13-acetate (PMA) as opposed to primary macrophages, as well as the higher concentration (625 nM) of TSA they used, which was highly toxic in our model.…”

Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth

“…Total RNA was extracted from PBMCs or macrophages using an RNeasy kit (Omega), and quantitative PCR was performed using a 7500 Fast Real-Time PCR System (Thermo Fisher Scientific) with SYBR Green PCR Master Mix (TaKaRa), according to the manufacturer’s instructions and as previously described ( 13 , 52 ). The primers obtained from the PrimerBank were as follows: FTH1 (forward: 5′-AGAACTACCACCAGGACTCA-3′; reverse: 5′-TCATCGCGGTCAAAGTAGTAAG-3′), FTL (forward: 5′-CAGCCTGGTCAATTTGTACCT-3′; reverse: 5′-GCCAATTCGCGGAAGAAGTG-3′), NCOA4 (forward: 5′-GAGGTGTAGTGATGCACGGAG-3′; reverse: 5′-GACGGCTTATGCAACTGTGAA-3′), HERC2 (forward: 5′-TCGCCTCGACTCCAAATGG-3′; reverse: 5′-TCTTTGTTCCACTTGGTTCGAC-3′), and TRIM21 (forward: 5′-TCAGCAGCACGCTTGACAAT-3′; reverse: 5′-GGCCACACTCGATGCTCAC -3′).…”

Flunarizine suppressesMycobacterium tuberculosisgrowth via calmodulin-dependent phagosome maturation

“…Macrophages were lysed in 300 μl of sterile PBS with 200 μl of 0.1% sodium dodecyl sulfate (SDS) (Sigma), and the lysates were plated at various dilutions on 7H9 plates, which were then incubated at 37°C for 21 days. The bactericidal activity of macrophages was determined by CFU counts 18 …”