A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome

Mathur, Anukriti; Feng, Shouya; Hayward, Jenni A.; Ngo, Chinh; Fox, Daniel; Atmosukarto, Ines I.; Price, John F.; Schauer, Kristina; Märtlbauer, Erwin; Robertson, Avril A. B.; Burgio, Gaétan; Fox, Edward M.; Leppla, Stephen H.; Kaakoush, Nadeem O.; Man, Si Ming

doi:10.1038/s41564-018-0318-0

Cited by 90 publications

(100 citation statements)

References 79 publications

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“…Stimulation of primary wildtype (WT) bone marrow-derived macrophages (BMDMs) with the supernatant of WT B. cereus led to activation of caspase-1, cleavage of GSDMD, secretion of IL-1β and IL-18, and pyroptosis within 3 h, whereas stimulation of WT BMDMs with the supernatant of an isogenic mutant of B. cereus lacking HBL (ΔHbl B. cereus) did not ( Fig. 1a-d), consistent with our previous findings 31 . However, we were surprised to find that WT BMDMs treated overnight with the supernatant of ΔHbl B. cereus underwent robust activation of caspase-1, cleavage of GSDMD, secretion of IL-1β and IL-18, and induction of cell death ( Fig.…”

Section: Resultssupporting

confidence: 91%

“…A non-redundant secreted factor of B. cereus activates NLRP3. We have previously demonstrated that innate immune recognition of Bacillus cereus infection requires inflammasome-mediated sensing of a toxin known as HBL 31 . Stimulation of primary wildtype (WT) bone marrow-derived macrophages (BMDMs) with the supernatant of WT B. cereus led to activation of caspase-1, cleavage of GSDMD, secretion of IL-1β and IL-18, and pyroptosis within 3 h, whereas stimulation of WT BMDMs with the supernatant of an isogenic mutant of B. cereus lacking HBL (ΔHbl B. cereus) did not ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We and others have shown that more structurally diverse toxins can induce activation of the NLRP3 inflammasome via a mechanism independent of entry to the host cell cytoplasm. These toxins include haemolysins of Staphylococcus aureus [25][26][27][28] and Escherichia coli 29,30 , and haemolysin BL (HBL) of B. cereus 31 .…”

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Bacillus cereus non-haemolytic enterotoxin activates the NLRP3 inflammasome

et al. 2020

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Inflammasomes are important for host defence against pathogens and homeostasis with commensal microbes. Here, we show non-haemolytic enterotoxin (NHE) from the neglected human foodborne pathogen Bacillus cereus is an activator of the NLRP3 inflammasome and pyroptosis. NHE is a non-redundant toxin to haemolysin BL (HBL) despite having a similar mechanism of action. Via a putative transmembrane region, subunit C of NHE initiates binding to the plasma membrane, leading to the recruitment of subunit B and subunit A, thus forming a tripartite lytic pore that is permissive to efflux of potassium. NHE mediates killing of cells from multiple lineages and hosts, highlighting a versatile functional repertoire in different host species. These data indicate that NHE and HBL operate synergistically to induce inflammation and show that multiple virulence factors from the same pathogen with conserved function and mechanism of action can be exploited for sensing by a single inflammasome.

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confidence: 91%

Section: Resultsmentioning

confidence: 99%

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Bacillus cereus non-haemolytic enterotoxin activates the NLRP3 inflammasome

et al. 2020

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“…The NCBI reference sequences of Bcp1 and PlyB are NC_024137 and YP_009031336, respectively. In the current study, we have extended our previous work to now provide a more detailed characterization of Bcp1 and PlyB (alone and in combination with PlyG endolysin) as antimicrobial agents to address the now growing threat of B. cereus sensu lato organisms as human pathogens (23)(24)(25)(26)(27). Novel antimicrobial agents with differentiated mechanisms of action are highly desirable in an age of emerging and spreading antibiotic resistance.…”

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confidence: 89%

The PlyB Endolysin of Bacteriophage vB_BanS_Bcp1 Exhibits Broad-Spectrum Bactericidal Activity against Bacillus cereus Sensu Lato Isolates

Schuch

Pelzek

Nelson

et al. 2019

Appl Environ Microbiol

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Lytic bacteriophages (or phages) drive bacterial mortality by elaborating exquisite abilities to bind, breach, and destroy bacterial cell membranes and subjugate critical bacterial cell functions. These antimicrobial activities make phages ideal candidates to serve as, or provide sources of, biological control measures for bacterial pathogens. In this study, we isolated the Myoviridae phage vB_BanS_Bcp1 (here referred to as Bcp1) from landfill soil, using a Bacillus anthracis host. The antimicrobial activities of both Bcp1 and its encoded endolysin, PlyB, were examined across different B. cereus sensu lato group species, including B. cereus sensu stricto, Bacillus thuringiensis, and Bacillus anthracis, with pathogenic potential in humans and multiple different uses in biotechnological applications. The Bcp1 phage infected only a subset (11 to 66%) of each B. cereus sensu lato species group tested. In contrast, functional analysis of purified PlyB revealed a potent bacteriolytic activity against all B. cereus sensu lato isolates tested (n ϭ 79). PlyB was, furthermore, active across broad temperature, pH, and salt ranges, refractory to the development of resistance, bactericidal as a single agent, and synergistic with a second endolysin, PlyG. To confirm the potential for PlyB as an antimicrobial agent, we demonstrated the efficacy of a single intravenous treatment with PlyB alone or combination with PlyG in a murine model of lethal B. anthracis infection. Overall, our findings show exciting potential for the Bcp1 bacteriophage and the PlyB endolysin as potential new additions to the antimicrobial armamentarium. IMPORTANCE Organisms of the Bacillus cereus sensu lato lineage are ubiquitous in the environment and are responsible for toxin-mediated infections ranging from severe food poisoning (B. cereus sensu stricto) to anthrax (Bacillus anthracis). The increasing incidence of many of these infections, combined with the specter of antibiotic resistance, has created a need for novel antimicrobials with potent activity, including bacteriophages (or phages) and phage-encoded products (i.e., endolysins). In this study, we describe a broadly infective phage, Bcp1, and its encoded endolysin, PlyB, which exhibited a rapidly bacteriolytic effect against all B. cereus sensu lato isolates tested with no evidence of evolving resistance. Importantly, PlyB was highly efficacious in a mouse model of lethal bacteremia with B. anthracis. Both the Bcp1 phage and the PlyB endolysin represent novel mechanisms of action compared to antibiotics, with potential applications to address the evolving problem of antimicrobial resistance.

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“…[22][23][24] The NLRP3 inflammasome has been extensively studied in the past two decades. Several stimuli have been reported to trigger NLRP3 inflammasome activation, including endogenous danger signals like ATP, [4][5][6] ionophores like nigericin, 5 particulate matter such as silica and uric acid crystals, 6 viral infection like influenza A virus (IAV), [25][26][27][28] Gram-positive bacterial infection such as Bacillus cereus, 29 Gram-negative bacterial infection like Citrobacter rodentium and Escherichia coli, [30][31][32] and fungal infection like Candida albicans and Aspergillus fumigatus [33][34][35] (Figure 1). Given the diverse stimuli that can activate the NLRP3 inflammasome, it is unlikely that NLRP3 directly binds to these diverse ligands.…”

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confidence: 99%

The regulation of the ZBP1‐NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)

Zheng

Kanneganti

2020

Immunological Reviews

298

172

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ZBP1 has been characterized as a critical innate immune sensor of not only viral RNA products but also endogenous nucleic acid ligands. ZBP1 sensing of the Z‐RNA produced during influenza virus infection induces cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). PANoptosis is a coordinated cell death pathway that is driven through a multiprotein complex called the PANoptosome and enables crosstalk and co‐regulation among these processes. During influenza virus infection, a key step in PANoptosis and PANoptosome assembly is the formation of the ZBP1‐NLRP3 inflammasome. When Z‐RNA is sensed, ZBP1 recruits RIPK3 and caspase‐8 to activate the ZBP1‐NLRP3 inflammasome. Several other host factors have been found to be important for ZBP1‐NLRP3 inflammasome assembly, including molecules involved in the type I interferon signaling pathway and caspase‐6. Additionally, influenza viral proteins, such as M2, NS1, and PB1‐F2, have also been shown to regulate the ZBP1‐NLRP3 inflammasome. This review explains the functions of ZBP1 and the mechanistic details underlying the activation of the ZBP1‐NLRP3 inflammasome and the formation of the PANoptosome. Improved understanding of the ZBP1‐NLRP3 inflammasome will direct the development of therapeutic strategies to target infectious and inflammatory diseases.

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A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome

Cited by 90 publications

References 79 publications

Bacillus cereus non-haemolytic enterotoxin activates the NLRP3 inflammasome

Bacillus cereus non-haemolytic enterotoxin activates the NLRP3 inflammasome

The PlyB Endolysin of Bacteriophage vB_BanS_Bcp1 Exhibits Broad-Spectrum Bactericidal Activity against Bacillus cereus Sensu Lato Isolates

The regulation of the ZBP1‐NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)

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