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Dimethyl itaconate is effective in host-directed antimicrobial responses against mycobacterial infections through multifaceted innate immune pathways

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Author(s)
Young Jae KimEun-Jin ParkSang-Hee LeePrashanta SilwalJin Kyung KimJeong Seong YangJake WhangJichan JangJin-Man KimEun-Kyeong Jo
Keimyung Author(s)
Kim, Jin Kyung
Department
Dept. of Microbiology (미생물학)
Journal Title
Cell Biosci
Issued Date
2023
Volume
13
Issue
1
Keyword
Antimicrobial responsesAutophagyDimethyl itaconateHost-directed therapeuticsInnate immunityMycobacterium tuberculosisNontuberculous mycobacteria
Abstract
Background:
Itaconate, a crucial immunometabolite, plays a critical role in linking immune and metabolic functions to influence host defense and inflammation. Due to its polar structure, the esterified cell-permeable derivatives of itaconate are being developed to provide therapeutic opportunities in infectious and inflammatory diseases. Yet, it remains largely uncharacterized whether itaconate derivatives have potentials in promoting host-directed therapeutics (HDT) against mycobacterial infections. Here, we report dimethyl itaconate (DMI) as the promising candidate for HDT against both Mycobacterium tuberculosis (Mtb) and nontuberculous mycobacteria by orchestrating multiple innate immune programs.

Results:
DMI per se has low bactericidal activity against Mtb, M. bovis Bacillus Calmette-Guérin (BCG), and M. avium (Mav). However, DMI robustly activated intracellular elimination of multiple mycobacterial strains (Mtb, BCG, Mav, and even to multidrug-resistant Mtb) in macrophages and in vivo. DMI significantly suppressed the production of interleukin-6 and -10, whereas it enhanced autophagy and phagosomal maturation, during Mtb infection. DMI-mediated autophagy partly contributed to antimicrobial host defenses in macrophages. Moreover, DMI significantly downregulated the activation of signal transducer and activator of transcription 3 signaling during infection with Mtb, BCG, and Mav.

Conclusion:
Together, DMI has potent anti-mycobacterial activities in macrophages and in vivo through promoting multifaceted ways for innate host defenses. DMI may bring light to new candidate for HDT against Mtb and nontuberculous mycobacteria, both of which infections are often intractable with antibiotic resistance.
Keimyung Author(s)(Kor)
김진경
Publisher
School of Medicine (의과대학)
Type
Article
ISSN
2045-3701
Source
https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-023-00992-x
DOI
10.1186/s13578-023-00992-x
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/44959
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Microbiology (미생물학)
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