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Mycobacterium tuberculosis Rv2626c-derived peptide as a therapeutic agent for sepsis.

ABSTRACT: The Rv2626c protein of Mycobacterium tuberculosis is a promising vaccine candidate owing to its strong serum antibody response in patients with tuberculosis. However, there is limited information regarding the intracellular response induced by Rv2626c in macrophages. In this study, we demonstrated that Rv2626c interacts with the RING domain of TRAF6 and inhibits lysine (K) 63-linked polyubiquitination of TRAF6 (E3 ubiquitin ligase activity); this results in the suppression of TLR4 inflammatory signaling in macrophages. Furthermore, we showed that the C-terminal 123-131-amino acid Rv2626c motif promotes macrophage recruitment, phagocytosis, M2 macrophage polarization, and subsequent bacterial clearance. We developed rRv2626c-CA, a conjugated peptide containing the C-terminal 123-131-amino acid Rv2626c that targets macrophages, penetrates the cell membrane, and has demonstrated significant therapeutic effects in a mouse model of cecal ligation and puncture-induced sepsis. This multifunctional rRv2626c-CA has considerably improved potency, with an IC₅₀ that is 250-fold (in vitro) or 1,000-fold (in vivo) lower than that of rRv2626c-WT. We provide evidence for new peptide-based drugs with anti-inflammatory and antibacterial properties for the treatment of sepsis.

SUBMITTER: Kim SY

PROVIDER: S-EPMC7721357 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Mycobacterium tuberculosis Rv2626c-derived peptide as a therapeutic agent for sepsis.

Kim Sun Young SY Kim Donggyu D Kim Sojin S Lee Daeun D Mun Seok-Jun SJ Cho Euni E Son Wooic W Jang Kiseok K Yang Chul-Su CS

EMBO molecular medicine 20201201 12

The Rv2626c protein of Mycobacterium tuberculosis is a promising vaccine candidate owing to its strong serum antibody response in patients with tuberculosis. However, there is limited information regarding the intracellular response induced by Rv2626c in macrophages. In this study, we demonstrated that Rv2626c interacts with the RING domain of TRAF6 and inhibits lysine (K) 63-linked polyubiquitination of TRAF6 (E3 ubiquitin ligase activity); this results in the suppression of TLR4 inflammatory s ...[more]

PMID: 33258196

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Project description:Nonribosomal peptide synthases produce short peptides in a manner that is distinct from classical mRNA-dependent ribosome-mediated translation. The Mycobacterium tuberculosis genome harbors a nonribosomal peptide synthase gene, nrp, which is part of a gene cluster proposed to be involved in the biosynthesis of isonitrile lipopeptides. Orthologous clusters are found in other slow-growing pathogenic mycobacteria and actinomycetes. To probe the role of the nrp gene in infection, we generated an nrp deletion mutant in M. tuberculosis H37Rv and tested its virulence in immunocompetent (C57BL/6) mice. The nrp mutant strain displayed lower initial growth rates in the lungs and a defective dissemination to the spleens of infected mice. Mice infected with the mutant strain also survived for twice as long as those infected with wild-type M. tuberculosis and, remarkably, showed subdued pathology, despite similar bacterial loads at later stages of infection. The differences in the course of infection between wild-type and nrp mutant strains were accompanied by distinct dynamics of the immune response. Most strikingly, the nrp mutant was highly attenuated in immunodeficient (SCID-, recombination activating 2 [RAG2]-, and gamma interferon [IFN-γ]-deficient) mice, suggesting that macrophages control the nrp mutant more efficiently than they control the wild-type strain. However, in the presence of IFN-γ, both strains were equally controlled. We propose that the nrp gene and its associated cluster are drivers of virulence during the early stages of infection.IMPORTANCE Over 10 million people developed tuberculosis (TB) in 2016, and over 1.8 million individuals succumbed to the disease. These numbers make TB the ninth leading cause of death worldwide and the leading cause from a single infectious agent. Therefore, finding novel therapeutic targets in Mycobacterium tuberculosis, the pathogen that causes most cases of human TB, is critical. In this study, we reveal a novel virulence factor in M. tuberculosis, the nrp gene. The lack of nrp highly attenuates the course of M. tuberculosis infection in the mouse model, which is particularly relevant in immune-deficient hosts. This is very relevant as TB is particularly incident in immune-suppressed individuals, such as HIV patients.

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Mycobacterium tuberculosis Rv2626c-derived peptide as a therapeutic agent for sepsis.

Publications

Mycobacterium tuberculosis Rv2626c-derived peptide as a therapeutic agent for sepsis.

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