Advanced search
Publication Cover
Human Vaccines & Immunotherapeutics Volume 18, 2022 - Issue 1
Submit an article Journal homepage
5,070
Views
6
CrossRef citations to date
0
Altmetric
Immunology – Reviews

Prophylactic and therapeutic insights into trained immunity: A renewed concept of innate immune memory

Suresh Bindua Immunology Section, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, IndiaORCID Iconhttps://orcid.org/0000-0001-9690-970XView further author information
ORCID Icon,
Satyabrata Dandapata Immunology Section, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, IndiaORCID Iconhttps://orcid.org/0000-0002-7780-3413View further author information
ORCID Icon,
Rajendran Manikandana Immunology Section, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, IndiaORCID Iconhttps://orcid.org/0000-0003-3831-6177View further author information
ORCID Icon,
Murali Dineshb Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, IndiaView further author information
,
Anbazhagan Subbaiyanc Division of Bacteriology and Mycology, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, IndiaORCID Iconhttps://orcid.org/0000-0002-9828-048XView further author information
ORCID Icon,
Pashupathi Manid Division of Animal Biochemistry, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, IndiaORCID Iconhttps://orcid.org/0000-0002-5998-1865View further author information
ORCID Icon,
Manish Dhawane Department of Microbiology, Punjab Agricultural University, Ludhiana, India;f Indian Council of Agricultural Research, The Trafford Group of Colleges, Manchester, UKORCID Iconhttps://orcid.org/0000-0002-7783-7138View further author information
ORCID Icon,
Ruchi Tiwarig Department of Veterinary Microbiology and Immunology, College of Veterinary Sciences, Uttar Pradesh Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, IndiaORCID Iconhttps://orcid.org/0000-0001-7763-5547View further author information
ORCID Icon,
Muhammad Bilalh School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian, ChinaORCID Iconhttps://orcid.org/0000-0001-5388-3183View further author information
ORCID Icon,
Talha Bin Emrani Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, BangladeshORCID Iconhttps://orcid.org/0000-0003-3188-2272View further author information
ORCID Icon,
Saikat Mitraj Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, BangldeshView further author information
,
Ali A. Rabaank Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia;l College of Medicine, Alfaisal University, Riyadh, Saudi Arabia;m Department of Public Health and Nutrition, The University of Haripur, Haripur, PakistanORCID Iconhttps://orcid.org/0000-0002-6774-9847View further author information
ORCID Icon,
Abbas Al Mutairn Research Center, Almoosa Specialist Hospital, Al-Ahsa, Saudi Arabia;o College of Nursing, Princess Norah Bint Abdulrahman University, Riyadh, Saudi Arabia;p School of Nursing, Wollongong University, Wollongong, AustraliaORCID Iconhttps://orcid.org/0000-0002-9471-2767View further author information
ORCID Icon,
Zainab Al Alawiq Division of Allergy and Immunology, College of Medicine, King Faisal University, Saudi ArabiaORCID Iconhttps://orcid.org/0000-0002-7004-7694View further author information
ORCID Icon,
Saad Alhumaidr Administration of Pharmaceutical Care, Al-Ahsa Health Cluster, Ministry of Health, Al-Ahsa, Saudi ArabiaORCID Iconhttps://orcid.org/0000-0003-4552-4513View further author information
ORCID Icon &
Kuldeep Dhamab Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, IndiaCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0001-7469-4752View further author information
ORCID Icon show all
Article: 2040238 | Received 14 Jul 2021, Accepted 04 Feb 2022, Published online: 03 Mar 2022

References

  • Bergman P, Raqib R, Rekha RS, Agerberth B, Gudmundsson GH. Host directed therapy against infection by boosting innate immunity. Front Immunol. 2020;11:11. doi:10.3389/fimmu.2020.01209.
  • Hewitt RJ, Lloyd CM. Regulation of immune responses by the airway epithelial cell landscape. Nat Rev Immunol. 2021;21(6):347–19. doi:10.1038/s41577-020-00477-9.
  • Janeway C, Travers P, Walport M, and Shlomick M. Immunobiology: the immune system in health and disease. 5thed. New York: Garland Science; 2001. p. 10775.
  • Mak TW, Saunders ME, and Jett BD. Primer to the immune response. 2nd ed. Burlington (MA): Newnes; 2014. p. 1–674.
  • Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, Jacobs C, van Loenhout J, de Jong D, Stunnenberg HG, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A. 2012;109(43):109. doi:10.1073/pnas.1202870109.
  • Bromuro C, Torosantucci A, Chiani P, Conti S, Polonelli L, Cassone A. Interplay between protective and inhibitory antibodies dictates the outcome of experimentally disseminated candidiasis in recipients of a Candida albicans vaccine. Infect Immun. 2002;70(10):5462–70. doi:10.1128/IAI.70.10.5462-5470.2002.
  • Netea MG, van der Meer JWM. Trained immunity: an ancient way of remembering. Cell Host Microbe. 2017;21:297–300. doi:10.1016/j.chom.2017.02.003.
  • Domínguez-Andrés J, Joosten LA, Netea MG. Induction of innate immune memory: the role of cellular metabolism. Curr Opin Immunol. 2019;56:10–16. doi:10.1016/j.coi.2018.09.001.
  • Basak P, Sachdeva N, Dayal D. Can BCG vaccine protect against COVID-19 via trained immunity and tolerogenesis? BioEssays. 2021;43(3):43. doi:10.1002/bies.202000200.
  • Mantovani A, Netea MG. Trained innate immunity, epigenetics, and Covid-19. N Engl J Med. 2020;383(11):1078–80. doi:10.1056/NEJMcibr2011679.
  • Netea MG, Joosten LAB, Latz E, Mills KHG, Natoli G, Stunnenberg HG, Oʻ-Neill LAJ, Xavier RJ. Trained immunity: a program of innate immune memory in health and disease. Science (80-). 2016;352:427. doi:10.1126/science.aaf1098.
  • Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, Joosten LAB, van der Meer JWM, Mhlanga MM, Mulder WJM, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020;20(6):375–88. doi:10.1038/s41577-020-0285-6.
  • Netea MG, Quintin J, Van Der Meer JWM. Trained immunity: a memory for innate host defense. Cell Host Microbe. 2011;9(5):355–61. doi:10.1016/j.chom.2011.04.006.
  • Arneth B. Trained innate immunity. Immunol Res. 2021;69(1):69. doi:10.1007/s12026-021-09170-y.
  • Hamada A, Torre C, Drancourt M, Ghigo E. Trained immunity carried by non-immune cells. Front Microbiol. 2018;9:10. doi:10.3389/fmicb.2018.03225.
  • Dominguez-Andres J, Netea MG. Long-term reprogramming of the innate immune system. J Leukoc Biol. 2019;105(2):329–38. doi:10.1002/JLB.MR0318-104R.
  • Oʻ-Neill LAJ, Netea MG. BCG-Induced trained immunity: can it offer protection against COVID-19? Nat Rev Immunol. 2020;20(6):335–37. doi:10.1038/s41577-020-0337-y.
  • Mulder WJM, Ochando J, Joosten LAB, Fayad ZA, Netea MG. Therapeutic targeting of trained immunity. Nat Rev Drug Discov. 2019;18(7):553–66. doi:10.1038/s41573-019-0025-4.
  • Liu GY, Liu Y, Lu Y, Qin YR, Di GH, Lei YH, Liu HX, Li YQ, Wu C, Hu XW, et al. Short-Term memory of danger signals or environmental stimuli in mesenchymal stem cells: implications for therapeutic potential. Cell Mel Immunol. 2016;13(3):369–78. doi:10.1038/cmi.2015.11.
  • Kaufmann E, Sanz J, Dunn JL, Khan N, MendonçMendonçA LE, Pacis A, Tzelepis F, Pernet E, Dumaine A, Grenier JC, et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell. 2018;172(1–2):176–90.e19. doi:10.1016/j.cell.2017.12.031.
  • Riksen NP. Trained immunity and atherosclerotic cardiovascular disease. Curr Opin Lipidol. 2019;30(5):395–400. doi:10.1097/MOL.0000000000000628.
  • Penkov S, Mitroulis I, Hajishengallis G, Chavakis T. Immunometabolic crosstalk: an ancestral principle of trained immunity? Trends Immunol. 2019;40(1):1–11. doi:10.1016/j.it.2018.11.002.
  • Donohoe DR, Bultman SJ. Metaboloepigenetics: interrelationships between energy metabolism and epigenetic control of gene expression. J Cell Physiol. 2012;227(9):3169–77. doi:10.1002/jcp.24054.
  • Wilson DF. Regulation of cellular metabolism: programming and maintaining metabolic homeostasis. J pppl Physiol. 2013;115(11):1583–88. doi:10.1152/japplphysiol.00894.2013.
  • Arts RJW, Carvalho A, La Rocca C, Palma C, Rodrigues F, Silvestre R, Kleinnijenhuis J, Lachmandas E, Gonçalves LG, Belinha A, et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 2016;17(10):2562–71. doi:10.1016/j.celrep.2016.11.011.
  • Ganeshan K, Chawla A. Metabolic regulation of immune responses. Annu Rev Immunol. 2014;32(1):609–34. doi:10.1146/annurev-immunol-032713-120236.
  • Hard GC. Some biochemical aspects of the immune macrophage. Br J Exp Pathol. 1970;51:97–105.
  • Riksen NP, Netea MG. Immunometabolic control of trained immunity. Mol Aspects Med. 2021;77:77. doi:10.1016/j.mam.2020.100897.
  • Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2014;111(6):2247–52. doi:10.1073/pnas.1322269111.
  • Kelly B, Oʻ-Neill LAJ. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res [Internet]. 2015;25(7):771–84. doi:10.1038/cr.2015.68%5Cnpapers3://publication/doi/10.1038/cr.2015.68.
  • Incalcaterra S, Dominguez JA. Trained immunity at a glance; A review on the innate immune memory and its potential role in infections, diseases and new therapeutic strategies. Adv J Grad Res. 2020;8(1):68–81. doi:10.21467/ajgr.8.1.68-81.
  • Arts RJW, Moorlag SJCFM, Novakovic B, Li Y, Wang SY, Oosting M, Kumar V, Xavier RJ, Wijmenga C, Joosten LAB, et al. BCG vaccination protects against experimental viral infection in humans through the induction of Cytokines associated with trained immunity. Cell Host Microbe. 2018;23(1):89–100.e5. doi:10.1016/j.chom.2017.12.010.
  • Acar M, Becskei A, Van Oudenaarden A. Enhancement of cellular memory by reducing stochastic transitions. Nature. 2005;435:228–32. doi:10.1038/nature03524.
  • Lambert G, Kussel E. Memory and fitness optimization of bacteria under fluctuating environments. PLoS Genet. 2014;10(9):10. doi:10.1371/journal.pgen.1004556.
  • Mutlu A, Trauth S, Ziesack M, Nagler K, Bergeest JP, Rohr K, Becker N, Höfer T, Bischofs IB. Phenotypic memory in Bacillus subtilis links dormancy entry and exit by a spore quantity-quality tradeoff. Nat Commun. 2018;9(1). doi:10.1038/s41467-017-02477-1.
  • Liu PS, Wang H, Li X, Chao T, Teav T, Christen S, DI Conza G, Cheng WC, Chou CH, Vavakova M, et al. Α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol. 2017;18(9):985–94. doi:10.1038/ni.3796.
  • Chen S, Yang J, Wei Y, Wei X. Epigenetic regulation of macrophages: from homeostasis maintenance to host defense. Cell Mol Immunol. 2020;17(1):36–49. doi:10.1038/s41423-019-0315-0.
  • Ghisletti S, Barozzi I, Mietton F, Polletti S, De Santa F, Venturini E, Gregory L, Lonie L, Chew A, Wei CL, et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity. 2010;32(3):317–28. doi:10.1016/j.immuni.2010.02.008.
  • Keating ST, El-Osta A. Epigenetics and metabolism. Circ Res. 2015;116(4):715–36. doi:10.1161/CIRCRESAHA.116.303936.
  • Van Der Heijden CDCC, Noz MP, Joosten LAB, Netea MG, Riksen NP, Keating ST. Epigenetics and trained immunity. Antioxidants Redox Signal. 2018;29(11):1023–40. doi:10.1089/ars.2017.7310.
  • Verma D, Parasa VR, Raffetseder J, Martis M, Mehta RB, Netea M, Lerm M. Anti-Mycobacterial activity correlates with altered DNA methylation pattern in immune cells from BCG-vaccinated subjects. Sci Rep. 2017;7(1). doi:10.1038/s41598-017-12110-2.
  • Keating ST, Groh L, Thiem K, Bekkering S, Li Y, Matzaraki V, van der Heijden CDCC, van Puffelen JH, Lachmandas E, Jansen T, et al. Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein. J Mol Med (Berl). 2020;98(6):819–31. doi:10.1007/s00109-020-01915-w.
  • Divangahi M, Aaby P, Khader SA, Barreiro LB, Bekkering S, Chavakis T, van Crevel R, Curtis N, DiNardo AR, Dominguez-Andres J, et al. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat Immunol. 2021;22(1):2–6. doi:10.1038/s41590-020-00845-6.
  • Khan N, Downey J, Sanz J, Kaufmann E, Blankenhaus B, Pacis A, Pernet E, Ahmed E, Cardoso S, Nijnik A, et al. M. tuberculosis reprograms hematopoietic stem cells to limit myelopoiesis and impair trained immunity. Cell. 2020;183(3):752–70.e22. doi:10.1016/j.cell.2020.09.062.
  • Patel AA, Zhang Y, Fullerton JN, Boelen L, Rongvaux A, Maini AA, Bigley V, Flavell RA, Gilroy DW, Asquith B, et al. The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J Exp Med. 2017;214(7):1913–23. doi:10.1084/jem.20170355.
  • Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–20. doi:10.1016/j.cell.2010.01.022.
  • Haley MJ, Brough D, Quintin J, Allan SM. Microglial priming as trained immunity in the brain. Neuroscience. 2019;405:47–54. doi:10.1016/j.neuroscience.2017.12.039.
  • Lelios I, Greter M. Trained microglia trigger memory loss. Immunity [Internet]. 2018;48:849–51.
  • Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, Wagner J, Häsler LM, Wild K, Skodras A, et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature. 2018;556(7701):332–38. doi:10.1038/s41586-018-0023-4.
  • Haley SL, Tzvetkov EP, Meuwissen S, Plummer JR, McGettigan JP. Targeting vaccine-induced extrafollicular pathway of B cell differentiation improves rabies postexposure prophylaxis. J Virol. 2017;91(8):91. doi:10.1128/JVI.02435-16.
  • Püntener U, Booth SG, Perry VH, Teeling JL. Long-Term impact of systemic bacterial infection on the cerebral vasculature and microglia. J Neuroinflammation. 2012;9(1). doi:10.1186/1742-2094-9-146.
  • Ochiel D, Fahey J, Ghosh M, Haddad S, Wira C. Innate immunity in the female reproductive tract: role of sex hormones in regulating uterine epithelial cell protection against pthogens. Curr Womens Health Rev. 2008;4(2):102–17. doi:10.2174/157340408784246395.
  • Naik S, Larsen SB, Gomez NC, Alaverdyan K, Sendoel A, Yuan S, Polak L, Kulukian A, Chai S, Fuchs E. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature. 2017;550:475–80. doi:10.1038/nature24271.
  • Owens BMJ, Simmons A. Intestinal stromal cells in mucosal immunity and homeostasis. Mucosal Immunol. 2013;6(2):224–34. doi:10.1038/mi.2012.125.
  • Augenlicht LH, Li W, Peregrina K, and Houston M. Abstract 1708: intestinal stem cells are sentinel cells for nutritional exposure. Cancer Res . 2016;76:1708.
  • Owens BMJ. Inflammation, innate immunity, and the intestinal stromal cell niche: opportunities and challenges. Front Immunol. 2015;6:319.
  • Ordovas-Montanes J, Beyaz S, Rakoff-Nahoum S, Shalek AK. Distribution and storage of inflammatory memory in barrier tissues. Nat Rev Immunol. 2020;20(5):308–20. doi:10.1038/s41577-019-0263-z.
  • Mitroulis I, Ruppova K, Wang B, Chen LS, Grzybek M, Grinenko T, Eugster A, Troullinaki M, Palladini A, Kourtzelis I, et al. Modulation of myelopoiesis progenitors is anintegral component of trained immunity. Cell. 2018;172(1–2):147–61.e12. doi:10.1016/j.cell.2017.11.034.
  • Machiels B, Dourcy M, Xiao X, Javaux J, Mesnil C, Sabatel C, Desmecht D, Lallemand F, Martinive P, Hammad H, et al. A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat Immunol. 2017;18(12):1310–20. doi:10.1038/ni.3857 .
  • Yao Y, Jeyanathan M, Haddadi S, Barra NG, Vaseghi-Shanjani M, Damjanovic D, Lai R, Afkhami S, Chen Y, Dvorkin-Gheva A, et al. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell. 2018;175(6):1634–50.e17. doi:10.1016/j.cell.2018.09.042.
  • Cirovic B, de Bree LCJ, Groh L, Blok BA, Chan J, van der Velden WJFM, Bremmers MEJ, van Crevel R, Händler K, Picelli S, et al. BCG vaccination in humans elicits trained immunity via the hematopoietic progenitor compartment. Cell Host Microbe. 2020;28(2):322–34.e5. doi:10.1016/j.chom.2020.05.014.
  • Quintin J, Saeed S, Martens JHA, Giamarellos-Bourboulis EJ, Ifrim DC, Logie C, Jacobs L, Jansen T, Kullberg BJ, Wijmenga C, et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe. 2012;12(2):223–32. doi:10.1016/j.chom.2012.06.006.
  • Ifrim DC, Quintin J, Joosten LAB, Jacobs C, Jansen T, Jacobs L, Gow NAR, Williams DL, Van Der Meer JWM, Netea MG. Trained immunity or tolerance: opposing functional programs induced in human monocytes after engagement of various pattern recognition receptors. Clin Vaccine Immunol. 2014;21(4):534–45. doi:10.1128/CVI.00688-13.
  • Dobrovolskaia MA, Vogel SN. Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect. 2002;4(9):903–14. doi:10.1016/S1286-4579(02)01613-1.
  • Bekkering S, Blok BA, Joosten LAB, Riksen NP, Van Crevel R, Netea MG. In vitro experimental model of trained innate immunity in human primary monocytes. Clin Vaccine Immunol. 2016;23(12):926–33. doi:10.1128/CVI.00349-16.
  • Bekkering S, Domínguez-Andrés J, Joosten LAB, Riksen NP, Netea MG. Trained immunity: reprogramming innate immunity in health and disease. Annu Rev Immunol. 2021;39:39. doi:10.1146/annurev-immunol-102119-073855.
  • Christ A, Latz E. The Western lifestyle has lasting effects on metaflammation. Nat Rev Immunol. 2019;19(5):267–68. doi:10.1038/s41577-019-0156-1.
  • Bekkering S, Quintin J, Joosten LAB, van der Meer JWM, Netea MG, Riksen NP. Trained innate immunity and atherosclerosis. Clin Ther. 2014;36(8):e3. doi:10.1016/j.clinthera.2014.05.016.
  • Bekkering S, Saner C, Riksen NP, Netea MG, Sabin MA, Saffery R, Stienstra R, Burgner DP. Trained immunity: linking obesity and cardiovascular disease across the life-course? Trends Endocrinol Metab. 2020;31(5):378–89. doi:10.1016/j.tem.2020.01.008.
  • Thiem K, Stienstra R, Riksen NP, Keating ST. Trained immunity and diabetic vascular disease. Clin Sci (Lond). 2019;133(2):195–203. doi:10.1042/CS20180905.
  • Bekkering S, Quintin J, Joosten LAB, Van Der Meer JWM, Netea MG, Riksen NP. Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler Thromb Vasc Biol. 2014;34(8):1731–38. doi:10.1161/ATVBAHA.114.303887.
  • Van Der Valk FM, Bekkering S, Kroon J, Yeang C, Van Den Bossche J, Van Buul JD, Ravandi A, Nederveen AJ, Verberne HJ, Scipione C, et al. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation. 2016;134:611–24. doi:10.1161/CIRCULATIONAHA.116.020838.
  • Van Der Heijden CDCC, Groh L, Keating ST, Kaffa C, Noz MP, Kersten S, Van Herwaarden AE, Hoischen A, Joosten LAB, Timmers HJLM, et al. Catecholamines induce trained immunity in monocytes in vitro and in vivo. Circ Res. 2020;127(2):269–83. doi:10.1161/CIRCRESAHA.119.315800.
  • Van Der Heijden CDCC, Keating ST, Groh L, Joosten LAB, Netea MG, Riksen NP. Aldosterone induces trained immunity: the role of fatty acid synthesis. Cardiovasc Res. 2020;116(2):317–28. doi:10.1093/cvr/cvz137.
  • Christ A, Bekkering S, Latz E, Riksen NP. Long-Term activation of the innate immune system in atherosclerosis. Semin Immunol. 2016;28(4):384–93. doi:10.1016/j.smim.2016.04.004.
  • Leentjens J, Bekkering S, Joosten LAB, Netea MG, Burgner DP, Riksen NP. Trained innate immunity as a novel mechanism linking infection and the development of atherosclerosis. Circ Res. 2018;122(5):664–69. doi:10.1161/CIRCRESAHA.117.312465.
  • Van Tuijl J, Joosten LAB, Netea MG, Bekkering S, Riksen NP. Immunometabolism orchestrates training of innate immunity in atherosclerosis. Cardiovasc Res. 2019;115(9):1416–24. doi:10.1093/cvr/cvz107.
  • Zhong C, Yang X, Feng Y, and Yu J. Trained immunity: an underlying driver of inflammatory atherosclerosis. Front Immunol. 2020;11:284.
  • Netea MG, Latz E, Mills KHG, Oʻ-Neill LAJ. Innate immune memory: A paradigm shift in understanding host defense. Nat Immunol. 2015;16(7):675–79. doi:10.1038/ni.3178.
  • Braza MS, van Leent MMT, Lameijer M, Sanchez-Gaytan BL, Arts RJW, Pérez-Medina C, Conde P, Garcia MR, Gonzalez-Perez M, Brahmachary M, et al. Inhibiting inflammation with myeloid cell-specific nanobiologics promotes organ transplant acceptance. Immunity. 2018;49(5):819–28.e6. doi:10.1016/j.immuni.2018.09.008.
  • Wang X, Antony V, Wang Y, Wu G, Liang G. Pattern recognition receptor-mediated inflammation in diabetic vascular complications. Med Res Rev. 2020;40(6):2466–84. doi:10.1002/med.21711.
  • Ochando J, Fayad ZA, Madsen JC, Netea MG, Mulder WJM. Trained immunity in organ transplantation. Am J Transplant. 2020;20(1):10–18. doi:10.1111/ajt.15620.
  • Wentowski C, Mewada N, Nielsen ND. Sepsis in 2018: a review. Anaesth Intensive Care Med. 2019;20(1):6–13. doi:10.1016/j.mpaic.2018.11.009.
  • Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science (80-). 2016;353(6301):777–83. doi:10.1126/science.aag2590.
  • Datta M, Staszewski O, Raschi E, Frosch M, Hagemeyer N, Tay TL, Blank T, Kreutzfeldt M, Merkler D, Ziegler-Waldkirch S, et al. Histone deacetylases 1 and 2 regulate microglia function during development, homeostasis, and neurodegeneration in a context-dependent manner. Immunity. 2018;48(3):514–29.e6. doi:10.1016/j.immuni.2018.02.016.
  • Williamson LL, Sholar PW, Mistry RS, Smith SH, Bilbo SD. Microglia and memory: modulation by early-life infection. J Neurosci. 2011;31(43):15511–21. doi:10.1523/JNEUROSCI.3688-11.2011.
  • Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat Rev Neurol. 2014;10(4):217–24. doi:10.1038/nrneurol.2014.38.
  • Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA, Toovey S, Prinssen EP. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol. 2014;10(11):643–60. doi:10.1038/nrneurol.2014.187.
  • Noz MP, Ter Telgte A, Wiegertjes K, Joosten LAB, Netea MG, De Leeuw FE, Riksen NP. Trained immunity characteristics are associated with progressive cerebral small vessel disease. Stroke. 2018;49(12):2910–17. doi:10.1161/STROKEAHA.118.023192.
  • Kim J, Choi SE, Lim BJ, Kim YS, Huh KH, Lee J, Kim SI, Kim MS, Jeong HJ. Clinical significance of macrophage polarization in antibody-mediated rejection of renal allograft. Transplant Proc. 2018;50(4):1005–08. doi:10.1016/j.transproceed.2018.02.037.
  • Zhao Y, Chen S, Lan P, Wu C, Dou Y, Xiao X, Zhang Z, Minze L, He X, Chen W, et al. Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model. Am J Transplant. 2018;18(3):604–16. doi:10.1111/ajt.14543.
  • Ordikhani F, Pothula V, Sanchez-Tarjuelo R, Jordan S, Ochando J. Macrophages in organ transplantation. Front Immunol. 2020;11:11. doi:10.3389/fimmu.2020.582939.
  • Brown GD, Herre J, Williams DL, Willment JA, Marshall ASJ, Gordon S. Dectin-1 mediates the biological effects of β-glucans. J Exp Med. 2003;197(9):1119–24. doi:10.1084/jem.20021890.
  • Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003;278(11):8869–72. doi:10.1074/jbc.C200651200.
  • Lührs H, Gerke T, Müller JG, Melcher R, Schauber J, Boxberger F, Scheppach W, Menzel T. Butyrate inhibits NF-κB activation in lamina propria macrophages of patients with ulcerative colitis. Scand J Gastroenterol. 2002;37(4):458–66. doi:10.1080/003655202317316105.
  • Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nũez G, Schnurr M, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357–61. doi:10.1038/nature08938.
  • Bosmans JL, Holvoet P, Dauwe SEH, Ysebaert DK, Chapelle T, Jürgens A, Kovacic V, Van Marck EA, De Broe ME, Verpooten GA. Oxidative modification of low-density lipoproteins and the outcome of renal allografts at 1 1/2 years. Kidney Int. 2001;59(6):2346–56. doi:10.1046/j.1523-1755.2001.00752.x.
  • Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, Becker CE, Ediriweera HN, Mullick AE, Golenbock DT, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013;14(8):812–20. doi:10.1038/ni.2639.
  • Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–31. doi:10.1056/NEJMoa1707914.
  • Chakraborty C, Sharma AR, Sharma G, Doss CGP, Lee SS. Therapeutic miRNA and siRNA: moving from bench to clinic as next generation medicine. Mol Ther Nucleic Acids. 2017;8:132–43. doi:10.1016/j.omtn.2017.06.005.
  • Dvir T, Timko BP, Kohane DS, and Langer R. Nanotechnological strategies for engineering complex tissues. Nat. Nanotechnol. 2020;6(1):13–22.
  • Netea MG, Schlitzer A, Placek K, Joosten LAB, Schultze JL. Innate and adaptive immune memory: an evolutionary continuum in the hostʻs response to pathogens. Cell Host Microbe. 2019;25(1):13–26. doi:10.1016/j.chom.2018.12.006.
  • Tough DF, Lewis HD, Rioja I, Lindon MJ, Prinjha RK. Epigenetic pathway targets for the treatment of disease: accelerating progress in the development of pharmacological tools: IUPHAR Review 11. Br J Pharmacol. 2014;171(22):4981–5010. doi:10.1111/bph.12848.
  • Grabiec AM, Krausz S, de Jager W, Burakowski T, Groot D, Sanders ME, Prakken BJ, Maslinski W, Eldering E, Tak PP, et al. Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue. J Immunol. 2010;184(5):2718–28. doi:10.4049/jimmunol.0901467.
  • Municio C, Criado G. Therapies targeting trained immune cells in inflammatory and autoimmune diseases. Front Immunol. 2021;11:11. doi:10.3389/fimmu.2020.631743.
  • Charlotte L, Mourits VP, Koeken VACM, Moorlag SJCFM, Janssen R, Folkman L, Barreca D, Krausgruber T, Fife-Gernedl V, Novakovic B, et al. Circadian rhythm influences induction of trained immunity by BCG vaccination. J Clin Invest. 2020;130(10):5603–17. doi:10.1172/JCI133934.
  • Parihar A, Eubank TD, Doseff AI. Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death. J Innate Immun. 2010;2(3):204–15. doi:10.1159/000296507.
  • Chilvers ER, Cadwallader KA, Reed BJ, White JF, Condliffe AM. The function and fate of neutrophils at the inflamed site: prospects for therapeutic intervention. J R Coll Physicians Lond. 2000;34:68–74.
  • Mackaness GB. The influence of immunologically committed lymphoid cells on macrophage activity in vivo. J Exp Med. 1969;129(5):973–92. doi:10.1084/jem.129.5.973.
  • Chumakov K, Avidan MS, Benn CS, Bertozzi SM, Blatt L, Chang AY, Jamison DT, Khader SA, Kottilil S, Netea MG, et al. Old vaccines for new infections: exploiting innate immunity to control COVID-19 and prevent future pandemics. Proc Natl Acad Sci U S A. 2021;118(21):118. doi:10.1073/pnas.2101718118.
  • Sánchez-Ramón S, Conejero L, Netea MG, Sancho D, Palomares Ó, Subiza JL. Trained immunity-based vaccines: a new paradigm for the development of broad-spectrum anti-infectious formulations. Front Immunol. 2018;9:2936. doi:10.3389/fimmu.2018.02936.
  • Cirauqui C, Benito-Villalvilla C, Sánchez-Ramón S, Sirvent S, Diez-Rivero CM, Conejero L, Brandi P, Hernández-Cillero L, Ochoa JL, Pérez-Villamil B, et al. Human dendritic cells activated with MV130 induce Th1, Th17 and IL-10 responses via RIPK2 and MyD88 signalling pathways. Eur J Immunol. 2018;48(1):180–93. doi:10.1002/eji.201747024.
  • Zanoni I, Tan Y, Di Gioia M, Broggi A, Ruan J, Shi J, Donado CA, Shao F, Wu H, Springstead JR, et al. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science (80). 2016;352:1232–36. doi:10.1126/science.aaf3036.
  • Kleinnijenhuis J, Quintin J, Preijers F, Benn CS, Joosten LAB, Jacobs C, Van Loenhout J, Xavier RJ, Aaby P, Van Der Meer JWM, et al. Long-Lasting effects of bcg vaccination on both heterologous th1/th17 responses and innate trained immunity. J Innate Immun. 2014;6(2):152–58. doi:10.1159/000355628.
  • Verrall AJ, Schneider M, Alisjahbana B, Apriani L, van Laarhoven A, Koeken VACM, van Dorp S, Diadani E, Utama F, Hannaway RF, et al. Early clearance of mycobacterium tuberculosis is associated with increased innate immune responses. J Infect Dis. 2020;221(8):1342–50. doi:10.1093/infdis/jiz147.
  • Kleinnijenhuis J, Van Crevel R, Netea MG. Trained immunity: consequences for the heterologous effects of BCG vaccination. Trans R Soc Trop Med Hyg. 2014;109(1):29–35. doi:10.1093/trstmh/tru168.
  • Covián C, Fernández-Fierro A, Retamal-Díaz A, Díaz FE, Vasquez AE, Lay MK, Riedcl CA, González PA, Bueno SM, Kalergis AM. BCG-Induced cross-protection and development of trained immunity: implication for vaccine design. Front Immunol. 2019;10:10. doi:10.3389/fimmu.2019.02806.
  • Benito-Villalvilla C, Cirauqui C, Diez-Rivero CM, Casanovas M, Subiza JL, Palomares O. MV140, a sublingual polyvalent bacterial preparation to treat recurrent urinary tract infections, licenses human dendritic cells for generating Th1, Th17, and IL-10 responses via Syk and MyD88. Mucosal Immunol. 2017;10(4):924–35. doi:10.1038/mi.2016.112.
  • Lorenzo-Gómez MF, Padilla-Fernández B, GarcíGarcíA-Cenador MB, Virseda-Rodríguez ÁJ, Martín-GarcíGarcíA I, Sánchez-Escudero A, Vicente-Arroyo MJ, Mirón-Canelo JA. Comparison of sublingual therapeutic vaccine with antibiotics for the prophylaxis of recurrent urinary tract infections. Front Cell Infect Microbiol. 2015;5:5. doi:10.3389/fcimb.2015.00050.
  • Jensen ML, Dave S, van der Loeff MS, da Costa C, Vincent T, Leligdowicz A, Benn CS, Roth A, Ravn H, Lisse IM, et al. Vaccinia scars associated with improved survival among adults in rural Guinea-Bissau. PLoS One. 2006:1. doi:10.1371/journal.pone.0000101.
  • Gillard GO, Bivas-Benita M, Hovav AH, Grandpre LE, Panas MW, Seaman MS, Haynes BF, Letvin NL. Correction: Thy1 + Nk cells from vaccinia virus-primed mice confer protection against vaccinia virus challenge in the absence of adaptive lymphocytes. PLoS Pathog. 2011;7(8). doi:10.1371/annotation/b29086ef-e08d-444c-8113-18a6dd429a7c.
  • Piedra PA, Gaglani MJ, Kozinetz CA, Herschler GB, Fewlass C, Harvey D, Zimmerman N, Glezen WP. Trivalent live attenuated intranasal influenza vaccine administered during the 2003-2004 influenza type A (H3N2) outbreak provided immediate, direct, and indirect protection in children. Pediatrics. 2007;120(3):120. doi:10.1542/peds.2006-2836.
  • Lee YJ, Lee JY, Jang YH, Seo SU, Chang J, and Seong BL. Non-Specific effect of vaccines: immediate protection against respiratory syncytial virus infection by a live attenuated influenza vaccine. Front Microbiol. 2018;9:83.
  • Pasquali C, Salami O, Taneja M, Gollwitzer ES, Trompette A, Pattaroni C, Yadava K, Bauer J, Marsland BJ. Enhanced mucosal antibody production and protection against respiratory infections following an orally administered bacterial extract. Front Med. 2014;1:1. doi:10.3389/fmed.2014.00041.
  • Roth M, Pasquali C, Stolz D, and Tamm M. Broncho Vaxom (OM-85) modulates rhinovirus docking proteins on human airway epithelial cells via Erk1/2 mitogen activated protein kinase and cAMP. PLoS One. 2017;12:e0188010.
  • Tarancón R, Domínguez-Andrés J, Uranga S, Ferreira AV., Groh LA, Domenech M, González-Camacho F, Riksen NP, Aguilo N, Yuste J, et al. New live attenuated tuberculosis vaccine MTBVAC induces trained immunity and confers protection against experimental lethal pneumonia. PLoS Pathog. 2020;16(4):e1008404. doi:10.1371/journal.ppat.1008404.
  • Libraty DH, Zhang L, Woda M, Acosta LP, Obcena A, Brion JD, Capeding RZ. Neonatal BCG vaccination is associated with enhanced T-helper 1 immune responses to heterologous infant vaccines. Trials Vaccinol. 2014;3:1–5. doi:10.1016/j.trivac.2013.11.004.
  • Goodridge HS, Ahmed SS, Curtis N, Kollmann TR, Levy O, Netea MG, Pollard AJ, Van Crevel R, Wilson CB. Harnessing the beneficial heterologous effects of vaccination. Nat Rev Immunol. 2016;16(6):392–400. doi:10.1038/nri.2016.43.
  • VANʻ-T Wout JW, Poell R, VAN Furth R. The role of BCG/PPD‐activated macrophages in resistance against systemic candidiasis in mice. Scand J Immunol. 1992;36(5):713–20. doi:10.1111/j.1365-3083.1992.tb03132.x.
  • Buffen K, Oosting M, Quintin J, Ng A, Kleinnijenhuis J, Kumar V, van de Vosse E, Wijmenga C, van Crevel R, Oosterwijk E, et al. Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathog. 2014;10(10):10. doi:10.1371/journal.ppat.1004485.
  • Saadatian-Elahi M, Aaby P, Shann F, Netea MG, Levy O, Louis J, Picot V, Greenberg M, Warren W. Heterologous vaccine effects. Vaccine. 2016;34:3923–30. doi:10.1016/j.vaccine.2016.06.020.
  • Pennington SH, Thompson AL, Wright AKA, Ferreira DM, Jambo KC, Wright AD, Faragher B, Gilmour JW, Gordon SB, Gordon MA. Oral typhoid vaccination with live-attenuated Salmonella Typhi Strain Ty21a generates Ty21a-responsive and heterologous influenza virus–responsive CD4 + and CD8 + T cells at the huian intestinal mucosa. J Infect Dis. 2016;213(11):1809–19. doi:10.1093/infdis/jiw030.
  • Di Luzio NR, Williams DL. Protective effect of glucan against systemic Staphylococcus aureus septicemia in normal and leukemic mice. Infect Immun. 1978;20(3):804–10. doi:10.1128/iai.20.3.804-810.1978.
  • Krahenbuhl JL, Sharma SD, Ferraresi RW, Remington JS. Effects of muramyl dipeptide treatment on resistance to infection with Toxoplasma gondii in mice. Infect Immun. 1981;31(2):716–22. doi:10.1128/iai.31.2.716-722.1981.
  • Ribes S, Meister T, Ott M, Redlich S, Janova H, Hanisch UK, Nessler S, and Nau R. Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection. J Neuroinflammation. 2014;11(1):1–11.
  • Khader SA, Divangahi M, Hanekom W, Hill PC, Maeurer M, Makar KW, Mayer-Barder KD, Mhlanga MM, Nemes E, Schlesinger LS, et al. Targeting innate immunity for tuberculosis vaccination. J Clin Invest. 2019;129(9):3482–91. doi:10.1172/JCI128877.
  • Dhama K, Khan S, Tiwari R, Sircar S, Bhat S, Malik YS, Singh KP, Chaicumpa W, Bonilla-Aldana D-R-M. Coronavirus disease 2019–COVID-19. Clin Microbiol Rev. 2020;33(4): e00028-20. doi:10.1128/CMR.00028-20.
  • WHO. WHO COVID-19 dashboard - up to date data on pandemic. WHO Heal Emerg Dasboard [Internet]. 2021. https://covid19.who.int/.
  • Rabaan AA, Al-Ahmed SH, Sah R, Tiwari R, Yatoo MI, Patel SK, Pathak M, Malik YS, Dhama K, and Singh KP, et al. SARS-CoV-2/COVID-19 and advances in developing potential therapeutics and vaccines to counter this emerging pandemic. Ann Clin Microbiol Antimicrob. 2020;19(1):1–37.
  • Chugh H, Awasthi A, Agarwal Y, Gaur RK, Dhawan G, Chandra R. A comprehensive review on potential therapeutics interventions for COVID-19. Eur J Pharmacol. 2021;890:890. doi:10.1016/j.ejphar.2020.173741.
  • Izda V, Jeffries MA, Sawalha AH. COVID-19: a review of therapeutic strategies and vaccine candidates. Clin Immunol. 2021;222:222. doi:10.1016/j.clim.2020.108634.
  • Iqbal Yatoo M, Hamid Z, Rather I, Nazir QUA, Bhat RA, Ul Haq A, Magray SN, Haq Z, Sah R, Tiwari R, et al. Immunotherapies and immunomodulatory approaches in clinical trials - a mini review. Hum Vaccines Immunother. 2021;17(7):1897–909. doi:10.1080/21645515.2020.1871295.
  • Hyder Pottoo F, Abu-Izneid T, Mohammad Ibrahim A, Noushad Javed M, AlHajri N, Hamrouni AM. Immune system response during viral infections: immunomodulators, Cytokine Storm (CS) and immunotherapeutics in COVID-19. Saudi Pharm J. 2021;29(2):173–87. doi:10.1016/j.jsps.2020.12.018.
  • Liu J, Liu Y, Xiang P, Pu L, Xiong H, Li C, Zhang M, Tan J, Xu Y, Song R, et al. Neutrophil-To-Lymphocyte ratio predicts severe illness patients with 2019 novel coronavirus in the early stage. medRxiv 2020.
  • Malik YS, Ansari MI, Ganesh B, Sircar S, Bhat S, Pande T, Vinodhkumar OR, Kumar P, Iqbal Yatoo M, Tiwari R, et al. BCG vaccine: a hope to control COVID-19 pandemic amid crisis. Hum Vaccines Immunother. 2020;16(12):2954–62. doi:10.1080/21645515.2020.1818522.
  • Covián C, Retamal-Díaz A, Bueno SM, and Kalergis AM. Could BCG vaccination induce protective trained immunity for SARS-CoV-2? Front Immunol. 2020;11:970.
  • Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F, Bilek N, Mabwe S, Makhethe L, Erasmus M, Toefy A, et al. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N Engl J Med. 2018;379(2):138–49. doi:10.1056/NEJMoa1714021.
  • Salem A, Nofal A, Hosny D. Treatment of common and plane warts in children with topical viable bacillus calmette-guerin. Pediatr Dermatol. 2013;30(1):60–63. doi:10.1111/j.1525-1470.2012.01848.x.
  • Mukherjee S, Subramaniam R, Chen H, Smith A, Keshava S, and Shams H. Boosting efferocytosis in alveolar space using BCG vaccine to protect host against influenza pneumonia. PLoS One. 2017;12(7):e0180143.
  • Giamarellos-Bourboulis EJ, Tsilika M, Moorlag S, Antonakos N, Kotsaki A, Domínguez-Andrés J, Kyriazopoulou E, Gkavogianni T, Adami ME, Damoraki G, et al. Activate: randomized clinical trial of BCG vaccination against infection in the elderly. Cell. 2020;183(2):315–23.e9. doi:10.1016/j.cell.2020.08.051.
  • Moorlag SJCFM, van Deuren RC, van Werkhoven CH, Jaeger M, Debisarun P, Taks E, Mourits VP, Koeken VACM, de Bree LCJ, and ten Doesschate T, et al. Safety and COVID-19 symptoms in individuals recently vaccinated with BCG: a retrospective Cohort study. Cell Reports Med. 2020;1(5):100073.
  • Dos Santos JC, Quixabeira VBL, Silva MVT, Damen MSMA, Schraa K, Jaeger M, Oosting M, Keating ST, Dorta ML, and Pinto SA, et al. Genetic variation in interleukin-32 influence the immune response against new world leishmania species and susceptibility to american tegumentary leishmaniasis. PLoS Negl Trop Dis. 2020;14(2):e0008029.
  • Bagheri N, Montazeri H. On BCG vaccine protection from COVID-19: a review. SN Compr Clin Med. 2021;3(6):1261–71. doi:10.1007/s42399-021-00835-1.
  • Schultze JL, Aschenbrenner AC. COVID-19 and the human innate immune system. Cell. 2021;184(7):1671–92. doi:10.1016/j.cell.2021.02.029.
  • Netea MG, Giamarellos-Bourboulis EJ, Domínguez-Andrés J, Curtis N, van Crevel R, van de Veerdonk FL, Bonten M. Trained immunity: a tool for reducing susceptibility to and the severity of SARS-CoV-2 infection. Cell. 2020;181:969–77. doi:10.1016/j.cell.2020.04.042.
  • de Chaisemartin C, de Chaisemartin L BCG vaccination in infancy does not protect against COVID‐19. Evidence from a natural experiment in Sweden. arXiv 2020.
  • Escobar LE, Molina-Cruz A, Barillas-Mury C. BCG vaccine protection from severe coronavirus disease 2019 (COVID-19). Proc Natl Acad Sci U S A. 2020;117(30):17720–26. doi:10.1073/pnas.2008410117.
  • Hamiel U, Kozer E, Youngster I. SARS-CoV-2 rates in BCG-raccinated and unvaccinated young adults. JAMA - J Am Med Assoc. 2020;323:2340–41. doi:10.1001/jama.2020.8189.
  • Kinoshita M, Tanaka M. Impact of routine infant BCG vaccination on COVID-19. J Infect. 2020;81(4):625–33. doi:10.1016/j.jinf.2020.08.013.
  • Arlehamn CSL, Sette A, Peters B. Lack of evidence for BCG vaccine protection from severe COVID-19. Proc Natl Acad Sci U S A. 2020;117(41):25203–04. doi:10.1073/pnas.2016733117.
  • Singh S, Maurya RP, Singh RK. “Trained immunity” from Mycobacterium spp. exposure or BCG vaccination and COVID-19 outcomes. PLoS Pathog. 2020;16(10):e1008969. doi:10.1371/journal.ppat.1008969.
  • Nowill AE, de Campos-Lima PO. Immune response resetting as a novel strategy to overcome SARS-CoV-2–induced Cytokine Storm. J Immunol. 2020;205(10):2566–75. doi:10.4049/jimmunol.2000892.
  • Tomita Y, Sato R, Ikeda T, Sakagami T. BCG vaccine may generate cross-reactive T cells against SARS-CoV-2: in silico analyses and a hypothesis. Vaccine. 2020;38:6352–56. doi:10.1016/j.vaccine.2020.08.045.
  • Myśliwska J, Trzonkowski P, Szmit E, Brydak LB, MachałMachałA M, Myśliwski A. Immunomodulating effect of influenza vaccination in the elderly differing in health status. Exp Gerontol. 2004;39(10):1447–58. doi:10.1016/j.exger.2004.08.005.
  • Young A, Neumann B, Mendez RF, Reyahi A, Joannides A, Modis Y, Franklin RJM Homologous protein domains in SARS-CoV-2 and measles, mumps and rubella viruses: preliminary evidence that MMR vaccine might provide protection against COVID-19. medRxiv 2020.
  • Hanker VS. Measles immunization: worth considering containment strategy for SARS-CoV-2 global outbreak. Indian Pediatr. 2020;57(4):380. doi:10.1007/s13312-020-1804-z.
  • Sinaei R, Pezeshki S, Parvaresh S, Sinaei R. Why COVID-19 is less frequent and severe in children: a narrative review. World J Pediatr. 2021;17(1):10–20. doi:10.1007/s12519-020-00392-y.
  • Valentini P, Sodero G, Buonsenso D. The relationship between COVID-19 and innate immunity in children: a review. Children. 2021;8:266. doi:10.3390/children8040266.
  • Rivas MN, Ebinger JE, Wu M, Sun N, Braun J, Sobhani K, van Eyk JE, Cheng S, and Arditi M. BCG vaccination history associates with decreased SARS-CoV-2 seroprevalence across a diverse cohort of health care workers. J Clin Invest. 2021;2:131.
  • Fu W, Ho PC, Liu CL, Tzeng KT, Nayeem N, Moore JS, Wang LS, and Chou SY. Reconcile the debate over protective effects of BCG vaccine against COVID-19. Sci Rep. 2021;11(1):1–9.
  • Teijaro JR, Farber DL. COVID-19 vaccines: modes of immune activation and future challenges. Nat Rev Immunol. 2021;21(4):195–97. doi:10.1038/s41577-021-00526-x.
  • Arts RJW, Joosten LAB, Netea MG. The potential role of trained immunity in autoimmune and autoinflammatory disorders. Front Immunol. 2018;9. doi:10.3389/fimmu.2018.00298.
  • Van Der Meer JWM, Radl J, Meyer CJLM, Vossen JM, Van Nieuwkoop JA, Lobatto S, Van Furth R. Hyperimmunoglobulinaemia D and periodic fever: a new syndrome. Lancet. 1984;323(8386):1087–90. doi:10.1016/S0140-6736(84)92505-4.
  • Walk J, de Bree LCJ, Graumans W, Stoter R, van Gemert GJ, van de Vegte-Bolmer M, Teelen K, Hermsen CC, Arts RJW, Behet MC, et al. Outcomes of controlled human malaria infection after BCG vaccination. Nat Commun. 2019;10(1):10. doi:10.1038/s41467-019-08659-3.
  • Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for bladder cancer—a current perspective. Nat Rev Urol. 2014;11(3):153–62. doi:10.1038/nrurol.2014.15.
  • Tulic MK, Hodder M, Forsberg A, McCarthy S, Richman T, Dvaz N, Van Den Biggelaar AHJ, Thornton CA, and Prescott SL. Differences in innate immune function between allergic and nonallergic children: new insights into immune ontogeny. J Allergy Clin Immunol. 2011;127(2):470–478.
  • Neeland MR, Koplin JJ, Dang TD, Dharmage SC, Tang ML, Prescott SL, Saffery R, Martino DJ, Allen KJ. Early life innate immune signatures of persistent food allergy. J Allergy Clin Immunol. 2018;142(3):857–64.e3. doi:10.1016/j.jaci.2017.10.024.
  • Imran S, Neeland MR, Shepherd R, Messina N, Perrett KP, Netea MG, Curtis N, Saffery R, Novakovic B. A potential role for epigenetically mediated trained immunity in food allergy. iScience. 2020;23(6):23. doi:10.1016/j.isci.2020.101171.
  • Zhang Y, Collier F, Naselli G, Saffery R, Tang ML, Allen KJ, Ponsonby AL, Harrison LC, Vuillermin P, Ranganathan S, et al. Cord blood monocyte–derived inflammatory cytokines suppress IL-2 and induce nonclassic “T H 2-type” immunity associated with development of food allergy. Sci Transl Med. 2016;8(321). doi:10.1126/scitranslmed.aad4322.
  • Neeland MR, Andorf S, Manohar M, Dunham D, Lyu SC, Dang TD, Peters RL, Perrett KP, Tang MLK, and Saffery R, et al. Mass cytometry reveals cellular fingerprint associated with IgE+ peanut tolerance and allergy in early life. Nat Commun. 2020;11(1):1–10.
  • Arnoldussen DL, Linehan M, and Sheikh A. BCG vaccination and allergy: a systematic review and meta-analysis. J Allergy Clin Immunol. 2011;127(1):246–253.
  • Herz U, Gerhold K, Grüber C, Braun A, Wahn U, Renz H, and Paul K. BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model. J Allergy Clin Immunol. 1998;102(5):867–74. doi:10.1016/S0091-6749(98)70030-2.
  • Estcourt MJ, Campbell DE, Gold MS, Richmond P, Allen KJ, Quinn HE, Marsh JA, Peters RL, Valerio C, Dai D, et al. Whole-cell pertussis vaccination and decreased rsk of IgE-mediated food allergy: a nested case-control study. J Allergy Clin Immunol Pract. 2020;8(6):2004–14. doi:10.1016/j.jaip.2019.12.020.
  • Messina NL, Gardiner K, Donath S, Flanagan K, Ponsonby AL, Shann F, Robins-Browne R, Freyne B, Abruzzo V, Morison C, et al. 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. 2019;9(12). doi:10.1136/bmjopen-2019-032844.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.