Trained Immunity: Reprogramming Innate Immunity in Health and Disease

Literature Cited

1. 1. 

   Naeslund C. 1931. Résultats des expériences de vaccination par le BCG poursuivies dans le Norrbotten (Suède) (Septembre 1927–Décembre 1931). Rev. Tuberc. 12:617–36
   [Google Scholar]
2. 2. 

   Netea M, Quintin J, van der Meer J. 2011. Trained immunity: a memory for innate host defense. Cell Host Microbe 9:5355–61
   [Google Scholar]
3. 3. 

   Durrant WE, Dong X. 2004. Systemic acquired resistance. Annu. Rev. Phytopathol. 42:1185–209
   [Google Scholar]
4. 4. 

   Fu ZQ, Dong X. 2013. Systemic acquired resistance: turning local infection into global defense. Annu. Rev. Plant Biol. 64:1839–63
   [Google Scholar]
5. 5. 

   Reimer-Michalski EM, Conrath U. 2016. Innate immune memory in plants. Semin. Immunol. 28:4319–27
   [Google Scholar]
6. 6. 

   Pham LN, Dionne MS, Shirasu-Hiza M, Schneider DS. 2007. A specific primed immune response in Drosophila is dependent on phagocytes. PLOS Pathog 3:3e26
   [Google Scholar]
7. 7. 

   Tate AT, Andolfatto P, Demuth JP, Graham AL. 2017. The within-host dynamics of infection in trans-generationally primed flour beetles. Mol. Ecol. 26:143794–807
   [Google Scholar]
8. 8. 

   Moret Y, Siva-Jothy MT. 2003. Adaptive innate immunity? Responsive-mode prophylaxis in the mealworm beetle, Tenebrio molitor. Proc. R. Soc. B 270: 1532.2475–80
   [Google Scholar]
9. 9. 

   Tribouley J, Tribouley-Duret J, Appriou M. 1978. Influence du bacille de Calmette et Guérin (BCG) sur la réceptivité de la souris nude vis-à-vis de Schistosoma mansoni [Effect of Bacillus Calmette-Guérin (BCG) on the receptivity of nude mice to Schistosoma mansoni]. C. R. Seances Soc. Biol. Fil. 172:5902–4
   [Google Scholar]
10. 10. 

    van't Wout JW, Poell R, van Furth R. 1992. The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand. J. Immunol. 36:5713–20
    [Google Scholar]
11. 11. 

    Hong M, Sandalova E, Low D, Gehring AJ, Fieni S et al. 2015. Trained immunity in newborn infants of HBV-infected mothers. Nat. Commun. 6:6588
    [Google Scholar]
12. 12. 

    Jensen KJ, Larsen N, Sorensen SB, Andersen A, Eriksen HB et al. 2015. Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial. J. Infect. Dis. 211:6956–67
    [Google Scholar]
13. 13. 

    Kleinnijenhuis J, Quintin J, Preijers F, Joosten LAB, Ifrim DC et al. 2012. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. PNAS 109:4317537–42
    [Google Scholar]
14. 14. 

    Kleinnijenhuis J, Quintin J, Preijers F, Benn CS, Joosten LAB et al. 2014. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J. Innate Immun. 6:2152–58
    [Google Scholar]
15. 15. 

    Nankabirwa V, Tumwine JK, Mugaba PM, Tylleskär T, Sommerfelt H et al. 2015. Child survival and BCG vaccination: a community based prospective cohort study in Uganda. BMC Public Health 15:1175
    [Google Scholar]
16. 16. 

    Berendsen M, Øland C, Bles P, Jensen A, Kofoed P et al. 2020. Maternal priming: Bacillus Calmette-Guérin (BCG) vaccine scarring in mothers enhances the survival of their child with a BCG vaccine scar. J. Pediatr. Infect. Dis. Soc. 9:2166–72
    [Google Scholar]
17. 17. 

    Tarancón R, Domínguez-Andrés J, Uranga S, Ferreira AV, Groh LA et al. 2020. New live attenuated tuberculosis vaccine MTBVAC induces trained immunity and confers protection against experimental lethal pneumonia. PLOS Pathog 16:4e1008404
    [Google Scholar]
18. 18. 

    Lund N, Andersen A, Hansen ASK, Jepsen FS, Barbosa A et al. 2015. The effect of oral polio vaccine at birth on infant mortality: a randomized trial. Clin. Infect. Dis. 61:101504–11
    [Google Scholar]
19. 19. 

    Rieckmann A, Villumsen M, Sørup S, Klingen Haugaard L, Ravn H et al. 2017. Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971–2010. Int. J. Epidemiol. 46:2695–705
    [Google Scholar]
20. 20. 

    Higgins JPT, Soares-Weiser K, López-López JA, Kakourou A, Chaplin K et al. 2016. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 355:i5170
    [Google Scholar]
21. 21. 

    Quintin J, Saeed S, Martens JHA, Giamarellos-Bourboulis EJ, Ifrim DC et al. 2012. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12:2223–32
    [Google Scholar]
22. 22. 

    Schrum JE, Crabtree JN, Dobbs KR, Kiritsy MC, Reed GW et al. 2018. Cutting edge: Plasmodium falciparum induces trained innate immunity. J. Immunol. 200:41243–48
    [Google Scholar]
23. 23. 

    Saeed S, Quintin J, Kerstens HHD, Rao NA, Aghajanirefah A et al. 2014. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345:62041251086
    [Google Scholar]
24. 24. 

    Ifrim DC, Quintin J, Joosten LAB, Jacobs C, Jansen T et al. 2014. Trained immunity or tolerance: opposing functional programs induced in human monocytes after engagement of various pattern recognition receptors. Clin. Vaccine Immunol. 21:4534–45
    [Google Scholar]
25. 25. 

    Bekkering S, Quintin J, Joosten LAB, van der Meer JWM, Netea MG, Riksen NP. 2014. Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler. Thromb. Vasc. Biol. 34:81731–38
    [Google Scholar]
26. 26. 

    van der Valk FM, Bekkering S, Kroon J, Yeang C, Van den Bossche J et al. 2016. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation 134:8611–24
    [Google Scholar]
27. 27. 

    Sohrabi Y, Sonntag GVH, Braun LC, Lagache SMM, Liebmann M et al. 2020. LXR activation induces a proinflammatory trained innate immunity-phenotype in human monocytes. Front. Immunol. 11:353
    [Google Scholar]
28. 28. 

    Fontaine C, Rigamonti E, Nohara A, Gervois P, Teissier E et al. 2007. Liver X receptor activation potentiates the lipopolysaccharide response in human macrophages. Circ. Res. 101:140–49
    [Google Scholar]
29. 29. 

    Crisan TO, Cleophas MCP, Oosting M, Lemmers H, Toenhake-Dijkstra H et al. 2016. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann. Rheum. Dis. 75:4755–62
    [Google Scholar]
30. 30. 

    Crişan TO, Cleophas MCP, Novakovic B, Erler K, van de Veerdonk FL et al. 2017. Uric acid priming in human monocytes is driven by the AKT-PRAS40 autophagy pathway. PNAS 114:215485–90
    [Google Scholar]
31. 31. 

    van der Heijden CDCC, Groh L, Keating ST, Kaffa C, Noz MP et al. 2020. Catecholamines induce trained immunity in monocytes in vitro and in vivo. Circ. Res. 127:2269–83
    [Google Scholar]
32. 32. 

    van der Heijden CDCC, Keating ST, Groh L, Joosten LAB, Netea MG, Riksen NP. 2020. Aldosterone induces trained immunity: the role of fatty acid synthesis. Cardiovasc. Res. 116:2317–28
    [Google Scholar]
33. 33. 

    Ulas T, Pirr S, Fehlhaber B, Bickes MS, Loof TG et al. 2017. S100-alarmin-induced innate immune programming protects newborn infants from sepsis. Nat. Immunol. 18:6622–32
    [Google Scholar]
34. 34. 

    Kamada R, Yang W, Zhang Y, Patel MC, Yang Y et al. 2018. Interferon stimulation creates chromatin marks and establishes transcriptional memory. PNAS 115:39E9162–71
    [Google Scholar]
35. 35. 

    Tarancón R, Uranga S, Martín C, Aguiló N. 2019. Mycobacterium tuberculosis infection prevents asthma and abrogates eosinophilopoiesis in an experimental model. Allergy 74:122512–14
    [Google Scholar]
36. 36. 

    Cavallo GP, Elia M, Giordano D, Baldi C, Cammarota R. 2002. Decrease of specific and total IgE levels in allergic patients after BCG vaccination: preliminary report. Arch. Otolaryngol. Head Neck Surg. 128:91058–60
    [Google Scholar]
37. 37. 

    Guo Y-J, Wu D, Wang K-Y, Sun S-H. 2007. Adjuvant effects of bacillus Calmette-Guerin DNA or CpG-oligonucleotide in the immune response to Taenia solium cysticercosis vaccine in porcine. Scand. J. Immunol. 66:6619–27
    [Google Scholar]
38. 38. 

    Nishida S, Tsuboi A, Tanemura A, Ito T, Nakajima H et al. 2019. Immune adjuvant therapy using Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS) in advanced malignancies: a phase 1 study of safety and immunogenicity assessments. Medicine 98:33e16771
    [Google Scholar]
39. 39. 

    Domínguez-Andrés J, Joosten LA, Netea MG. 2019. Induction of innate immune memory: the role of cellular metabolism. Curr. Opin. Immunol. 56:10–16
    [Google Scholar]
40. 40. 

    Bekkering S, Blok BA, Joosten LAB, Riksen NP, van Crevel R, Netea MG. 2016. In vitro experimental model of trained innate immunity in human primary monocytes. Clin. Vaccine Immunol. 23:12926–33 Erratum. 2017. Clin. Vaccine Immunol. 24(5):e00096-17
    [Google Scholar]
41. 41. 

    Wang T, Liu H, Lian G, Zhang S-Y, Wang X, Jiang H. 2017. HIF1α-induced glycolysis metabolism is essential to the activation of inflammatory macrophages. Mediators Inflamm 2017:9029327
    [Google Scholar]
42. 42. 

    Cheng S-C, Quintin J, Cramer RA, Shepardson KM, Saeed S et al. 2014. mTOR- and HIF-1-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345:62041250684
    [Google Scholar]
43. 43. 

    Arts RJW, Novakovic B, ter Horst R, Carvalho A, Bekkering S et al. 2016. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab 24:6807–19
    [Google Scholar]
44. 44. 

    Etchegaray JP, Mostoslavsky R. 2016. Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes. Mol. Cell 62:5695–711
    [Google Scholar]
45. 45. 

    Arts RJW, Carvalho A, La Rocca C, Palma C, Rodrigues F et al. 2016. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep 17:102562–71
    [Google Scholar]
46. 46. 

    Keating ST, Groh L, Thiem K, Bekkering S, Li Y et al. 2020. Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein. J. Mol. Med. 98:6819–31
    [Google Scholar]
47. 47. 

    Keating ST, Groh L, van der Heijden CDCC, Rodriguez H, dos Santos JC et al. 2020. The Set7 lysine methyltransferase regulates plasticity in oxidative phosphorylation necessary for trained immunity induced by β-glucan. Cell Rep 31:3107548
    [Google Scholar]
48. 48. 

    Sohrabi Y, Lagache SMM, Schnack L, Godfrey R, Kahles F et al. 2019. mTOR-dependent oxidative stress regulates oxLDL-induced trained innate immunity in human monocytes. Front. Immunol. 9:3155
    [Google Scholar]
49. 49. 

    Xiao M, Yang H, Xu W, Ma S, Lin H et al. 2012. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 26:121326–38
    [Google Scholar]
50. 50. 

    Tannahill GM, Curtis AM, Adamik J, Palsson-Mcdermott EM, McGettrick AF et al. 2013. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496:7444238–42
    [Google Scholar]
51. 51. 

    Friedmann DR, Marmorstein R. 2013. Structure and mechanism of non-histone protein acetyltransferase enzymes. FEBS J 280:225570–81
    [Google Scholar]
52. 52. 

    Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. 2009. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324:59301076–80
    [Google Scholar]
53. 53. 

    Domínguez-Andrés J, Novakovic B, Li Y, Scicluna BP, Gresnigt MS et al. 2019. The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab 29:1211–20.e5
    [Google Scholar]
54. 54. 

    Bekkering S, Arts RJW, Novakovic B, Kourtzelis I, van der Heijden CDCC et al. 2018. Metabolic induction of trained immunity through the mevalonate pathway. Cell 172:1–2135–46.e9
    [Google Scholar]
55. 55. 

    Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B et al. 2013. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol. 14:8812–20
    [Google Scholar]
56. 56. 

    Mitroulis I, Ruppova K, Wang B, Chen L-S, Grzybek M et al. 2018. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172:1–2147–61.e12
    [Google Scholar]
57. 57. 

    van der Heijden CD, Smeets EM, Aarntzen EH, Noz MP, Monajemi H et al. 2020. Arterial wall inflammation and increased hematopoietic activity in patients with primary aldosteronism. J. Clin. Endocrinol. Metab. 105:5e1967–80
    [Google Scholar]
58. 58. 

    Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M et al. 2020. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20:6375–88
    [Google Scholar]
59. 59. 

    Novakovic B, Habibi E, Wang SY, Arts RJW, Davar R et al. 2016. β-Glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167:51354–68.e14
    [Google Scholar]
60. 60. 

    Bekkering S, Stiekema LCA, Bernelot Moens S, Verweij SL, Novakovic B et al. 2019. Treatment with statins does not revert trained immunity in patients with familial hypercholesterolemia. Cell Metab 30:11–2
    [Google Scholar]
61. 61. 

    Bekkering S, van den Munckhof I, Nielen T, Lamfers E, Dinarello C et al. 2016. Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo. Atherosclerosis 254:228–36
    [Google Scholar]
62. 62. 

    Fok ET, Davignon L, Fanucchi S, Mhlanga MM. 2019. The lncRNA connection between cellular metabolism and epigenetics in trained immunity. Front. Immunol. 29:93184
    [Google Scholar]
63. 63. 

    Fanucchi S, Mhlanga MM. 2019. Lnc-ing trained immunity to chromatin architecture. Front. Cell Dev. Biol. 7:2
    [Google Scholar]
64. 64. 

    Verma D, Parasa VR, Raffetseder J, Martis M, Mehta RB et al. 2017. Anti-mycobacterial activity correlates with altered DNA methylation pattern in immune cells from BCG-vaccinated subjects. Sci. Rep. 7:112305
    [Google Scholar]
65. 65. 

    Das J, Verma D, Gustafsson M, Lerm M. 2019. Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naïve subjects. Epigenetics 14:6589–601
    [Google Scholar]
66. 66. 

    Kleinnijenhuis J, Quintin J, Preijers F, Joosten LAB, Jacobs C et al. 2014. BCG-induced trained immunity in NK cells: role for non-specific protection to infection. Clin. Immunol. 155:2213–19
    [Google Scholar]
67. 67. 

    Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonça LE et al. 2018. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172:1–2176–90.e19
    [Google Scholar]
68. 68. 

    dos Santos JC, Barroso de Figueiredo AM, Teodoro Silva MV, Cirovic B, de Bree LCJ et al. 2019. β-Glucan-induced trained immunity protects against Leishmania braziliensis infection: a crucial role for IL-32. Cell Rep 28:102659–72.e6
    [Google Scholar]
69. 69. 

    Cirovic B, de Bree LCJ, Groh L, Blok BA, Chan J et al. 2020. BCG vaccination in humans elicits trained immunity via the hematopoietic progenitor compartment. Cell Host Microbe 28:2322–34.e5
    [Google Scholar]
70. 70. 

    Christ A, Günther P, Lauterbach MAR, Duewell P, Biswas D et al. 2018. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 172:1–2162–75.e14
    [Google Scholar]
71. 71. 

    Machiels B, Dourcy M, Xiao X, Javaux J, Mesnil C et al. 2017. A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat. Immunol. 18:121310–20
    [Google Scholar]
72. 72. 

    Yao Y, Jeyanathan M, Haddadi S, Barra NG, Vaseghi-Shanjani M et al. 2018. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 175:61634–50.e17
    [Google Scholar]
73. 73. 

    Hoyer FF, Naxerova K, Schloss MJ, Hulsmans M, Nair AV et al. 2019. Tissue-specific macrophage responses to remote injury impact the outcome of subsequent local immune challenge. Immunity 51:5899–914.e7
    [Google Scholar]
74. 74. 

    Roquilly A, Jacqueline C, Davieau M, Mollé A, Sadek A et al. 2020. Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis. Nat. Immunol. 21:6636–48
    [Google Scholar]
75. 75. 

    Haley MJ, Brough D, Quintin J, Allan SM 2019. Microglial priming as trained immunity in the brain. Neuroscience 405:47–54
    [Google Scholar]
76. 76. 

    Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T et al. 2018. Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556:7701332–38
    [Google Scholar]
77. 77. 

    Perry VH, Holmes C. 2014. Microglial priming in neurodegenerative disease. Nat. Rev. Neurol. 10:4217–24
    [Google Scholar]
78. 78. 

    Roquilly A, McWilliam HEG, Jacqueline C, Tian Z, Cinotti R et al. 2017. Local modulation of antigen-presenting cell development after resolution of pneumonia induces long-term susceptibility to secondary infections. Immunity 47:1135–47.e5
    [Google Scholar]
79. 79. 

    Hole CR, Wager CML, Castro-Lopez N, Campuzano A, Cai H et al. 2019. Induction of memory-like dendritic cell responses in vivo. Nat. Commun. 10:12955
    [Google Scholar]
80. 80. 

    Placek K, Schultze JL, Netea MG. 2019. Immune memory characteristics of innate lymphoid cells. Curr. Opin. Infect. Dis. 32:3196–203
    [Google Scholar]
81. 81. 

    O'Sullivan TE, Sun JC, Lanier LL. 2015. Natural killer cell memory. Immunity 43:4634–45
    [Google Scholar]
82. 82. 

    Dou Y, Fu B, Sun R, Li W, Hu W et al. 2015. Influenza vaccine induces intracellular immune memory of human NK cells. PLOS ONE 10:3e0121258
    [Google Scholar]
83. 83. 

    Nielsen CM, White MJ, Bottomley C, Lusa C, Rodríguez-Galán A et al. 2015. Impaired NK cell responses to pertussis and H1N1 influenza vaccine antigens in human cytomegalovirus-infected individuals. J. Immunol. 194:104657–67
    [Google Scholar]
84. 84. 

    McCall MBB, Roestenberg M, Ploemen I, Teirlinck A, Hopman J et al. 2010. Memory-like IFN-γ response by NK cells following malaria infection reveals the crucial role of T cells in NK cell activation by P. falciparum. Eur. J. Immunol. 40:123472–77
    [Google Scholar]
85. 85. 

    O'Leary JG, Goodarzi M, Drayton DL, von Andrian UH. 2006. T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat. Immunol. 7:5507–16
    [Google Scholar]
86. 86. 

    Sun JC, Ma A, Lanier LL. 2009. Cutting edge: IL-15-independent NK cell response to mouse cytomegalovirus infection. J. Immunol. 183:52911–14
    [Google Scholar]
87. 87. 

    Romee R, Maximillian R, Berrien-Elliott MM, Wagner JA, Jewell BA et al. 2015. Human cytokine-induced memory-like NK cells exhibit in vivo anti-leukemia activity in xenografted NSG mice and in patients with acute myeloid leukemia (AML). Blood 126:23101
    [Google Scholar]
88. 88. 

    Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, Yokoyama WM. 2009. Cytokine-induced memory-like natural killer cells. PNAS 106:61915–19
    [Google Scholar]
89. 89. 

    Gamliel M, Goldman-Wohl D, Isaacson B, Gur C, Stein N et al. 2018. Trained memory of human uterine NK cells enhances their function in subsequent pregnancies. Immunity 48:5951–62.e5
    [Google Scholar]
90. 90. 

    Donnelly RP, Loftus RM, Keating SE, Liou KT, Biron CA et al. 2014. mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J. Immunol. 193:94477–84
    [Google Scholar]
91. 91. 

    Schlums H, Cichocki F, Tesi B, Theorell J, Beziat V et al. 2015. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42:3443–56
    [Google Scholar]
92. 92. 

    Cichocki F, Wu CY, Zhang B, Felices M, Tesi B et al. 2018. ARID5B regulates metabolic programming in human adaptive NK cells. J. Exp. Med. 215:92379–95
    [Google Scholar]
93. 93. 

    Rasid O, Chevalier C, Camarasa TMN, Fitting C, Cavaillon JM, Hamon MA. 2019. H3K4me1 supports memory-like NK cells induced by systemic inflammation. Cell Rep 29:123933–45.e3
    [Google Scholar]
94. 94. 

    Weizman O, Song E, Adams NM, Hildreth AD, Riggan L et al. 2019. Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12. Nat. Immunol. 20:81004–11
    [Google Scholar]
95. 95. 

    Martinez-Gonzalez I, Mathä L, Steer CA, Ghaedi M, Poon GFT, Takei F. 2016. Allergen-experienced group 2 innate lymphoid cells acquire memory-like properties and enhance allergic lung inflammation. Immunity 45:1198–208
    [Google Scholar]
96. 96. 

    Cassone A. 2018. The case for an expanded concept of trained immunity. mBio 9:3e00570–18
    [Google Scholar]
97. 97. 

    Liu GY, Liu Y, Lu Y, Qin YR, Di GH et al. 2016. Short-term memory of danger signals or environmental stimuli in mesenchymal stem cells: implications for therapeutic potential. Cell. Mol. Immunol. 13:3369–78
    [Google Scholar]
98. 98. 

    Naik S, Larsen SB, Gomez NC, Alaverdyan K, Sendoel A et al. 2017. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550:7677475–80
    [Google Scholar]
99. 99. 

    Ordovas-Montanes J, Dwyer DF, Nyquist SK, Buchheit KM, Vukovic M et al. 2018. Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560:7720649–54
    [Google Scholar]
100. 100. 

     Bigot J, Guillot L, Guitard J, Ruffin M, Corvol H et al. 2020. Respiratory epithelial cells can remember infection: a proof-of-concept study. J. Infect. Dis. 221:61000–5
     [Google Scholar]
101. 101. 

     El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL et al. 2008. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J. Exp. Med. 205:102409–17
     [Google Scholar]
102. 102. 

     Schnitzler JG, Hoogeveen RM, Ali L, Prange KHM, Waissi F et al. 2020. Atherogenic lipoprotein(a) increases vascular glycolysis, thereby facilitating inflammation and leukocyte extravasation. Circ. Res. 126:101346–59
     [Google Scholar]
103. 103. 

     Schnack L, Sohrabi Y, Lagache SMM, Kahles F, Bruemmer D et al. 2019. Mechanisms of trained innate immunity in oxLDL primed human coronary smooth muscle cells. Front. Immunol. 10:13
     [Google Scholar]
104. 104. 

     Ospelt C, Reedquist KA, Gay S, Tak PP. 2011. Inflammatory memories: Is epigenetics the missing link to persistent stromal cell activation in rheumatoid arthritis?. Autoimmun. Rev. 10:9519–24
     [Google Scholar]
105. 105. 

     Ara T, Kurata K, Hirai K, Uchihashi T, Uematsu T et al. 2009. Human gingival fibroblasts are critical in sustaining inflammation in periodontal disease. J. Periodontal Res. 44:121–27
     [Google Scholar]
106. 106. 

     Sohn C, Lee A, Qiao Y, Loupasakis K, Ivashkiv LB, Kalliolias GD. 2015. Prolonged tumor necrosis factor α primes fibroblast-like synoviocytes in a gene-specific manner by altering chromatin. Arthritis Rheumatol 67:186–95
     [Google Scholar]
107. 107. 

     Klein K, Frank-Bertoncelj M, Karouzakis E, Gay RE, Kolling C et al. 2017. The epigenetic architecture at gene promoters determines cell type-specific LPS tolerance. J. Autoimmun. 83:122–33
     [Google Scholar]
108. 108. 

     Crowley T, O'Neil JD, Adams H, Thomas AM, Filer A et al. 2017. Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not dermal fibroblasts. Arthritis Res. Ther. 19:135
     [Google Scholar]
109. 109. 

     Stensballe LG, Nante E, Jensen IP, Kofoed PE, Poulsen A et al. 2005. Acute lower respiratory tract infections and respiratory syncytial virus in infants in Guinea-Bissau: a beneficial effect of BCG vaccination for girls; community based case-control study. Vaccine 23:101251–57
     [Google Scholar]
110. 110. 

     Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A et al. 2011. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?. J. Infect. Dis. 204:2245–52
     [Google Scholar]
111. 111. 

     Aaby P, Mogensen SW, Rodrigues A, Benn CS. 2018. Evidence of increase in mortality after the introduction of diphtheria-tetanus-pertussis vaccine to children aged 6–35 months in Guinea-Bissau: a time for reflection?. Front. Public Health 6:79
     [Google Scholar]
112. 112. 

     Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F et al. 2018. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N. Engl. J. Med. 379:2138–49
     [Google Scholar]
113. 113. 

     Arts RJW, Moorlag SJCFM, Novakovic B, Li Y, Wang SY et al. 2018. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe 23:189–100.e5
     [Google Scholar]
114. 114. 

     Blok BA, Arts RJW, van Crevel R, Aaby P, Joosten LAB et al. 2020. Differential effects of BCG vaccine on immune responses induced by vi polysaccharide typhoid fever vaccination: an explorative randomized trial. Eur. J. Clin. Microbiol. Infect. Dis. 39:61177–84
     [Google Scholar]
115. 115. 

     Blok BA, de Bree LCJ, Diavatopoulis DA, Langereis JD, Joosten LA et al. 2020. Interacting, nonspecific, immunological effects of Bacille Calmette-Guérin and tetanus-diphtheria-pertussis inactivated polio vaccinations: an explorative, randomized trial. Clin. Infect. Dis. 70:3455–63
     [Google Scholar]
116. 116. 

     ten Doesschate T, Moorlag SJCFM, van der Vaart TW, Taks E, Debisarun P et al. 2020. Two randomized controlled trials of Bacillus Calmette-Guérin vaccination to reduce absenteeism among health care workers and hospital admission by elderly persons during the COVID-19 pandemic: a structured summary of the study protocols for two randomised controlled trials. Trials 21:1481 Erratum. 2020. Trials 21(1):555
     [Google Scholar]
117. 117. 

     Giamarellos-Bourboulis EJ, Tsilika M, Moorlag S, Antonakos N, Kotsaki A et al. 2020. Activate: randomized clinical trial of BCG vaccination against infection in the elderly. Cell 183:2315–23.e9
     [Google Scholar]
118. 118. 

     Walk J, de Bree LCJ, Graumans W, Stoter R, van Gemert GJ et al. 2019. Outcomes of controlled human malaria infection after BCG vaccination. Nat. Commun. 10:1874
     [Google Scholar]
119. 119. 

     Barton ES, White DW, Cathelyn JS, Brett-McClellan KA, Engle M et al. 2007. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447:7142326–29
     [Google Scholar]
120. 120. 

     Ribes S, Meister T, Ott M, Redlich S, Janova H et al. 2014. Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection. J. Neuroinflamm. 11:14
     [Google Scholar]
121. 121. 

     Li R, Lim A, Phoon MC, Narasaraju T, Ng JKW et al. 2010. Attenuated Bordetella pertussis protects against highly pathogenic influenza A viruses by dampening the cytokine storm. J. Virol. 84:147105–13
     [Google Scholar]
122. 122. 

     van der Poll T, Opal SM. 2008. Host-pathogen interactions in sepsis. Lancet Infect. Dis. 8:132–43
     [Google Scholar]
123. 123. 

     Cheng SC, Scicluna BP, Arts RJW, Gresnigt MS, Lachmandas E et al. 2016. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat. Immunol. 17:4406–13
     [Google Scholar]
124. 124. 

     Netea MG, Giamarellos-Bourboulis EJ, Domínguez-Andrés J, Curtis N, van Crevel R et al. 2020. Trained immunity: a tool for reducing susceptibility and severity of SARS-CoV-2 infection. Cell 181:5969–77
     [Google Scholar]
125. 125. 

     Gursel M, Gursel I. 2020. Is global BCG vaccination-induced trained immunity relevant to the progression of SARS-CoV-2 pandemic?. Allergy 75:71815–19
     [Google Scholar]
126. 126. 

     Faust L, Huddart S, MacLean E, Svadzian A. 2020. Universal BCG vaccination and protection against COVID-19: critique of an ecological study. Nature Research Microbiology Community https://naturemicrobiologycommunity.nature.com/users/36050-emily-maclean/posts/64892-universal-bcg-vaccination-and-protection-against-covid-19-critique-of-an-ecological-study
     [Google Scholar]
127. 127. 

     O'Neill LAJ, Netea MG 2020. BCG-induced trained immunity: Can it offer protection against COVID-19?. Nat. Rev. Immunol. 20:6335–37
     [Google Scholar]
128. 128. 

     Curtis N, Sparrow A, Ghebreyesus TA, Netea MG. 2020. Considering BCG vaccination to reduce the impact of COVID-19. Lancet 395:102361545–46
     [Google Scholar]
129. 129. 

     Aaby P, Benn CS, Flanagan KL, Klein SL, Kollmann TR et al. 2020. The non-specific and sex-differential effects of vaccines. Nat. Rev. Immunol. 20:8464–70
     [Google Scholar]
130. 130. 

     Sylvester RJ, van der Meijden APM, Lamm DL. 2002. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J. Urol. 168:51964–70
     [Google Scholar]
131. 131. 

     Morton DL, Eilber FR, Holmes EC, Hunt JS, Ketcham AS et al. 1974. BCG immunotherapy of malignant melanoma: summary of a seven year experience. Ann. Surg. 180:4635–43
     [Google Scholar]
132. 132. 

     Sokal JE, Aungst CW, Snyderman M, Sokal PJ. 1974. Delay in progression of malignant lymphoma after BCG vaccination. N. Engl. J. Med. 291:231226–30
     [Google Scholar]
133. 133. 

     Buffen K, Oosting M, Quintin J, Ng A, Kleinnijenhuis J et al. 2014. Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLOS Pathog 10:10e1004485
     [Google Scholar]
134. 134. 

     Kar UK, Joosten LAB. 2020. Training the trainable cells of the immune system and beyond. Nat. Immunol. 21:2115–19
     [Google Scholar]
135. 135. 

     Netea MG, Joosten LAB, van der Meer JWM. 2017. Hypothesis: stimulation of trained immunity as adjunctive immunotherapy in cancer. J. Leukoc. Biol. 102:61323–32
     [Google Scholar]
136. 136. 

     Owens BMJ. 2015. Inflammation, innate immunity, and the intestinal stromal cell niche: opportunities and challenges. Front. Immunol. 6:319
     [Google Scholar]
137. 137. 

     Foster SL, Hargreaves DC, Medzhitov R. 2007. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447:7147972–78
     [Google Scholar]
138. 138. 

     Negi S, Das DK, Pahari S, Nadeem S, Agrewala JN. 2019. Potential role of gut microbiota in induction and regulation of innate immune memory. Front. Immunol. 10:2441
     [Google Scholar]
139. 139. 

     Han F, Fan H, Yao M, Yang S, Han J 2017. Oral administration of yeast β-glucan ameliorates inflammation and intestinal barrier in dextran sodium sulfate-induced acute colitis. J. Funct. Foods. 35:115–26
     [Google Scholar]
140. 140. 

     Heinsbroek SEM, Williams DL, Welting O, Meijer SL, Gordon S, de Jonge WJ. 2015. Orally delivered β-glucans aggravate dextran sulfate sodium (DSS)-induced intestinal inflammation. Nutr. Res. 35:121106–12
     [Google Scholar]
141. 141. 

     Iliev ID, Funari VA, Taylor KD, Nguyen Q, Reyes CN et al. 2012. Interactions between commensal fungi and the C-type lectin receptor dectin-1 influence colitis. Science 336:60861314–17
     [Google Scholar]
142. 142. 

     Wheeler ML, Limon JJ, Bar AS, Leal CA, Gargus M et al. 2016. Immunological consequences of intestinal fungal dysbiosis. Cell Host Microbe 19:6865–73
     [Google Scholar]
143. 143. 

     Bekkering S, Joosten LAB, van der Meer JWM, Netea MG, Riksen NP. 2013. Trained innate immunity and atherosclerosis. Curr. Opin. Lipidol. 24:487–92
     [Google Scholar]
144. 144. 

     Bekkering S, Saner C, Riksen NP, Netea MG, Sabin MA et al. 2020. Trained immunity: linking obesity and cardiovascular disease across the life-course?. Trends Endocrinol. Metab. 31:5378–89
     [Google Scholar]
145. 145. 

     Thiem K, Stienstra R, Riksen NP, Keating ST. 2019. Trained immunity and diabetic vascular disease. Clin. Sci. 133:2195–203
     [Google Scholar]
146. 146. 

     Leentjens J, Bekkering S, Joosten LAB, Netea MG, Burgner DP, Riksen NP. 2018. Trained innate immunity as a novel mechanism linking infection and the development of atherosclerosis. Circ. Res. 122:5664–69
     [Google Scholar]
147. 147. 

     Brasacchio D, Okabe J, Tikellis C, Balcerczyk A, George P et al. 2009. Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes 58:51229–36
     [Google Scholar]
148. 148. 

     Yun JM, Jialal I, Devaraj S. 2011. Epigenetic regulation of high glucose-induced proinflammatory cytokine production in monocytes by curcumin. J. Nutr. Biochem. 22:5450–58
     [Google Scholar]
149. 149. 

     Hoyer FF, Zhang X, Coppin E, Vasamsetti SB, Modugu G et al. 2020. Bone marrow endothelial cells regulate myelopoiesis in diabetes mellitus. Circulation 142:3244–58
     [Google Scholar]
150. 150. 

     Barman PK, Urao N, Koh TJ. 2019. Diabetes induces myeloid bias in bone marrow progenitors associated with enhanced wound macrophage accumulation and impaired healing. J. Pathol. 249:4435–46
     [Google Scholar]
151. 151. 

     Shirai T, Nazarewicz RR, Wallis BB, Yanes RE, Watanabe R et al. 2016. The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J. Exp. Med. 213:3337–54
     [Google Scholar]
152. 152. 

     Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA et al. 2016. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 388:100572239–53
     [Google Scholar]
153. 153. 

     Schnitzler JG, Poels K, Stiekema LCA, Yeang C, Tsimikas S et al. 2020. Short-term regulation of hematopoiesis by lipoprotein(a) results in the production of pro-inflammatory monocytes. Int. J. Cardiol. 315:81–85
     [Google Scholar]
154. 154. 

     Schloss MJ, Swirski FK, Nahrendorf M. 2020. Modifiable cardiovascular risk, hematopoiesis, and innate immunity. Circ. Res. 126:91242–59
     [Google Scholar]
155. 155. 

     Datta M, Staszewski O, Raschi E, Frosch M, Hagemeyer N et al. 2018. Histone deacetylases 1 and 2 regulate microglia function during development, homeostasis, and neurodegeneration in a context-dependent manner. Immunity 48:3514–29.e6
     [Google Scholar]
156. 156. 

     Püntener U, Booth SG, Perry VH, Teeling JL. 2012. Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia. J. Neuroinflamm. 9:146
     [Google Scholar]
157. 157. 

     Ramirez K, Shea DT, McKim DB, Reader BF, Sheridan JF. 2015. Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav. Immun. 46:212–20
     [Google Scholar]
158. 158. 

     Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M et al. 2014. Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol. 10:11643–60
     [Google Scholar]
159. 159. 

     Bilbo SD, Biedenkapp JC, Der-Avakian A, Watkins LR, Rudy JW, Maier SF 2005. Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition. J. Neurosci. 25:358000–9
     [Google Scholar]
160. 160. 

     Williamson LL, Sholar PW, Mistry RS, Smith SH, Bilbo SD. 2011. Microglia and memory: modulation by early-life infection. J. Neurosci. 31:4315511–21
     [Google Scholar]
161. 161. 

     Noz MP, ter Telgte A, Wiegertjes K, Joosten LAB, Netea MG et al. 2018. Trained immunity characteristics are associated with progressive cerebral small vessel disease. Stroke 49:122910–17
     [Google Scholar]
162. 162. 

     Arts RJW, Joosten LAB, Netea MG. 2018. The potential role of trained immunity in autoimmune and autoinflammatory disorders. Front. Immunol. 9:298
     [Google Scholar]
163. 163. 

     Van Der Meer JWM, Radl J, Meyer CJLM, Vossen JM, Van Nieuwkoop JA et al. 1984. Hyperimmunoglobulinaemia D and periodic fever: a new syndrome. Lancet 323:83861087–90
     [Google Scholar]
164. 164. 

     Grigoriou M, Banos A, Filia A, Pavlidis P, Giannouli S et al. 2019. Transcriptome reprogramming and myeloid skewing in haematopoietic stem and progenitor cells in systemic lupus erythematosus. Ann. Rheum. Dis. 79:2242–53
     [Google Scholar]
165. 165. 

     Oduro KA, Liu F, Tan Q, Kim CK, Lubman O et al. 2012. Myeloid skewing in murine autoimmune arthritis occurs in hematopoietic stem and primitive progenitor cells. Blood 120:112203–13
     [Google Scholar]
166. 166. 

     Jeljeli M, Riccio LGC, Doridot L, Chêne C, Nicco C et al. 2019. Trained immunity modulates inflammation-induced fibrosis. Nat. Commun. 10:15670
     [Google Scholar]
167. 167. 

     Imran S, Neeland MR, Shepherd R, Messina N, Perrett KP et al. 2020. A potential role for epigenetically mediated trained immunity in food allergy. iScience 23:6101171
     [Google Scholar]
168. 168. 

     Tulic MK, Hodder M, Forsberg A, McCarthy S, Richman T et al. 2011. Differences in innate immune function between allergic and nonallergic children: new insights into immune ontogeny. J. Allergy Clin. Immunol. 127:2470–78.e1
     [Google Scholar]
169. 169. 

     Neeland MR, Koplin JJ, Dang TD, Dharmage SC, Tang ML et al. 2018. Early life innate immune signatures of persistent food allergy. J. Allergy Clin. Immunol. 142:3857–64.e3
     [Google Scholar]
170. 170. 

     Neeland MR, Andorf S, Manohar M, Dunham D, Lyu SC et al. 2020. Mass cytometry reveals cellular fingerprint associated with IgE⁺ peanut tolerance and allergy in early life. Nat. Commun. 11:11091
     [Google Scholar]
171. 171. 

     Zhang Y, Collier F, Naselli G, Saffery R, Tang ML et al. 2016. Cord blood monocyte-derived inflammatory cytokines suppress IL-2 and induce nonclassic “T_H2-type” immunity associated with development of food allergy. Sci. Transl. Med. 8:321321ra8
     [Google Scholar]
172. 172. 

     Arnoldussen DL, Linehan M, Sheikh A. 2011. BCG vaccination and allergy: a systematic review and meta-analysis. J. Allergy Clin. Immunol. 127:1246–53
     [Google Scholar]
173. 173. 

     Herz U, Gerhold K, Grüber C, Braun A, Wahn U et al. 1998. BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model. J. Allergy Clin. Immunol. 102:5867–74
     [Google Scholar]
174. 174. 

     Estcourt MJ, Campbell DE, Gold MS, Richmond P, Allen KJ et al. 2019. Whole-cell pertussis vaccination and decreased risk of IgE-mediated food allergy: a nested case-control study. J. Allergy Clin. Immunol. Pract. 8:62004–14
     [Google Scholar]
175. 175. 

     Messina NL, Gardiner K, Donath S, Flanagan K, Ponsonby AL et al. 2019. Study protocol for the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR), a randomised controlled trial to determine the non-specific effects of neonatal BCG vaccination in a low-mortality setting. BMJ Open 9:12e032844
     [Google Scholar]
176. 176. 

     Ochando J, Fayad ZA, Madsen JC, Netea MG, Mulder WJM. 2020. Trained immunity in organ transplantation. Am. J. Transplant. 20:110–18
     [Google Scholar]
177. 177. 

     Braza MS, van Leent MMT, Lameijer M, Sanchez-Gaytan BL, Arts RJW et al. 2018. Inhibiting inflammation with myeloid cell-specific nanobiologics promotes organ transplant acceptance. Immunity 49:5819–28.e6
     [Google Scholar]
178. 178. 

     Mulder WJM, Ochando J, Joosten LAB, Fayad ZA, Netea MG. 2019. Therapeutic targeting of trained immunity. Nat. Rev. Drug Discov. 18:7553–66
     [Google Scholar]
179. 179. 

     van der Heijden CDCC, Noz MP, Joosten LAB, Netea MG, Riksen NP, Keating ST. 2018. Epigenetics and trained immunity. Antioxid. Redox Signal. 29:111023–40
     [Google Scholar]
180. 180. 

     Rodriguez RM, Suarez-Alvarez B, Lopez-Larrea C. 2019. Therapeutic epigenetic reprogramming of trained immunity in myeloid cells. Trends Immunol 40:166–80
     [Google Scholar]
181. 181. 

     Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S et al. 2010. Suppression of inflammation by a synthetic histone mimic. Nature 468:73271119–23
     [Google Scholar]
182. 182. 

     Domínguez-Andrés J, Ferreira AV, Jansen T, Smithers N, Prinjha RK et al. 2019. Bromodomain inhibitor I-BET151 suppresses immune responses during fungal-immune interaction. Eur. J. Immunol. 49:112044–50
     [Google Scholar]
183. 183. 

     Klein K, Kabala PA, Grabiec AM, Gay RE, Kolling C et al. 2016. The bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matrix degrading enzymes in rheumatoid arthritis synovial fibroblasts. Ann. Rheum. Dis. 75:2422–29
     [Google Scholar]
184. 184. 

     Fu W, Farache J, Clardy SM, Hattori K, Mander P et al. 2014. Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells. eLife 3:e04631
     [Google Scholar]
185. 185. 

     Perrotta P, Van Der Veken B, Van Der Veken P, Pintelon I, Roosens L et al. 2020. Partial inhibition of glycolysis reduces atherogenesis independent of intraplaque neovascularization in mice. Arterioscler. Thromb. Vasc. Biol. 40:51168–81
     [Google Scholar]
186. 186. 

     Duivenvoorden R, Tang J, Cormode DP, Mieszawska AJ, Izquierdo-Garcia D et al. 2014. A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nat. Commun. 5:3065
     [Google Scholar]