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Bacterial toxin sensing induces inflammasome-dependent innate immune memory that improves survival during sepsis [ATAC-seq]

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 in mouse macrophages 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 a murine sepsis model, toxin-induced TI enhanced host resistance and improved survival. These findings establish toxin-driven inflammasome activation as trigger of TI and reveal its protective function during bacterial sepsis.

ORGANISM(S): Mus musculus

PROVIDER: GSE337610 | GEO | 2026/10/01

REPOSITORIES: GEO

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

Project description: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 in mouse macrophages 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 a murine sepsis model, toxin-induced TI enhanced host resistance and improved survival. These findings establish toxin-driven inflammasome activation as trigger of TI and reveal its protective function during bacterial sepsis.

2026-10-01 | GSE337763 | GEO

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Project description:Bacterial sepsis is a major killer in hospitalized patients. Coagulase-negative staphylococci (CNS) with the leading species Staphylococcus epidermidis are the most frequent causes of nosocomial sepsis, with most infectious isolates being methicillin resistant. However, which bacterial factors underlie the pathogenesis of CNS sepsis is unknown. While it has been commonly believed that invariant structures on the surface of CNS trigger sepsis by causing an over-reaction of the immune system, we show here that sepsis caused my methicillin-resistant S. epidermidis is to a large extent mediated by the methicillin resistance island-encoded peptide toxin, PSM-mec. PSM-mec contributed to bacterial survival in whole human blood and resistance to neutrophil-mediated killing, and caused significantly increased mortality and cytokine expression in a mouse sepsis model. Furthermore, we show that the PSM-mec peptide itself, rather than the regulatory RNA in which its gene is embedded, is responsible for the observed virulence phenotype. While toxins have never been clearly indicated in CNS infections, our study shows that an important type of infection caused by the predominant CNS species, S. epidermidis, is mediated to a large extent by a toxin. Of note, these findings suggest that CNS infections may be amenable to virulence-targeted drug development approaches. We used microarrays to detail the global gene expression between S. epidermidis strain Rp62A and S. epidermidis strain Rp62A isogenic Δpsm-mec deletion mutants

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