Abstract

Histone deacetylases (HDACs) mediate the removal of acetyl groups from the histones of chromatin and regulate the expression of the genes involved in cancer development and immune cell functions. Our previous study showed that HDAC2 enhances IL-1β production by Mycobacterium tuberculosis (Mtb) infected macrophages by promoting inflammasome activation. HDAC1, on the other hand, regulates macrophage phagocytosis of Mtb. However, the mechanisms by which HDAC1 controls macrophage phagocytosis remain unclear.

Using human monocyte-derived macrophages (MDMs) and Mtb strains, we explore the mechanism of HDAC1 in macrophage phagocytosis of Mtb. Our results showed that blocking HDAC1, either chemically or genetically, reduced macrophage phagocytosis of Mtb and increased tubulin acetylation despite its colocalization with bacteria, decreased expression of Cdc42 and actin polymerization, important factors involved in the early steps of macrophage phagocytosis. Inhibiting HDAC6, a tubulin deacetylase, also decreased macrophage phagocytosis of Mtb and promoted tubulin acetylation. Notably, HDAC6 expression was minimal in human MDMs and macrophage cell lines compared to lung epithelial cells. Inhibition of HDAC6 increased IL-1β and suppressed IL-10 production by Mtb-infected macrophages in a similar manner as the inhibitor of HDAC1/2. Consistent with these results, molecular docking studies suggested that HDAC6 inhibitors could also interact with HDAC1 and HDAC2. Finally, genetic knockdown of HDAC1 reduced macrophage phagocytosis of Mtb increased acetylation of tubulin, and reduced expression of the key proteins of early phagocytosis.

These findings will help us understand tuberculosis pathogenesis and pave the way for developing novel host-directed therapeutics for controlling tuberculosis

Date of publication

Spring 5-28-2024

Document Type

Thesis

Language

english

Persistent identifier

http://hdl.handle.net/10950/4714

Committee members

Buka Samten, M.D, L. Vijaya Mohan Rao, Ph.D, Ramakrishna Vankayalapati, Ph.D, Pierre Neuenschwander, Ph.D.

Degree

Master of Science in Biotechnology

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