Staphylococcus aureus is a major human pathogen that causes an array of infections ranging from minor skin infections to more serious infections including osteomyelitis, endocarditis, necrotizing pneumonia and sepsis 1 . These more serious infections usually arise from an initial bloodstream infection and are frequently recalcitrant to antibiotic treatment 1 . Phagocytosis by macrophages and neutrophils is the primary mechanism by which S. aureus infection is controlled by the immune system 2 . Macrophages have been shown to be a major reservoir of S. aureus in vivo 3 but the role of macrophages in the induction of antibiotic tolerance has not been explored. Here we show that macrophages not only fail to efficiently kill phagocytosed S. aureus but also induce tolerance to multiple antibiotics. Reactive oxygen species (ROS) generated by respiratory burst attack iron-sulfur (Fe-S) cluster containing proteins, including TCA cycle enzymes, resulting in decreased respiration, lower ATP and increased antibiotic tolerance. We further show that during a murine systemic infection, respiratory burst induces antibiotic tolerance in the spleen. These Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

SUMMARY Increased glucose metabolism in immune cells not only serves as a hallmark feature of acute inflammation, but also profoundly affects disease outcome following bacterial infection and tissue damage. However, the role of individual glucose metabolic pathways during viral infection remains largely unknown. Here we demonstrate an essential function of the hexosamine biosynthesis pathway (HBP)-associated O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in promoting antiviral innate immunity. Challenge of macrophages with vesicular stomatitis viruses (VSV) enhances HBP activity and downstream protein O-GlcNAcylation. Human and murine cells deficient of O-GlcNAc transferase, a key enzyme for protein O-GlcNAcylation, show defective antiviral immune responses upon VSV challenge. Mechanistically, OGT-mediated O-GlcNAcylation of the signaling adaptor MAVS on serine 366 (S366) is required for K63-linked ubiquitination of MAVS and subsequent downstream RLR-antiviral signaling activation. Thus, our study identifies a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates MAVS function and highlights the importance of glucose metabolism on antiviral innate immunity.

Li et al. show that OGT-mediated STAT3 O-GlcNAcylation, which is modulated by CUL3-Nrf2 signaling, negatively regulates STAT3 phosphorylation and IL-10 production in macrophages and exacerbates experimental colitis and colitis-associated cancer.

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Intracellular pathogens pose a significant threat to animals. In defense, innate immune sensors attempt to detect these pathogens using pattern recognition receptors that either directly detect microbial molecules or indirectly detect their pathogenic activity. These sensors trigger different forms of regulated cell death, including pyroptosis, apoptosis, and necroptosis, which eliminate the infected host cell niche while simultaneously promoting beneficial immune responses. These defenses force intracellular pathogens to evolve strategies to minimize or completely evade the sensors. In this review, we discuss recent advances in our understanding of the cytosolic pattern recognition receptors that drive cell death, including NLRP1, NLRP3, NLRP6, NLRP9, NLRC4, AIM2, IFI16, and ZBP1. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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This study aims to investigate the menstrual recovery outcome of scar pregnancy patients who received uterine artery embolization combined with curettage, and its influencing factors.The data of 119 patients with scar pregnancy, who received uterine artery embolization combined with curettage between December 2012 and December 2016 in Henan Provincival People's Hospital, were collected. The menstruation recovery of these patients was followed up, and factors that have influence on menstrual blood volume were analyzed using SPSS V.17.0.Follow-up data were available in 101/119 (84.9%) women. The median follow-up time was 22.7 months (range: 1.6–50.6 months); 58 (57.4%) patients had reduced menstrual blood volume, and 2 patients (2%) had amenorrhea. The proportion of patients with reduced menstrual blood volume, who were embolized with polyvinyl alcohol (PVA), PVA combined with gelatin sponge, and gelatin sponge between < and ≥33 years old was 41.7% versus 66.7%, 40% versus 57.1% and 60.6% versus 68.0%. The average age of patients with reduced menstrual blood volume (34.3 years) was greater than patients with normal menstrual blood volume (31.4 years), but the difference was not statistically significant (P = .07).Reduced menstrual blood volume can occur in scar pregnancy patients who received uterine artery embolization combined with curettage. The influence of the embolic agent PVA on menstrual blood volume depends on age, but the difference was not statistically significant.

Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in regulating innate immune function. Mitochondrial Ca 2+ uptake via the mitochondrial Ca 2+ uniporter (MCU) is an essential process regulating mitochondrial metabolism by targeting key enzymes involved in the tricarboxylic acid cycle (TCA). Accumulative evidence suggests MCU-dependent mitochondrial Ca 2+ signaling may bridge the metabolic reprogramming and regulation of immune cell function. However, the mechanism by which MCU regulates inflammation and its related disease remains elusive. Here we report a critical role of MCU in promoting phagocytosis-dependent activation of NLRP3 (nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain-containing 3) inflammasome by inhibiting phagolysosomal membrane repair. Myeloid deletion of MCU ( Mcu Δmye ) resulted in an attenuated phagolysosomal rupture, leading to decreased caspase-1 cleavage and interleukin (IL)-1β release, in response to silica or alum challenge. In contrast, other inflammasome agonists such as adenosine triphosphate (ATP), nigericin, poly(dA:dT), and flagellin induced normal IL-1β release in Mcu Δmye macrophages. Mechanistically, we demonstrated that decreased NLRP3 inflammasome activation in Mcu Δmye macrophages was caused by improved phagolysosomal membrane repair mediated by ESCRT (endosomal sorting complex required for transport)-III complex. Furthermore, Mcu Δmye mice showed a pronounced decrease in immune cell recruitment and IL-1β production in alum-induced peritonitis, a typical IL-1–dependent inflammation model. In sum, our results identify a function of MCU in promoting phagocytosis-dependent NLRP3 inflammatory response via an ESCRT-mediated phagolysosomal membrane repair mechanism.