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The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome.

• Numerous hospital disinfectants are known to affect N95 FFR filtration performance. • Hypochlorous acid spray does not affect N95 FFR material's filtration performance. • Soaking N95 FFRs in HOCl can achieve decontamination, but not HOCl spray. Stabilized hypochlorous acid (HOCl) is increasingly used as a hospital disinfectant and antiseptic, yet its effect on N95 filtration facemask respirators (FFR) is unknown. These FFRs could also contribute to fomite-based transmission of nosocomial infections if worn for extended use between patient rooms. Filtration performance of N95 FFR fabric swatches was assessed after various levels of HOCl exposure. N95 swatches were then contaminated with 108 Escherichia coli or 108 Staphylococci aureus and treated with HOCl solution, 70% ethyl alcohol, or normal saline. Surviving bacterial numbers were assessed by plate counts. The size-dependent filtration efficiency of HOCl-sprayed N95 FFR fabric ranged from 96% to 100%, showing no significant change. Flow resistance testing revealed almost no change compared to control. Submersion in HOCl, but not spraying, had an excellent bactericidal effect on contaminated swatches. The role of the outer hydrophobic layer of N95 FFRs is discussed regarding the effects of HOCl on filtration and bacterial decontamination. N95 material, sprayed with or briefly submerged in HOCl, maintained its filtration function. HOCl delivery by spray pump, however, would not accomplish decontamination of extended use FFRs between patient encounters. HOCl submersion of intact FFRs, contaminated with various hospital pathogens, is worth further study. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a gaseous signalling molecule that plays diverse physiological functions including antimicrobial host defence. During microbial infection, NO is synthesized by inducible NO synthase (iNOS), which is expressed by host immune cells through the recognition of microbial pattern molecules. Therefore, sensing pathogens or their pattern molecules by pattern recognition receptors (PRRs), which are located at the cell surface, endosomal and phagosomal compartment, or in the cytosol, is key in inducing iNOS and eliciting antimicrobial host defence. A group of cytosolic PRRs is involved in inducing NO and other antimicrobial molecules by forming a molecular complex called the inflammasome. Assembled inflammasomes activate inflammatory caspases, such as caspase-1 and caspase-11, which in turn process proinflammatory cytokines IL-1ß and IL-18 into their mature forms and induce pyroptotic cell death. IL-1ß and IL-18 play a central role in immunity against microbial infection through activation and recruitment of immune cells, induction of inflammatory molecules, and regulation of antimicrobial mediators including NO. Interestingly, NO can also regulate inflammasome activity in an autocrine and paracrine manner. Here, we discuss molecular mechanisms of inflammasome formation and the inflammasome-mediated regulation of host defence responses during microbial infections. [ABSTRACT FROM AUTHOR]

Pathogen recognition receptors are vital components of the immune system. Engagement of these receptors is important not only for instigation of innate immune responses to invading pathogens but also for initiating the adaptive immune response. Members of the NOD-like receptor (NLR) family of pathogen recognition receptors have important roles in orchestrating this response. The NLR family member NLRC5 regulates major histocompatibility complex class I (MHC-I) expression during various types of infections, but its role in immunity to influenza A virus (IAV) is not well studied. Here we show that Nlrc5-/- mice exhibit an altered CD8+ T cell response during IAV infection compared to that of wild-type (WT) mice. Nlrc5-/- mice have decreased MHC-I expression on hematopoietic cells and fewer CD8+ T cells prior to infection. NLRC5 deficiency does not affect the generation of antigen-specific CD8+ T cells following IAV infection; however, a change in epitope dominance is observed in Nlrc5-/- mice. Moreover, IAV-specific CD8+ T cells from Nlrc5-/- mice have impaired effector functions. This change in the adaptive immune response is associated with impaired viral clearance in Nlrc5-/- mice. Collectively, our results demonstrate an important role for NLRC5 in regulation of antiviral immune responses and viral clearance during IAV infection. IMPORTANCE The NOD-like receptor family member NLRC5 is known to regulate expression of MHC-I as well as other genes required for antigen processing. In addition, NLRC5 also regulates various immune signaling pathways. In this study, we investigated the role of NLRC5 during influenza virus infection and found a major role for NLRC5 in restricting virus replication and promoting viral clearance. The observed increases in viral titers in NLRC5-deficient mice correlated with impaired effector CD8+ T cell responses. Although NLRC5-deficient mice were defective at clearing the virus, they did not show an increase in morbidity or mortality following influenza virus infection because of other compensatory immune mechanisms. Therefore, our study highlights how NLRC5 regulates multiple immune effector mechanisms to promote the host defense during influenza virus infection. [ABSTRACT FROM AUTHOR]