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

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.

Emerging Issues and Initial Insights into Bacterial Biofilms: From Orthopedic Infection to Metabolomics

“…Kim et al report host-directed therapeutic effects against mycobacterial infections. In their study, itaconate significantly suppressed the production of interleukin-6 and 10, whereas it enhanced phagosome maturation [151].…”

Itaconic acid inhibits nontuberculous mycobacterial growth in pH dependent manner while 4-octyl-itaconic acid enhances THP-1 clearance of nontuberculous mycobacteria in vitro

“…If a sufficient amount of itaconate is located in the airway and/or readily available to the macrophages encountering mycobacteria it could potentially serve to completely halt and/or eliminate any bacterial proliferation. A recent study by Kim et al found that dimethyl itaconate (DMI) could be a promising candidate for host-directed therapeutics against both MTB and NTM due to its ability to activate multiple innate immune responses [84].…”

Itaconate family-based host-directed therapeutics for infections

“…Moreover, ITA reduces intracellular Escherichia coli at later time points in macrophages, at least in part by increasing phagocytosis and bactericidal activity ( 41 ). In addition, DMI suppresses intracellular growth of Mtb, M. avium , even of multidrug resistant Mtb in macrophages, partly associated with the induction of autophagy ( 22 ). In Zika virus infection of neurons, receptor interacting protein kinase 1 (RIPK1) and RIPK3 signaling suppresses viral replication via IRG1-mediated ITA production ( 42 ).…”