bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022‒12‒04
27 papers selected by
Dylan Ryan
University of Cambridge
  1. Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut-lung axis.
  2. Intestinal microbe-derived metabolites instruct macrophages in the lungs.
  3. IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein.
  4. Vitamin B5 rewires Th17 cell metabolism via impeding PKM2 nuclear translocation.
  5. Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.
  6. Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.
  7. mTORC1 links pathology in experimental models of Still's disease and macrophage activation syndrome.
  8. ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
  9. Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages.
  10. MyD88-dependent signaling drives toll-like receptor-induced trained immunity in macrophages.
  11. The signaling pathways and therapeutic potential of itaconate to alleviate inflammation and oxidative stress in inflammatory diseases.
  12. Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment - Disease-Specific Findings (Part 1).
  13. Two for the price of one: itaconate and its derivatives as an anti-infective and anti-inflammatory immunometabolite.
  14. D-2HG comes out of its shell: Metabolic effects on the immune environment.
  15. Human cytomegalovirus induces neuronal enolase to support virally mediated metabolic remodeling.
  16. Deficiency of immune-responsive gene 1 exacerbates interleukin-1beta-elicited the inflammatory response of chondrocytes via enhancing the activation of NLRP3 inflammasome.
  17. Tim-4 reprograms cholesterol metabolism to suppress antiviral innate immunity by disturbing the Insig1-SCAP interaction in macrophages.
  18. The mitochondrial gene-CMPK2 functions as a rheostat for macrophage homeostasis.
  19. Indoleamine 2,3-dioxygenase 1 signaling orchestrates immune tolerance in Echinococcus multilocularis-infected mice.
  20. Decorin promotes decidual M1-like macrophage polarization via mitochondrial dysfunction resulting in recurrent pregnancy loss.
  21. 4-Octyl itaconate regulates immune balance by activating Nrf2 and negatively regulating PD-L1 in a mouse model of sepsis.
  22. Impact of ATP-citrate lyase catalytic activity and serine 455 phosphorylation on histone acetylation and inflammatory responses in human monocytic THP-1 cells.
  23. The role of NAD+ metabolism in macrophages in age-related macular degeneration.
  24. Substrate stiffness enhances human regulatory T cell induction and metabolism.
  25. NAMPT inhibition reduces macrophage inflammation through the NAD+/PARP1 pathway to attenuate liver ischemia-reperfusion injury.
  26. Manganese enhances macrophage defense against Mycobacterium tuberculosis via the STING-TNF signaling pathway.
  27. Bacterial origins of cyclic nucleotide-activated antiviral immune signaling.
  1. Nat Immunol. 2022 Dec 01.
    Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut-lung axis.
    Mangalakumari Jeyanathan, Maryam Vaseghi-Shanjani, Sam Afkhami, Jensine A Grondin, Alisha Kang, Michael R D'Agostino, Yushi Yao, Shreya Jain, Anna Zganiacz, Zachary Kroezen, Meera Shanmuganathan, Ramandeep Singh, Anna Dvorkin-Gheva, Philip Britz-McKibbin, Waliul I Khan, Zhou Xing.
      Aside from centrally induced trained immunity in the bone marrow (BM) and peripheral blood by parenteral vaccination or infection, evidence indicates that mucosal-resident innate immune memory can develop via a local inflammatory pathway following mucosal exposure. However, whether mucosal-resident innate memory results from integrating distally generated immunological signals following parenteral vaccination/infection is unclear. Here we show that subcutaneous Bacillus Calmette-Guérin (BCG) vaccination can induce memory alveolar macrophages (AMs) and trained immunity in the lung. Although parenteral BCG vaccination trains BM progenitors and circulating monocytes, induction of memory AMs is independent of circulating monocytes. Rather, parenteral BCG vaccination, via mycobacterial dissemination, causes a time-dependent alteration in the intestinal microbiome, barrier function and microbial metabolites, and subsequent changes in circulating and lung metabolites, leading to the induction of memory macrophages and trained immunity in the lung. These data identify an intestinal microbiota-mediated pathway for innate immune memory development at distal mucosal tissues and have implications for the development of next-generation vaccine strategies against respiratory pathogens.
    DOI:  https://doi.org/10.1038/s41590-022-01354-4
  2. Nat Immunol. 2022 Dec 01.
    Intestinal microbe-derived metabolites instruct macrophages in the lungs.
    Antoine Roquilly, Jose A Villadangos.
      
    DOI:  https://doi.org/10.1038/s41590-022-01358-0
  3. Sci Immunol. 2022 Dec 09. 7(78): eade5686
    IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein.
    Silvia Gaggero, Jonathan Martinez-Fabregas, Adeline Cozzani, Paul K Fyfe, Malo Leprohon, Jie Yang, F Emil Thomasen, Hauke Winkelmann, Romain Magnez, Alberto G Conti, Stephan Wilmes, Elizabeth Pohler, Manuel van Gijsel Bonnello, Xavier Thuru, Bruno Quesnel, Fabrice Soncin, Jacob Piehler, Kresten Lindorff-Larsen, Rahul Roychoudhuri, Ignacio Moraga, Suman Mitra.
      Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin-2 (IL-2), a cytokine critical to T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation, and antitumor immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Rα with higher affinity, triggers STAT5 activation, and drives CD8+ T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Last, we show that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.
    DOI:  https://doi.org/10.1126/sciimmunol.ade5686
  4. Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01619-9. [Epub ahead of print]41(9): 111741
    Vitamin B5 rewires Th17 cell metabolism via impeding PKM2 nuclear translocation.
    Chen Chen, Weiqiao Zhang, Tingyue Zhou, Qiuyuan Liu, Chao Han, Zonghui Huang, Si Chen, Qiao Mei, Cunjin Zhang, Kaiguang Zhang, Hongdi Ma, Rongbin Zhou, Wei Jiang, Wen Pan, Shu Zhu.
      Metabolic rewiring is essential for Th17 cells' functional identity to sense and interpret environmental cues. However, the environmental metabolic checkpoints with specific regulation of Th17 cells, manifesting potential therapeutic opportunities to autoimmune diseases, remain largely unknown. Here, by screening more than one hundred compounds derived from intestinal microbes or diet, we found that vitamin B5 (VB5) restrains Th17 cell differentiation as well as related autoimmune diseases such as experimental autoimmune encephalomyelitis and colitis. Mechanistically, VB5 is catabolized into coenzyme A (CoA) in a pantothenate kinase (PANK)-dependent manner, and in turn, CoA binds to pyruvate kinase isoform 2 (PKM2) to impede its phosphorylation and nuclear translocation, thus inhibiting glycolysis and STAT3 phosphorylation. In humans, reduced serum VB5 levels are found in both IBD and MS patients. Collectively, our study demonstrates a role of VB5 in Th17 cell metabolic reprograming, thus providing a potential therapeutic intervention for Th17 cell-associated autoimmune diseases.
    Keywords:  CP: Immunology; CP: Microbiology; CoA; PKM2; Th17; glucose metabolism; vitamin B5
    DOI:  https://doi.org/10.1016/j.celrep.2022.111741
  5. Sci Adv. 2022 Dec 02. 8(48): eadc9657
    Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.
    Marc Scherlinger, Wenliang Pan, Ryo Hisada, Afroditi Boulougoura, Nobuya Yoshida, Milena Vukelic, Masataka Umeda, Suzanne Krishfield, Maria G Tsokos, George C Tsokos.
      Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (Treg) cells. Here, we demonstrate that a T cell-specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6.lpr lupus-prone mice and expands Treg cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In Treg cells, a CRISPR-Cas9-enabled Pfkp deletion recapitulated the metabolism of Camk4-/- Treg cells and improved their function and stability in vitro and in vivo. In SLE CD4+ T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced Treg cell function. In conclusion, we provide molecular insights in the defective metabolism and function of Treg cells in SLE and identify PFKP as a target to fine-tune Treg cell metabolism and thereby restore their function.
    DOI:  https://doi.org/10.1126/sciadv.adc9657
  6. Nat Commun. 2022 Nov 28. 13(1): 7338
    Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.
    Claudio Bussi, Tiaan Heunis, Enrica Pellegrino, Elliott M Bernard, Nourdine Bah, Mariana Silva Dos Santos, Pierre Santucci, Beren Aylan, Angela Rodgers, Antony Fearns, Julia Mitschke, Christopher Moore, James I MacRae, Maria Greco, Thomas Reinheckel, Matthias Trost, Maximiliano G Gutierrez.
      Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of lysosomal contents into the cytosol affects the function of cytoplasmic organelles is unknown. Here, we show that sterile and non-sterile lysosomal damage triggers a cell death independent proteolytic remodelling of the mitochondrial proteome in macrophages. Mitochondrial metabolic reprogramming required leakage of lysosomal cathepsins and was independent of mitophagy, mitoproteases and proteasome degradation. In an in vivo mouse model of endomembrane damage, live lung macrophages that internalised crystals displayed impaired mitochondrial function. Single-cell RNA-sequencing revealed that lysosomal damage skewed metabolic and immune responses in alveolar macrophages subsets with increased lysosomal content. Functionally, drug modulation of macrophage metabolism impacted host responses to Mycobacterium tuberculosis infection in an endomembrane damage dependent way. This work uncovers an inter-organelle communication pathway, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprograming after endomembrane damage.
    DOI:  https://doi.org/10.1038/s41467-022-34632-8
  7. Nat Commun. 2022 Nov 28. 13(1): 6915
    mTORC1 links pathology in experimental models of Still's disease and macrophage activation syndrome.
    Zhengping Huang, Xiaomeng You, Liang Chen, Yan Du, Kailey Brodeur, Hyuk Jee, Qiang Wang, Grace Linder, Roxane Darbousset, Pierre Cunin, Margaret H Chang, Alexandra Wactor, Brian M Wauford, Marc J C Todd, Kevin Wei, Ying Li, Anais Levescot, Yoichiro Iwakura, Virginia Pascual, Nicole E Baldwin, Pierre Quartier, Tianwang Li, Maria T Gianatasio, Robert P Hasserjian, Lauren A Henderson, David B Sykes, Elizabeth D Mellins, Scott W Canna, Julia F Charles, Peter A Nigrovic, Pui Y Lee.
      Still's disease is a severe inflammatory syndrome characterized by fever, skin rash and arthritis affecting children and adults. Patients with Still's disease may also develop macrophage activation syndrome, a potentially fatal complication of immune dysregulation resulting in cytokine storm. Here we show that mTORC1 (mechanistic target of rapamycin complex 1) underpins the pathology of Still's disease and macrophage activation syndrome. Single-cell RNA sequencing in a murine model of Still's disease shows preferential activation of mTORC1 in monocytes; both mTOR inhibition and monocyte depletion attenuate disease severity. Transcriptomic data from patients with Still's disease suggest decreased expression of the mTORC1 inhibitors TSC1/TSC2 and an mTORC1 gene signature that strongly correlates with disease activity and treatment response. Unrestricted activation of mTORC1 by Tsc2 deletion in mice is sufficient to trigger a Still's disease-like syndrome, including both inflammatory arthritis and macrophage activation syndrome with hemophagocytosis, a cellular manifestation that is reproduced in human monocytes by CRISPR/Cas-mediated deletion of TSC2. Consistent with this observation, hemophagocytic histiocytes from patients with macrophage activation syndrome display prominent mTORC1 activity. Our study suggests a mechanistic link of mTORC1 to inflammation that connects the pathogenesis of Still's disease and macrophage activation syndrome.
    DOI:  https://doi.org/10.1038/s41467-022-34480-6
  8. Microbiol Spectr. 2022 Dec 01. e0389322
    ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
    Manuel Albert, Jesús Vázquez, Juan M Falcón-Pérez, María A Balboa, Marc Liesa, Jesús Balsinde, Susana Guerra.
      Interferon-stimulated gene 15 (ISG15) is a 15-kDa ubiquitin-like modifier that binds to target proteins in a process termed ISGylation. ISG15, first described as an antiviral molecule against many viruses, participates in numerous cellular processes, from immune modulation to the regulation of genome stability. Interestingly, the role of ISG15 as a regulator of cell metabolism has recently gained strength. We previously described ISG15 as a regulator of mitochondrial functions in bone marrow-derived macrophages (BMDMs) in the context of Vaccinia virus (VACV) infection. Here, we demonstrate that ISG15 regulates lipid metabolism in BMDMs and that ISG15 is necessary to modulate the impact of VACV infection on lipid metabolism. We show that Isg15-/- BMDMs demonstrate alterations in the levels of several key proteins of lipid metabolism that result in differences in the lipid profile compared with Isg15+/+ (wild-type [WT]) BMDMs. Specifically, Isg15-/- BMDMs present reduced levels of neutral lipids, reflected by decreased lipid droplet number. These alterations are linked to increased levels of lipases and are independent of enhanced fatty acid oxidation (FAO). Moreover, we demonstrate that VACV causes a dysregulation in the proteomes of BMDMs and alterations in the lipid content of these cells, which appear exacerbated in Isg15-/- BMDMs. Such metabolic changes are likely caused by increased expression of the metabolic regulators peroxisome proliferator-activated receptor-γ (PPARγ) and PPARγ coactivator-1α (PGC-1α). In summary, our results highlight that ISG15 controls BMDM lipid metabolism during viral infections, suggesting that ISG15 is an important host factor to restrain VACV impact on cell metabolism. IMPORTANCE The functions of ISG15 are continuously expanding, and growing evidence supports its role as a relevant modulator of cell metabolism. In this work, we highlight how the absence of ISG15 impacts macrophage lipid metabolism in the context of viral infections and how poxviruses modulate metabolism to ensure successful replication. Our results open the door to new advances in the comprehension of macrophage immunometabolism and the interaction between VACV and the host.
    Keywords:  host-pathogen interactions; innate immunity; interferons
    DOI:  https://doi.org/10.1128/spectrum.03893-22
  9. Int J Biol Sci. 2022 ;18(16): 6210-6225
    Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages.
    Jizhuang Wang, Peilang Yang, Tianyi Yu, Min Gao, Dan Liu, Jie Zhang, Chenghao Lu, Xuelian Chen, Xiong Zhang, Yan Liu.
      Emerging evidence suggests that metabolic adaptation is a vital hallmark and prerequisite for macrophage phenotype transition. Pyruvate kinase M2 (PKM2) is an essential molecular determinant of metabolic adaptions in pro-inflammatory macrophages. Post-translational modifications play a central role in the regulation of PKM2. However, doubt remains on whether lactylation in PKM2 exists and how lactylation modulates the function of PKM2. For the first time, our study reports that lactate inhibits the Warburg effect by activating PKM2, promoting the transition of pro-inflammatory macrophages towards a reparative phenotype. We identify PKM2 as a lactylation substrate and confirm that lactylation occurs mainly at the K62 site. We find that lactate increases the lactylation level of PKM2, which inhibits its tetramer-to-dimer transition, promoting its pyruvate kinase activity and reducing nuclear distribution. In short, our study reports a novel post-translational modification type in PKM2 and clarifies its potential role in regulating inflammatory metabolic adaptation in pro-inflammatory macrophages.
    Keywords:  Glycolysis; Lactylation; Macrophage; PKM2
    DOI:  https://doi.org/10.7150/ijbs.75434
  10. Front Immunol. 2022 ;13 1044662
    MyD88-dependent signaling drives toll-like receptor-induced trained immunity in macrophages.
    Allison M Owen, Liming Luan, Katherine R Burelbach, Margaret A McBride, Cody L Stothers, Olivia A Boykin, Kalkena Sivanesam, Jessica F Schaedel, Tazeen K Patil, Jingbin Wang, Antonio Hernandez, Naeem K Patil, Edward R Sherwood, Julia K Bohannon.
      Immunocompromised populations are highly vulnerable to developing life-threatening infections. Strategies to protect patients with weak immune responses are urgently needed. Employing trained immunity, whereby innate leukocytes undergo reprogramming upon exposure to a microbial product and respond more robustly to subsequent infection, is a promising approach. Previously, we demonstrated that the TLR4 agonist monophosphoryl lipid A (MPLA) induces trained immunity and confers broad resistance to infection. TLR4 signals through both MyD88- and TRIF-dependent cascades, but the relative contribution of each pathway to induction of trained immunity is unknown. Here, we show that MPLA-induced resistance to Staphylococcus aureus infection is lost in MyD88-KO, but not TRIF-KO, mice. The MyD88-activating agonist CpG (TLR9 agonist), but not TRIF-activating Poly I:C (TLR3 agonist), protects against infection in a macrophage-dependent manner. MPLA- and CpG-induced augmentation of macrophage metabolism and antimicrobial functions is blunted in MyD88-, but not TRIF-KO, macrophages. Augmentation of antimicrobial functions occurs in parallel to metabolic reprogramming and is dependent, in part, on mTOR activation. Splenic macrophages from CpG-treated mice confirmed that TLR/MyD88-induced reprogramming occurs in vivo. TLR/MyD88-triggered metabolic and functional reprogramming was reproduced in human monocyte-derived macrophages. These data show that MyD88-dependent signaling is critical in TLR-mediated trained immunity.
    Keywords:  MyD88; TLR4; innate immune memory; innate immunity; macrophage; metabolic reprogramming; toll-like receptor (TLR); trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2022.1044662
  11. Redox Biol. 2022 Nov 23. pii: S2213-2317(22)00325-1. [Epub ahead of print]58 102553
    The signaling pathways and therapeutic potential of itaconate to alleviate inflammation and oxidative stress in inflammatory diseases.
    Xuan Shi, Huanping Zhou, Juan Wei, Wei Mo, Quanfu Li, Xin Lv.
      Endogenous small molecules are metabolic regulators of cell function. Itaconate is a key molecule that accumulates in cells when the Krebs cycle is disrupted. Itaconate is derived from cis-aconitate decarboxylation by cis-aconitate decarboxylase (ACOD1) in the mitochondrial matrix and is also known as immune-responsive gene 1 (IRG1). Studies have demonstrated that itaconate plays an important role in regulating signal transduction and posttranslational modification through its immunoregulatory activities. Itaconate is also an important bridge among metabolism, inflammation, oxidative stress, and the immune response. This review summarizes the structural characteristics and classical pathways of itaconate, its derivatives, and the compounds that release itaconate. Here, the mechanisms of itaconate action, including its transcriptional regulation of ATF3/IκBζ axis and type I IFN, its protein modification regulation of KEAP1, inflammasome, JAK1/STAT6 pathway, TET2, and TFEB, and succinate dehydrogenase and glycolytic enzyme metabolic action, are presented. Moreover, the roles of itaconate in diseases related to inflammation and oxidative stress induced by autoimmune responses, viruses, sepsis and IRI are discussed in this review. We hope that the information provided in this review will help increase the understanding of cellular immune metabolism and improve the clinical treatment of diseases related to inflammation and oxidative stress.
    Keywords:  Antioxidant therapeutics; COVID-19; IRG1; Inflammation; Itaconate; Metabolism
    DOI:  https://doi.org/10.1016/j.redox.2022.102553
  12. Curr Allergy Asthma Rep. 2022 Nov 28.
    Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment - Disease-Specific Findings (Part 1).
    A Goretzki, J Zimmermann, H Rainer, Y-J Lin, Stefan Schülke.
      PURPOSE OF REVIEW: Recent high-level publications have shown an intricate connection between immune effector function and the metabolic state of the respective cells. In the last years, studies have begun analyzing the metabolic changes associated with allergies. As the first part of a two-article series, this review will briefly summarize the basics of immune metabolism and then focus on the recently published studies on metabolic changes observed in allergic patients.RECENT FINDINGS: In the last 3 years, immune-metabolic research in allergology had a clear focus on asthma with some studies also reporting findings in food allergy and atopic dermatitis. Current results suggest asthma to be associated with a shift in cellular metabolism towards increased aerobic glycolysis (Warburg metabolism), while also displaying substantial changes in fatty acid- and amino acid metabolism (depending on investigated patient collective, asthma phenotype, and disease severity). Understanding immune-metabolic changes in allergies will allow us to (I) better understand allergic disease pathology and (II) modulate immune-metabolic pathways to improve allergy treatment.
    Keywords:  Allergic dermatitis; Allergy; Asthma; Food allergy; Immune metabolism; Immunotherapy
    DOI:  https://doi.org/10.1007/s11882-022-01057-8
  13. Curr Opin Immunol. 2022 Nov 25. pii: S0952-7915(22)00115-7. [Epub ahead of print]80 102268
    Two for the price of one: itaconate and its derivatives as an anti-infective and anti-inflammatory immunometabolite.
    Anne F McGettrick, Luke Aj O'Neill.
      The metabolite itaconate (ITA) and its derivatives, both chemically synthesized and endogenous, have emerged as immunoregulators, with roles in limiting inflammation but also having effects on bacterial and viral infection. Some members of the ITA family have been shown to target and inhibit multiple processes in macrophages with recently identified targets, including NLRP3, JAK1, ten-eleven translocation-2 dioxygenases, and TFEB, a key transcription factor for lysosomal biogenesis. They have also been shown to target multiple bacteria, inhibiting their replication, as well as having antiviral effects against viruses such as SARS-CoV2, Zika virus, and Influenza virus. The importance of ITA is highlighted by the fact that several pathogens have developed mechanisms to evade ITA and can manipulate ITA for their own gain. Two newly discovered isomers of ITA, mesaconate and citraconate, are also discussed, which also have immunomodulatory effects. ITA continues to be a fascination, both in terms of inflammation but also as an antibacterial and antiviral agent, with therapeutic potential in immune and inflammatory diseases.
    DOI:  https://doi.org/10.1016/j.coi.2022.102268
  14. Mol Cell. 2022 Dec 01. pii: S1097-2765(22)01067-X. [Epub ahead of print]82(23): 4407-4409
    D-2HG comes out of its shell: Metabolic effects on the immune environment.
    Juan Manuel Schvartzman, Andrew M Intlekofer.
      A recent study by Notarangelo et al.1 highlights the potential for tumor-derived D-2HG to inhibit neighboring T cell function through a novel mechanism.
    DOI:  https://doi.org/10.1016/j.molcel.2022.11.005
  15. Proc Natl Acad Sci U S A. 2022 Dec 06. 119(49): e2205789119
    Human cytomegalovirus induces neuronal enolase to support virally mediated metabolic remodeling.
    Isreal Moreno, Irene Rodríguez-Sánchez, Xenia Schafer, Joshua Munger.
      Viruses depend on cellular metabolic resources to supply the energy and biomolecular building blocks necessary for their replication. Human cytomegalovirus (HCMV), a leading cause of birth defects and morbidity in immunosuppressed individuals, induces numerous metabolic activities that are important for productive infection. However, many of the mechanisms through which these metabolic activities are induced and how they contribute to infection are unclear. We find that HCMV infection of fibroblasts induces a neuronal gene signature as well as the expression of several metabolic enzyme isoforms that are typically expressed in other tissue types. Of these, the most substantially induced glycolytic gene was the neuron-specific isoform of enolase 2 (ENO2). Induction of ENO2 expression is important for HCMV-mediated glycolytic activation as well as for the virally induced remodeling of pyrimidine-sugar metabolism, which provides the glycosyl subunits necessary for protein glycosylation. Inhibition of ENO2 expression or activity reduced uridine diphosphate (UDP)-sugar pools, attenuated the accumulation of viral glycoproteins, and induced the accumulation of noninfectious viral particles. In addition, our data indicate that the induction of ENO2 expression depends on the HCMV UL38 protein. Collectively, our data indicate that HCMV infection induces a tissue atypical neuronal glycolytic enzyme to activate glycolysis and UDP-sugar metabolism, increase the accumulation of glycosyl building blocks, and enable the expression of an essential viral glycoprotein and the production of infectious virions.
    Keywords:  enolase; human cytomegalovirus; infection; metabolism; virus
    DOI:  https://doi.org/10.1073/pnas.2205789119
  16. Int Immunopharmacol. 2022 Nov 25. pii: S1567-5769(22)00941-9. [Epub ahead of print]114 109456
    Deficiency of immune-responsive gene 1 exacerbates interleukin-1beta-elicited the inflammatory response of chondrocytes via enhancing the activation of NLRP3 inflammasome.
    Liang Cai, Jingyuan Huang, Daiqiang Huang, Haigang Lv, Dezhi Wang, Haili Wang, Hailong Miao, Li Wu, Fang Wang.
      Immune-responsive gene 1 (IRG1) is a multifunctional protein that mediates inflammatory responses in numerous pathological conditions. However, whether IRG1 has a relevance with osteoarthritis remains unaddressed. The inflammatory response of chondrocytes contributes to the progression of osteoarthritis. This study focused on assessing the functional link between IRG1 and interleukin-1beta (IL-1β)-elicited the inflammatory response of chondrocytes. The expression levels of IRG1 increased markedly in osteoarthritis cartilage compared to normal healthy cartilage. IRG1 level also increased after IL-1β stimulation in chondrocytes. The knockdown of IRG1 exacerbated IL-1β-elicited apoptosis and degradation of the extracellular matrix in chondrocytes. The nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome activation evoked by IL-1β stimulation was enhanced in IRG1-deficient chondrocytes. Importantly, restraint of the NLRP3 inflammasome was able to diminish IRG1-deficiency-amplified effects on IL-1β-stimulated chondrocytes. Additionally, the supplement of itaconate could ameliorate IL-1β-induced the inflammatory response of chondrocytes and reverse any IRG1-deficiency-induced effects. Altogether, our findings document a vital role for IRG1/itaconate in settling the inflammatory response of chondrocytes via effects on the NLRP3 inflammasome.
    Keywords:  Chondrocyte; IRG1; Inflammation; Itaconate; NLRP3; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.intimp.2022.109456
  17. Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01616-3. [Epub ahead of print]41(9): 111738
    Tim-4 reprograms cholesterol metabolism to suppress antiviral innate immunity by disturbing the Insig1-SCAP interaction in macrophages.
    Yingchun Wang, Yuzhen Wang, Lu Ding, Xiaolei Ren, Bo Wang, Liyuan Wang, Songbo Zhao, Xuetian Yue, Zhuanchang Wu, Chunyang Li, Xiaohong Liang, Chunhong Ma, Lifen Gao.
      Accumulating evidence indicates that macrophages reshape their cholesterol metabolism in response to pathogens to support host defense. Intervention of host cholesterol homeostasis has emerged as a promising strategy for antiviral therapy. T cell immunoglobulin and mucin domain-containing molecule 4 (Tim-4) is indispensable in maintaining the homeostasis of macrophages. However, its role in antiviral innate immunity and cholesterol metabolism remains unknown. Here, we report that Tim-4 deficiency results in boosted interferon (IFN) signaling and decreased viral load. Mechanistically, Tim-4 disturbs the Insig1-SCAP interaction and promotes SCAP-SREBP2 complex translocation to the Golgi apparatus, eventually leading to the upregulation of cholesterol biosynthesis in macrophages, which limits the type I IFN response. Our findings demonstrate that Tim-4 suppresses type I IFN signaling by enhancing SREBP2 activation, delineating the role of Tim-4 in antiviral innate immunity and cholesterol metabolism, which sheds light on the mechanism by which Tim-4 orchestrates macrophage homeostasis.
    Keywords:  CP: Immunology; Insig1; SCAP; SREBP2; Tim-4; antiviral innate immune response; cholesterol metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2022.111738
  18. Front Immunol. 2022 ;13 935710
    The mitochondrial gene-CMPK2 functions as a rheostat for macrophage homeostasis.
    Prabhakar Arumugam, Meghna Chauhan, Thejaswitha Rajeev, Rahul Chakraborty, Kanika Bisht, Mahima Madan, Deepthi Shankaran, Sivaprakash Ramalingam, Sheetal Gandotra, Vivek Rao.
      In addition to their role in cellular energy production, mitochondria are increasingly recognized as regulators of the innate immune response of phagocytes. Here, we demonstrate that altering expression levels of the mitochondria-associated enzyme, cytidine monophosphate kinase 2 (CMPK2), disrupts mitochondrial physiology and significantly deregulates the resting immune homeostasis of macrophages. Both CMPK2 silenced and constitutively overexpressing macrophage lines portray mitochondrial stress with marked depolarization of their membrane potential, enhanced reactive oxygen species (ROS), and disturbed architecture culminating in the enhanced expression of the pro-inflammatory genes IL1β, TNFα, and IL8. Interestingly, the long-term modulation of CMPK2 expression resulted in an increased glycolytic flux of macrophages akin to the altered physiological state of activated M1 macrophages. While infection-induced inflammation for restricting pathogens is regulated, our observation of a total dysregulation of basal inflammation by bidirectional alteration of CMPK2 expression only highlights the critical role of this gene in mitochondria-mediated control of inflammation.
    Keywords:  CMPK2; M1 macrophage; immuno-metabolism; infection; mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2022.935710
  19. Front Immunol. 2022 ;13 1032280
    Indoleamine 2,3-dioxygenase 1 signaling orchestrates immune tolerance in Echinococcus multilocularis-infected mice.
    Ru Meng, Yong Fu, Yaogang Zhang, Yalin Mou, Gongguan Liu, Haining Fan.
      The cestode Echinococcus multilocularis larva infection causes lethal zoonotic alveolar echinococcosis (AE), a disease posing a great threat to the public health worldwide. This persistent hepatic tumor-like disease in AE patients has been largely attributed to aberrant T cell responses, of which Th1 responses are impeded, whilst Th2 and regulatory T cell responses are elevated, creating an immune tolerogenic microenvironment in the liver. However, the immune tolerance mechanisms are not fully understood. Dendritic cells (DCs) are key cellular components in facilitating immune tolerance in chronic diseases, including AE. Here, we demonstrate that indoleamine 2,3-dioxygenase 1-deficient (IDO1-/-) mice display less severe AE as compared to wild-type (WT) mice during the infection. Mechanistically, IDO1 prevents optimal T cells responses by programming DCs into a tolerogenic state. Specifically, IDO1 prevents the maturation and migration potential of DCs, as shown by the significantly enhanced expression of the antigen-presenting molecule (MHC II), costimulatory molecules (CD80 and CD86), and chemokine receptors (CXCR4 and CCR7) in infected IDO1-/- mice as compared to infected wild-type mice. More importantly, the tolerogenic phenotype of DCs is partly reverted in IDO1-/- mice, as indicated by enhanced activation, proliferation, and differentiation of both CD4+ and CD8+ - T cells upon infection with Echinococcus multilocularis, in comparison with WT mice. Interestingly, in absence of IDO1, CD4+ T cells are prone to differentiate to effector memory cells (CD44+CD62L-); in contrast, CD8+ T cells are highly biased to the central memory phenotype (CD44+CD62L+). Overall, these data are the first to demonstrate the essential role of IDO1 signaling in inducing immunosuppression in mice infected with Echinococcus multilocularis.
    Keywords:  Echinococcus multilocularis; alveolar echinococcosis; dendritic cells; immunosuppression; indoleamine 2,3-dioxygenase 1
    DOI:  https://doi.org/10.3389/fimmu.2022.1032280
  20. Theranostics. 2022 ;12(17): 7216-7236
    Decorin promotes decidual M1-like macrophage polarization via mitochondrial dysfunction resulting in recurrent pregnancy loss.
    Liling Wang, Huan Wang, Jing Luo, Ting Xie, Gil Mor, Aihua Liao.
      Rationale: Recurrent pregnancy loss (RPL) is a distressing disorder that seriously affects the physical and psychological health of women. RPL is also a sentinel risk marker for future obstetric complications and warrants in-depth investigation. Abnormal polarization and functions of decidual macrophages are associated with RPL; however, the underlying mechanisms remain poorly understood. Methods: Decorin expression, localization, and content in the decidua of women with normal pregnancy (NP) and those with RPL were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting, immunofluorescence, and enzyme-linked immunosorbent assay. The profiles of decidual macrophage subsets were determined using flow cytometry and immunofluorescence in both groups. The correlation between decorin content and the proportion of decidual macrophage subsets in the decidua of early NP women was determined using Pearson analysis. The effects of decorin on the polarization and functions of macrophages were assessed in an in-vitro model of Raw264.7 cells via flow cytometry, western blotting, and RT-qPCR. Moreover, the mitochondrial metabolism in Raw264.7 cells under decorin administration was measured via flow cytometry, western blotting, and immunofluorescence. Thirty-three pregnant mice were included in the in vivo model and underwent different treatments. The embryo abortion rate, macrophage phenotype in the spleen and uteri, and placental development were evaluated using flow cytometry and hematoxylin-eosin staining. Results: Decorin, derived from decidual stromal cells, was highly expressed in the decidua of women with RPL. A positive correlation between decorin content and the proportion of M1-like macrophages was also observed in the decidua of early NP women. In vitro studies showed that decorin treatment inhibited macrophage polarization to M2-like subsets and boosted the inflammatory response, which was related to enhanced anaerobic glycolysis, increased mitochondrial membrane potential and intracellular reactive oxygen species levels, reduced mitochondrial mass, and activation of the myeloid differentiation primary response 88-nuclear factor-κB signaling pathway. Adoptive transfer of decorin-treated bone marrow-derived macrophages in pregnant C57BL/6 mice increased the embryo absorption, accompanied by impaired fetal vascularization. Conclusions: Decidual stromal cell-derived decorin can polarize decidual macrophages toward the M1 phenotype by regulating mitochondrial metabolism, resulting in the occurrence of RPL.
    Keywords:  decidual macrophages; decidual stromal cells; decorin; mitochondrial metabolism; normal pregnancy; recurrent pregnancy loss
    DOI:  https://doi.org/10.7150/thno.78467
  21. Int J Biol Sci. 2022 ;18(16): 6189-6209
    4-Octyl itaconate regulates immune balance by activating Nrf2 and negatively regulating PD-L1 in a mouse model of sepsis.
    Peng Zhang, Yaxin Wang, Wengchang Yang, Yuping Yin, Chengguo Li, Xianxiong Ma, Liang Shi, Ruidong Li, Kaixiong Tao.
      Introduction: Sepsis is a major global health challenge with high mortality rates and no effective treatment. Recent studies have suggested that sepsis may be associated with immune system dysfunction. Itaconate may exert anti-inflammatory effects via Nrf2 signaling. Although Nrf2 regulates oxidative/exogenous stress responses and inhibits inflammatory responses, the mechanism via which Nrf2 regulates immune checkpoints in sepsis remains unclear. Objectives: This study aimed to investigate the role of the Nrf2 signaling pathway in sepsis immunosuppression injury by exploring Nrf2 target genes in inflammatory macrophages in a mouse model of sepsis. Methods: We evaluated the effects of 4-octyl itaconate (OI) on pro-inflammatory and anti-inflammatory cytokines in a mouse model of sepsis and RAW264.7 cells. In addition, we investigated if OI could inhibit LPS-induced oxidative stress by activating Nrf2 signaling in vitro and in vivo. Results: OI reduced the release of pro-inflammatory cytokines and increased the release of anti-inflammatory cytokines, thereby inhibiting inflammation. OI increased glutathione synthase (GSS) expression by activating the Nrf2 signaling pathway to promote GSH synthesis, thus, inhibiting oxidative stress. OI inhibited the early release of inflammatory and oxidative stress-related factors to reduce tissue and organ injury in mice with sepsis, while Nrf2 interfered with PD-L1 induction and inhibited PD-L1 expression at an advanced stage to reduce the occurrence of sepsis immunosuppression. Conclusions: This study indicates that Nrf2 is a novel negative regulator of PD-L1 that functions at immune checkpoints and suggests an underlying mechanism for the anti-inflammatory process mediated by Nrf2.
    Keywords:  Itaconate; Macrophage; Nrf2; PD-L1; ROS; Sepsis
    DOI:  https://doi.org/10.7150/ijbs.74456
  22. Front Immunol. 2022 ;13 906127
    Impact of ATP-citrate lyase catalytic activity and serine 455 phosphorylation on histone acetylation and inflammatory responses in human monocytic THP-1 cells.
    Monica Dominguez, Verena Truemper, Ana Carolina Mota, Bernhard Brüne, Dmitry Namgaladze.
      ATP-citrate lyase (ACLY) is a key enzyme provoking metabolic and epigenetic gene regulation. Molecularly, these functions are exerted by the provision of acetyl-coenzyme A, which is then used as a substrate for de novo lipogenesis or as an acetyl-group donor in acetylation reactions. It has been demonstrated that ACLY activity can be positively regulated via phosphorylation at serine 455 by Akt and protein kinase A. Nonetheless, the impact of phosphorylation on ACLY function in human myeloid cells is poorly understood. In this study we reconstituted ACLY knockout human monocytic THP-1 cells with a wild type ACLY as well as catalytically inactive H760A, and phosphorylation-deficient S455A mutants. Using these cell lines, we determined the impact of ACLY activity and phosphorylation on histone acetylation and pro-inflammatory gene expression in response to lipopolysaccharide (LPS). Our results show that ACLY serine 455 phosphorylation does not influence the proper enzymatic function of ACLY, since both, wild type ACLY and phosphorylation-deficient mutant, exhibited increased cell growth and histone acetylation as compared to cells with a loss of ACLY activity. Transcriptome analysis revealed enhanced expression of pro-inflammatory and interferon response genes in ACLY knockout and H760A THP-1 cells under unstimulated or LPS-treated conditions. At the same time, S455A ACLY-expressing cells showed a phenotype very similar to wild type cells. Contrary to ACLY knockout, pharmacological inhibition of ACLY in THP-1 cells or in primary human macrophages does not enhance LPS-triggered pro-inflammatory gene expression. Our data thus suggest that ACLY retains functionality in the absence of Akt/PKA-mediated phosphorylation in human myeloid cells. Furthermore, loss of ACLY activity may elicit long-term adaptive mechanisms, increasing inflammatory responses.
    Keywords:  ATP-citrate lyase; histone acetylation; inflammation; macrophages; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2022.906127
  23. Mech Ageing Dev. 2022 Nov 23. pii: S0047-6374(22)00137-3. [Epub ahead of print]209 111755
    The role of NAD+ metabolism in macrophages in age-related macular degeneration.
    Ruoyi Lin, Jing Yu.
      Age-related macular degeneration (AMD) is a leading cause of legal blindness and moderate and severe vision impairment (MSVI) in people older than 50 years. It is classified in various stages including early, intermediate, and late stage. In the early stages, innate immune system, especially macrophages, play an essential part in disease onset and progression. NAD+ is an essential coenzyme involved in cellular senescence and immune cell function, and its role in age-related diseases is gaining increasing attention. The imbalance between the NAD+ synthesis and consumption causes the fluctuation of intracellular NAD+ level which determines the polarization fate of macrophages. In AMD, the over-expression of NAD+-consuming enzymes in macrophages leads to declining of NAD+ concentrations in the microenvironment. This phenomenon triggers the activation of inflammatory pathways in macrophages, positive feedback aggregation of inflammatory cells and accumulation of reactive oxygen species (ROS). This review details the role of NAD+ metabolism in macrophages and molecular mechanisms during AMD. The selected pathways were identified as potential targets for intervention in AMD, pending further investigation.
    Keywords:  Age-related macular degeneration; M1 macrophages; Macrophages; NAD(+) metabolism
    DOI:  https://doi.org/10.1016/j.mad.2022.111755
  24. Biomaterials. 2022 Nov 26. pii: S0142-9612(22)00568-3. [Epub ahead of print]292 121928
    Substrate stiffness enhances human regulatory T cell induction and metabolism.
    Lingting Shi, Jee Yoon Lim, Lance C Kam.
      Regulatory T cells (Tregs) provide an essential tolerance mechanism to suppress the immune response. Induced Tregs hold the potential to treat autoimmune diseases in adoptive therapy and can be produced with stimulating signals to CD3 and CD28 in presence of the cytokine TGF-β and IL-2. This report examines the modulation of human Treg induction by leveraging the ability of T cells to sense the mechanical stiffness of an activating substrate. Treg induction on polyacrylamide gels (PA-gels) was sensitive to the substrate's elastic modulus, increasing with greater material stiffness. Single-cell RNA-Seq analysis revealed that Treg induction on stiffer substrates involved greater use of oxidative phosphorylation (OXPHOS). Inhibition of ATP synthase significantly reduced the rate of Treg induction and abrogated the difference among gels while activation of AMPK (AMP-activated protein kinase) increased Treg induction on the softer sample but not on the harder sample. Treg induction is thus mechanosensitive and OXPHOS-dependent, providing new strategies for improving the production of these cells for cellular immunotherapy.
    Keywords:  Mechanosensing; Metabolism; Transcriptomes; Treg induction
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121928
  25. Chem Biol Interact. 2022 Nov 29. pii: S0009-2797(22)00499-9. [Epub ahead of print] 110294
    NAMPT inhibition reduces macrophage inflammation through the NAD+/PARP1 pathway to attenuate liver ischemia-reperfusion injury.
    Jiao Lu, Menghao Wang, Yucheng Chen, Hua Song, Diguang Wen, Jianfei Tu, Yuan Guo, Zuojin Liu.
      BACKGROUND: Liver ischemia-reperfusion injury (IRI) is a major complication in the perioperative period and often leads to liver failure and even systemic inflammation. Previous studies have suggested that the inflammatory response participated in the liver damage during liver IRI. Nicotinamide phosphoribosyl transferase (NAMPT) is required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD+) levels, catalyzing the rate-limiting step in the NAD + salvage pathway. NAMPT is strongly upregulated during inflammation and constitutes an important mechanistic link between inflammatory, metabolic, and transcriptional pathways. The aim of our study was to investigate the role of NAMPT in liver IRI.METHODS: We investigated the effect of pharmacological inhibition of NAMPT with FK866 in models of liver IRI. Liver damage was assessed by HE staining, serum ALT/AST, and TUNEL staining. To examine the mechanism, primary hepatocytes, liver macrophages and RAW264.7 cells were treated with or without NAMPT inhibitors before hypoxia-reoxygenation. Liver macrophages and RAW 264.7 cells activation in vitro was evaluated by western blotting, flow cytometry, and ELISA.
    RESULT: We found that NAMPT was upregulated in liver IRI. Treatment with the NAMPT inhibitor FK866 ameliorated liver IRI and suppressed inflammation in mice. Although NAMPT plays an important role both in hepatocytes and liver macrophages, we focused on the impact of NAMPT on liver macrophages. The mechanism revealed that FK866 potently inhibited NAMPT activity, as demonstrated by reduced liver NAD+ and intracellular NAD+, resulting in reduced abundance and activity of NAD + -dependent enzymes, including poly (ADP-ribose) polymerase 1 (PARP1), thus inhibiting macrophage M1 polarization by reducing CD86, iNOS, TNF-α, and interleukin (IL)-1β. Taken together, our data suggested that NAMPT can regulate macrophage polarization through NAD+/PARP1 to ameliorate liver injury, and that FK866-mediated NAMPT blockade may be a therapeutic approach in liver IRI.
    Keywords:  FK866; Inflammation; Liver ischemia‒reperfusion injury; Liver macrophages; NAMPT; PARP1
    DOI:  https://doi.org/10.1016/j.cbi.2022.110294
  26. Int Immunopharmacol. 2022 Dec;pii: S1567-5769(22)00956-0. [Epub ahead of print]113(Pt B): 109471
    Manganese enhances macrophage defense against Mycobacterium tuberculosis via the STING-TNF signaling pathway.
    Kaiqiang Qian, Lidong Shan, Shengwen Shang, Tianyue Li, Shuxin Wang, Meili Wei, Bikui Tang, Jun Xi.
      The host cell antiviral response pathway depends heavily on manganese (Mn), but its role in defense against Mycobacterium tuberculosis (M. tuberculosis) infection is rarely reported. In this study, we found that, in H37Ra-infected macrophages, Mn2+ increases the phosphorylation of stimulator of interferon genes (STING) and P65, as well as triggers the phosphorylation cascade of tumor necrosis factor (TNF) signaling pathway proteins, signal-regulated kinase (ERK), P38, and c-Jun N-terminal kinase (JNK). The activation of the TNF signaling pathway stimulated the expression of downstream inflammatory factors TNF-α, C-X-C Motif Chemokine Ligand 10(CXCL10), CC Motif Chemokine Ligand 20(CCL20), Colony Stimulating Factor 1(CSF1), Colony Stimulating Factor 2(CSF2), and Jagged Canonical Notch Ligand 1(JAG1), thereby triggering a strong inflammatory response in the cells. The excessive accumulation of TNF-α in macrophages induces necroptosis and inhibits the survival of M. tuberculosis in macrophages. When we treated macrophages with the STING inhibitor H-151, the phosphorylation of P38 was reduced, and the secretion of downstream inflammatory factors TNF-α and CXCL10, CCL20, CSF1, and CSF2 were also inhibited. Overall, this study reveals that Mn2+ plays a crucial role in host cell defense against M. tuberculosis infection, contributes to a deeper understanding of pathogen-host interactions, and offers theoretical support for the use of Mn2+ as a drug cofactor for the treatment of tuberculosis and the development of a new generation of drugs and vaccine adjuvants.
    Keywords:  Innate immunity; Macrophages; Manganese; Mycobacterium tuberculosis; STING
    DOI:  https://doi.org/10.1016/j.intimp.2022.109471
  27. Mol Cell. 2022 Nov 23. pii: S1097-2765(22)01068-1. [Epub ahead of print]
    Bacterial origins of cyclic nucleotide-activated antiviral immune signaling.
    Dinshaw J Patel, You Yu, Ning Jia.
      Second-messenger-mediated signaling by cyclic oligonucleotides (cOs) composed of distinct base, ring size, and 3'-5'/2'-5' linkage combinations constitutes the initial trigger resulting in activation of signaling pathways that have an impact on immune-mediated antiviral defense against invading viruses and phages. Bacteria and archaea have evolved CRISPR, CBASS, Pycsar, and Thoeris surveillance complexes that involve cO-mediated activation of effectors resulting in antiviral defense through either targeted nuclease activity, effector oligomerization-mediated depletion of essential cellular metabolites or disruption of host cell membrane functions. Notably, antiviral defense capitalizes on an abortive infection mechanism, whereby infected cells die prior to completion of the phage replication cycle. In turn, phages have evolved small proteins that target and degrade/sequester cOs, thereby suppressing host immunity. This review presents a structure-based mechanistic perspective of recent advances in the field of cO-mediated antiviral defense, in particular highlighting the ancient evolutionary adaptation by metazoans of bacterial cell-autonomous innate immune mechanisms.
    Keywords:  CBASS; CRISPR; Pycsar; Thoeris; antiviral defense; cyclic nucleotides; signaling pathways
    DOI:  https://doi.org/10.1016/j.molcel.2022.11.006
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