Pyruvate dehydrogenase kinase inhibitor dichloroacetate augments autophagy mediated constraining the replication of Mycobacteroides massiliense in macrophages

Hailian Quan; Hyewon Chung; Sungmo Je; Jung Joo Hong; Bum-Joon Kim; Yi Rang Na; Seung Hyeok Seok

doi:10.1016/j.micinf.2023.105139

Pyruvate dehydrogenase kinase inhibitor dichloroacetate augments autophagy mediated constraining the replication of Mycobacteroides massiliense in macrophages

Microbes Infect. 2023 Sep-Oct;25(7):105139. doi: 10.1016/j.micinf.2023.105139. Epub 2023 Apr 19.

Authors

Hailian Quan¹, Hyewon Chung², Sungmo Je¹, Jung Joo Hong³, Bum-Joon Kim⁴, Yi Rang Na⁵, Seung Hyeok Seok⁶

Affiliations

¹ Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, Republic of Korea.
² Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, Republic of Korea; Bio-MAX Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
³ National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si, South Korea; KRIBB School of Bioscience, Korea University of Science & Technology (UST), Daejeon, South Korea.
⁴ Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁵ Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address: [email protected].
⁶ Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: [email protected].

PMID: 37085043
DOI: 10.1016/j.micinf.2023.105139

Abstract

Increasing evidence indicates a strong interaction between cellular metabolism and innate macrophage immunity. Here, we show that the intracellular replication of Mycobacteroides massiliense in macrophages depends on host pyruvate dehydrogenase kinase (PDK) activity. Infection with M. massiliense induced a metabolic switch in macrophages by increasing glycolysis and decreasing oxidative phosphorylation. Treatment with dichloroacetate (DCA), a PDK inhibitor, converts this switch in M. massiliense-infected macrophages and restricts intracellular bacterial replication. Mechanistically, DCA resulted in AMPKα1 activation via increased AMP/ATP ratio, consequently inducing autophagy to constrain bacterial proliferation in the phagolysosome. This study suggests that the pharmacological inhibition of PDK could be a strategy for host-directed therapy to control virulent M. massiliense infections.

Keywords: Antimicrobial activity; Autophagy; Dichloroacetate; Host immune defense; Mycobacteroides massiliense.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autophagy
Glycolysis*
Macrophages / metabolism
Protein Serine-Threonine Kinases* / metabolism
Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism

Substances

Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Protein Serine-Threonine Kinases