リステリア菌研究が独自のがん治療法開発につながる (Basic research on Listeria bacteria leads to unique cancer therapy)

2026-02-12 カリフォルニア大学バークレー校(UCB)

An electron micrograph of Listeria monocytogenes bacteria.Creative Commons

<関連情報>

• https://news.berkeley.edu/2026/02/12/basic-research-on-listeria-bacteria-leads-to-unique-cancer-therapy/
• https://journals.asm.org/doi/10.1128/mbio.03652-25
• https://www.biorxiv.org/content/10.1101/2025.10.13.682223v1
• https://www.nature.com/articles/s41586-018-0498-z

リステリア・モノサイトゲネスのフラビン代謝を再プログラム化することで、治療安全性プロファイルを改善し、自然T細胞活性化を拡大する Reprogramming Listeria monocytogenes flavin metabolism to improve its therapeutic safety profile and broaden innate T-cell activation

Victoria Chevée, Mariya Lobanovska, Rafael Rivera-Lugo, Leslie Güereca, Ying Feng, Andrea Anaya-Sanchez, Jesse Garcia Castillo, … , Daniel A. Portnoy
mBio  Published:31 December 2025
DOI:https://doi.org/10.1128/mbio.03652-25

ABSTRACT

Listeria monocytogenes is a facultative intracellular bacterial pathogen that is a potent inducer of cell-mediated immunity, which has led to the development of attenuated, Listeria-based cancer vaccines. L. monocytogenes strains, such as live-attenuated double-deleted Listeria (LADD), lacking two key virulence factors, ΔactA and ΔinlB, have been used safely in clinical trials and showed promising anti-tumor activity. Despite early clinical success, improving potency and safety by preventing extracellular bacterial growth is paramount for the development of further clinical applications. We describe a quadruple attenuated intracellular Listeria (QUAIL) strain that, in addition to ΔactAΔinlB, lacks ribC and ribF, which encode enzymes required for generating the essential flavin cofactors flavin mononucleotide (FMN) and flavin adenine nucleotide (FAD). QUAIL imported FMN and FAD during intracellular growth but was unable to grow extracellularly in blood or on vascular catheters in mice, which reduced its lethality. Despite its lack of extracellular growth, QUAIL maintained its immunoprotective properties, which were comparable to LADD. Furthermore, we showed that QUAIL can be engineered to synthesize riboflavin, leading to expansion and activation of mucosal-associated invariant T cells. Together, our data support the use of QUAIL as a promising therapeutic platform with an improved safety profile that is amenable to further modifications to expand its immune-activating potential.

遺伝子組み換えリステリアによって誘導されたMAIT細胞は抗菌および抗腫瘍活性を示す MAIT cells induced by engineered Listeria exhibit antibacterial and antitumor activity

Rafael Rivera-Lugo, Jesse Garcia Castillo, Mariya Lobanovska, Eugene Tang, Andrea Anaya-Sanchez, Scott Espich, Sarah A. Stanley, Michel DuPage, Daniel A. Portno
bioRXiv  Posted: October 14, 2025
DOI:https://doi.org/10.1101/2025.10.13.682223

Summary

Mucosal-associated invariant T (MAIT) cells are among the most conserved and abundant innate-like T cells in humans that recognize microbial-derived riboflavin precursors and elicit potent antimicrobial responses¹. The foodborne pathogen Listeria monocytogenes is a broad host-range facultative intracellular pathogen² that lacks the riboflavin biosynthetic pathway³, leading us to hypothesize that this deficiency is pathoadaptive and allows the pathogen to evade MAIT cells. Here, we show that L. monocytogenes strains engineered to produce riboflavin (L. monocytogenes-ribDEAHT) are attenuated in wild-type mice but fully virulent in MAIT cell-deficient mice. Infection with L. monocytogenes-ribDEAHT prompted rapid and robust MAIT cell expansion in multiple tissues and required the cytolytic effector perforin to eliminate infected cells in vivo and in vitro. We also assessed the therapeutic potential of L. monocytogenes-ribDEAHT- stimulated MAIT cells in both infectious disease and cancer mouse models. Infection with L. monocytogenes-ribDEAHT provided protection against Francisella tularensis in the lungs and inhibited tumor growth even in the absence of CD8⁺ T cells. These findings highlighted the importance of MAIT cell evasion during L. monocytogenes infection and reveal the therapeutic potential of engineered L. monocytogenes to activate and harness MAIT cells for protection against infectious disease and cancer.

多様なグラム陽性細菌におけるフラビンをベースとした細胞外電子伝達機構 A flavin-based extracellular electron transfer mechanism in diverse Gram-positive bacteria

Samuel H. Light,Lin Su,Rafael Rivera-Lugo,Jose A. Cornejo,Alexander Louie,Anthony T. Iavarone,Caroline M. Ajo-Franklin & Daniel A. Portnoy
Nature  Published:12 September 2018
DOI:https://doi.org/10.1038/s41586-018-0498-z

Abstract

Extracellular electron transfer (EET) describes microbial bioelectrochemical processes in which electrons are transferred from the cytosol to the exterior of the cell¹. Mineral-respiring bacteria use elaborate haem-based electron transfer mechanisms^2,3,4 but the existence and mechanistic basis of other EETs remain largely unknown. Here we show that the food-borne pathogen Listeria monocytogenes uses a distinctive flavin-based EET mechanism to deliver electrons to iron or an electrode. By performing a forward genetic screen to identify L. monocytogenes mutants with diminished extracellular ferric iron reductase activity, we identified an eight-gene locus that is responsible for EET. This locus encodes a specialized NADH dehydrogenase that segregates EET from aerobic respiration by channelling electrons to a discrete membrane-localized quinone pool. Other proteins facilitate the assembly of an abundant extracellular flavoprotein that, in conjunction with free-molecule flavin shuttles, mediates electron transfer to extracellular acceptors. This system thus establishes a simple electron conduit that is compatible with the single-membrane structure of the Gram-positive cell. Activation of EET supports growth on non-fermentable carbon sources, and an EET mutant exhibited a competitive defect within the mouse gastrointestinal tract. Orthologues of the genes responsible for EET are present in hundreds of species across the Firmicutes phylum, including multiple pathogens and commensal members of the intestinal microbiota, and correlate with EET activity in assayed strains. These findings suggest a greater prevalence of EET-based growth capabilities and establish a previously underappreciated relevance for electrogenic bacteria across diverse environments, including host-associated microbial communities and infectious disease.