Bacterial toxin sensing induces transient inflammasome-dependent innate immune memory that improves survival during sepsis

Abstract Adaptive immune memory generated by bacterial toxin vaccination is well established, but whether bacterial toxins can also induce innate immune memory, or trained immunity (TI), remains unclear. Here, we show that bacterial toxins elicit TI through NLRP3 inflammasome activation both in vitro and in vivo in mice, and that this response is conserved in primary human macrophages. Stimulation with the CNF1 toxin induced an epigenetic remodeling, defining a TI-associated transcriptional signature. A targeted RNAi screen identified Bcl2a1 as a required mediator of TI, and epistasis analyses demonstrated that IL-1 signaling is essential for TI induction in macrophages. In our mouse sepsis model, toxin-induced TI enhanced host resistance and improved survival. These findings establish toxin-driven inflammasome activation as trigger of transient TI and demonstrate that this response enhance resistance during experimental bacterial sepsis.

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Publication Details

Journal
Nature Communications
Published
2026-10-08
DOI
https://doi.org/10.1038/s41467-026-78499-5
Primary Topic
Immune responses and vaccinations
Type
article
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article

Bacterial toxin sensing induces transient inflammasome-dependent innate immune memory that improves survival during sepsis

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Immune responses and vaccinations
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Bacterial toxin sensing induces transient inflammasome-dependent innate immune memory that improves survival during sepsis

Paul Chaintreuil, Els Verhoeyen, Patrick M. Munro, Bénédicte F. Py, Stoyan Ivanov, Céline Loubatier, Jessica Quintin, Valentine Marion, Orane Visvikis, Dorota Czerucka, Cédric Torre, Grégory Michel, Anne Doye, Océane Dufies, Alexandre Gallerand, Laurent Boyer, Ludovic Batistic, Margot Saissi, Zakaryia Caillot
article en

Abstract

Abstract Adaptive immune memory generated by bacterial toxin vaccination is well established, but whether bacterial toxins can also induce innate immune memory, or trained immunity (TI), remains unclear. Here, we show that bacterial toxins elicit TI through NLRP3 inflammasome activation both in vitro and in vivo in mice, and that this response is conserved in primary human macrophages. Stimulation with the CNF1 toxin induced an epigenetic remodeling, defining a TI-associated transcriptional signature. A targeted RNAi screen identified Bcl2a1 as a required mediator of TI, and epistasis analyses demonstrated that IL-1 signaling is essential for TI induction in macrophages. In our mouse sepsis model, toxin-induced TI enhanced host resistance and improved survival. These findings establish toxin-driven inflammasome activation as trigger of transient TI and demonstrate that this response enhance resistance during experimental bacterial sepsis.

Nature Communications
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Immune responses and vaccinations
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