The pseudokinase MLKL contributes to host defense against Streptococcus pluranimalium infection by mediating NLRP3 inflammasome activation and extracellular trap formation.

Host innate immunity plays a pivotal role in the early detection and neutralization of invading pathogens. Here, we show that pseudokinase mixed lineage kinase-like protein (MLKL) is required for host defence against Streptococcus pluranimalium infection by enhancing NLRP3 inflammasome activation and extracellular trap formation. Notably, Mlkl deficiency leads to increased mortality, increased bacterial colonization, severe destruction of organ architecture, and elevated inflammatory cell infiltration in murine models of S. pluranimalium pulmonary and systemic infection. In vivo and in vitro data provided evidence that potassium efflux-dependent NLRP3 inflammasome signalling downstream of active MLKL confers host protection against S. pluranimalium infection and initiates bacterial killing and clearance. Moreover, Mlkl deficiency results in defects in extracellular trap-mediated bactericidal activity. In summary, this study revealed that MLKL mediates the host defence response to S. pluranimalium, and suggests that MLKL is a potential drug target for preventing and controlling pathogen infection.

G Protein-Coupled Receptor 120 Mediates Host Defense against Clostridium perfringens Infection through Regulating NOD-like Receptor Family Pyrin Domain-Containing 3 Inflammasome Activation.

Clostridium perfringens is a major cause of infectious foodborne disease, frequently associated with the consumption of raw and undercooked food. Despite intensive studies on clarifying C. perfringens pathogenesis, the molecular mechanisms of host-pathogen interactions remain poorly understood. In soft tissue and mucosal infection models, Gpr120-/- mice, G protein-coupled receptor 120 (GPR120), are more susceptible to C. perfringens infection. Gpr120 deficiency leads to a low survival rate (30 and 10%, p < 0.01), more bacterial loads in the muscle (2.26 × 108 ± 2.08 × 108 CFUs/g, p < 0.01), duodenum (2.80 × 107 ± 1.61 × 107 CFUs/g, p < 0.01), cecum (2.50 × 108 ± 2.05 × 108 CFUs/g, p < 0.01), and MLN (1.23 × 106 ± 8.06 × 105 CFUs/g, p < 0.01), less IL-18 production in the muscle (8.54 × 103 ± 1.20 × 103 pg/g, p < 0.01), duodenum (3.34 × 103 ± 2.46 × 102 pg/g, p < 0.01), and cecum (3.81 × 103 ± 5.29 × 102 pg/g, p < 0.01), and severe organ injury. Obviously, GPR120 facilitates IL-18 production and pathogen control via potassium efflux-dependent NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling. Mechanistically, GPR120 interaction with NLRP3 potentiates the NLRP3 inflammasome assembly. Thus, this study uncovers a novel role of GPR120 in host protection and reveals that GPR120 may be a potential therapeutic target for limiting pathogen infection.

Erratum: Mixed lineage kinase-like protein protects against Clostridium perfringens infection by enhancing NLRP3 inflammasome-extracellular traps axis.

[This corrects the article DOI: 10.1016/j.isci.2022.105121.].

Mixed lineage kinase-like protein protects against Clostridium perfringens infection by enhancing NLRP3 inflammasome-extracellular traps axis.

Despite intense research in understanding Clostridium perfringens (C. perfringens) pathogenesis, the mechanisms by which it is cleared from the host are largely unclarified. In C. perfringens gas gangrene and enterocolitis model, Mlkl -/- mice, lacking mixed lineage kinase-like protein (MLKL), are more susceptible to C. perfringens infection. Mlkl deficiency results in a defect in inflammasome activation, and IL-18 and IL-1ß releases. Exogenous administration of recombinant IL-18 is able to rescue the susceptibility of Mlkl -/- mice. Notably, K+ efflux-dependent NLRP3 inflammasome signaling downstream of active MLKL promotes bacterial killing and clearance. Interestingly, the defect of bactericidal activity is also mediated by decreased classical extracellular trap formation in the absence of Mlkl. Our results demonstrate that MLKL mediates extracellular trap formation in a NLRP3 inflammasome-dependent manner. These findings highlight the requirement of MLKL for host defense against C. perfringens infection through enhancing NLRP3 inflammasome-extracellular traps axis.

Clinical value of dual-energy spectral imaging with adaptive statistical iterative reconstruction for reducing contrast medium dose in CT portal venography: in comparison with standard 120-kVp imaging protocol.

OBJECTIVE: To evaluate the clinical value of dual-energy spectral CT with adaptive statistical iterative reconstruction (ASiR) for reducing contrast medium dose in CT portal venography (CTPV). METHODS: This prospective study was institutional review board-approved, and written informed consent was obtained from all patients. 50 patients undergoing abdominal CT were randomized to 2 groups: Group A (n = 25), using spectral CT and 350 mgI kg(-1) contrast injection protocol; Group B (n = 25), using standard 120 kVp and 500 mgI kg(-1) contrast. Spectral CT images at 60 keV and standard 120-kVp images were both reconstructed with 50% ASiR. CT number and contrast-to-noise ratio (CNR) for intrahepatic and extrahepatic portal veins were measured. The maximum intensity projection (MIP) and volume-rendering (VR) images were used for subjective evaluation. These two kinds of results were statistically analyzed. RESULTS: CNR values for the intrahepatic portal vein of the 60-keV spectral images (4.2 ± 1.1) were higher than those of 120-kVp images (3.0 ± 2.1) (p = 0.03) and were the same for the extrahepatic portal vein (5.9 ± 1.4 vs 5.9 ± 1.6, p = 0.90). The portal vein and left and right branches in the 60-keV spectral images had higher CT number and lower standard deviation than the 120-kVp images (p < 0.05). Radiation dose (dose-length product and effective dose) and subjective image quality were similar for the two groups, while the spectral CT group required 25% less iodine dose (23.1 ± 3.2 g vs 30.5 ± 5.0 g). CONCLUSION: The 60-keV spectral CT images with ASiR allow 25% reduction in the iodine dose while providing better or equal image quality as the standard 120-kVp images in portal venography with comparable radiation dose. ADVANCES IN KNOWLEDGE: Compared with conventional 120-kVp CT, the use of 60-keV spectral CT images provides 25% contrast dose reduction with similar image quality in CTPV. Compared with conventional 120-kVp CT, the use of 60-keV spectral CT images with ASiR algorithm improves CNR values for the intrahepatic portal vein.