Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health emergency. Macrophages are critical in protection against TB by phagocytosis of Mtb. Although histone deacetylases (HDACs), are critical in macrophage differentiations, their roles in macrophage phagocytosis of Mtb remain unexplored. To explore this, I first established human monocyte derived macrophages (MDMs) phagocytosis of red zymosan beads. MDM phagocytosed zymosan beads at 37°C in a dose dependent manner in contrast to suppressed phagocytosis by the MDMs incubated with beads at 4°C or in the presence of cytochalasin D, actin polymerization inhibitor. Incubation of MDMs with 11 zinc-dependent HDAC inhibitors did not suppress MDM phagocytosis of zymosan beads though pan-HDAC inhibitor Trichostatin A showed moderate inhibition effects. MDMs showed time, dose, and actin polymerization dependent phagocytosis of Mtb. Screening 11 zinc-dependent HDACs with their chemical inhibitors, DHOB, targeting HDAC1, and MS-275, targeting HDAC1 & 3, but not RGFP966, targeting HDAC3, suppressed macrophage phagocytosis of Mtb without affecting the cell viability as confirmed with MTT assay, indicating the role of HDAC1 in regulation of macrophage phagocytosis of Mtb. Knockdown (KD) of HDAC1 in human THP1 cell line with CRISPR-Cas9 significantly reduced Mtb phagocytosis compared to HDAC1 intact cells. Therefore, we conclude that HDAC1 is required for macrophage phagocytosis of Mtb.

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Buka Samten, MD, Thesis Director, L. Vijaya Mohan Rao, PhD, Committee Chair, RamaKrishna Vankayalapati, PhD, Committee Member, Nagarjun Konduru Venkata, PhD, Committee Member .


Masters of Science in Biotechnology

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