Trained Immunity at a Glance; A Review on the Innate Immune Memory and its Potential Role in Infections, Diseases and New Therapeutic Strategies

  • Silvia Incalcaterra Faculty of Science, Radboud University, Nijmegen, The Netherlands
  • Jorge Andres Dominguez Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

Abstract

Despite the existence of two different branches of immunity, innate and adaptive, it has been described that both systems are characterized by the establishment of memory responses. Indeed, it has been shown that cells belonging to the innate immune system can express a so-called “trained” memory, although it has different features from the adaptive immune memory. Adaptive memory is a long-lasting specific memory whereas innate memory involves non-specific responses which enhance the immune response during a second reinfection. However, many aspects of the trained immunity are still unclear. Metabolic and epigenetic reprogramming have been pointed as the two processes responsible for the establishment of the innate memory. Trained immunity seems to be responsible for the heterologous effect of many vaccines such as BCG, thus giving insights for the development of new therapies. Although its potential beneficial role, trained immunity could also have detrimental effects that might worsen the progress of certain diseases. The purpose of this literature review is to provide an in-depth review on the major characteristics of trained immunity, describing the main pathways at the basis of the evolution and establishment of memory in innate cells. In addition, the present review assesses the modern evidence of the impact of trained immunity in health and disease, strengthening the hypotheses that this innate memory may be considered both in the formulation of new therapeutic strategies and in the current therapeutic approaches.

Keywords: Trained immunity, innate immunity, adaptive immunity, innate memory, vaccines, BCG

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References


  1. Chaplin, D.D., Overview of the immune response. The Journal of allergy and clinical immunology, 2010. 125(2 Suppl 2): p. S3-S23. https://doi.org/1016/j.jaci.2009.12.980.

  2. Chaplin, D.D., Overview of the human immune response. Journal of Allergy and Clinical Immunology, 2006. 117(2, Supplement 2): p. S430-S435. https://doi.org/10.1016/j.jaci.2005.09.034

  3. Accolla, R., Host Defense Mechanisms against Pathogens. 7 (supplement 2): p.s5-s7. https://doi.org/10.1089/sur.2006.7.s2-5

  4. Furman, D. and M.M. Davis, New approaches to understanding the immune response to vaccination and infection. Vaccine, 2015. 33(40): p. 5271-5281. https://doi.org/1016/j.vaccine.2015.06.117

  5. Netea, M.G., et al., Innate and Adaptive Immune Memory: an Evolutionary Continuum in the Host’s Response to Pathogens. Cell Host & Microbe, 2019. 25(1): p. 13-26. https://doi.org/1016/j.chom.2018.12.006

  6. Dranoff, G., Cytokines in cancer pathogenesis and cancer therapy. Nature Reviews Cancer, 2004. 4(1): p. 11-22. https://doi.org/1038/nrc1252

  7. Janeway CA Jr, T.P., Walport M, et al., The front line of host defense. Immunobiology: The Immune System in Health and Disease, 2001. 5th edition. https://www.ncbi.nlm.nih.gov/books/NBK10757/

  8. Mathern, D.R. and P.S. Heeger, Molecules Great and Small: The Complement System. Clinical journal of the American Society of Nephrology : CJASN, 2015. 10(9): p. 1636-1650. https://doi.org/2215/CJN.06230614

  9. Schroeder, H.W., Jr. and L. Cavacini, Structure and function of immunoglobulins. The Journal of allergy and clinical immunology, 2010. 125(2 Suppl 2): p. S41-S52. https://doi.org/1016/j.jaci.2009.09.046.

  10. Schenten, D. and R. Medzhitov, Chapter 3 - The Control of Adaptive Immune Responses by the Innate Immune System, in Advances in Immunology, F.W. Alt, Editor. 2011, Academic Press. p. 87-124. https://doi.org/1016/B978-0-12-387664-5.00003-0.

  11. Noah W. Palm, R.M., Pattern recognition receptors and control of adaptive immunity. Immunological Reviews, 19 December 2008. https://doi.org/10.1111/j.1600-065X.2008.00731.x

  12. Beutler, B., Innate immunity: an overview. Molecular Immunology, 2004. 40(12): p. 845-859. https://doi.org/1016/j.molimm.2003.10.005

  13. Mushegian, A. and R. Medzhitov, Evolutionary perspective on innate immune recognition. The Journal of cell biology, 2001. 155(5): p. 705-710. https://doi.org/1083/jcb.200107040

  14. Tang, D., et al., PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunological reviews, 2012. 249(1): p. 158-175. https://doi.org/1111/j.1600-065X.2012.01146.x.

  15. Brubaker, S.W., et al., Innate immune pattern recognition: a cell biological perspective. Annual review of immunology, 2015. 33: p. 257-290. https://doi.org/1146/annurev-immunol-032414-112240.

  16. Romagnolo, A.G., et al., Role of Dectin-1 receptor on cytokine production by human monocytes challenged with Paracoccidioides brasiliensis. 61(4): p. 222-230. https://doi.org/10.1111/myc.12725

  17. Lamkanfi, M. and Vishva M. Dixit, Mechanisms and Functions of Inflammasomes. Cell, 2014. 157(5): p. 1013-1022. https://doi.org/1016/j.cell.2014.04.007.

  18. Ulevitch, R.J., Regulation of Receptor-Dependent Activation of the Innate Immune Response. The Journal of Infectious Diseases, 2003. 187(Supplement_2): p. S351-5. https://doi.org/1086/374605

  19. Goldman AS, P.B., Immunology Overview. Medical Microbiology, 1996. 4th edition. https://www.ncbi.nlm.nih.gov/books/NBK7795/

  20. Bonilla, F.A. and H.C. Oettgen, Adaptive immunity. Journal of Allergy and Clinical Immunology, 2010. 125(2, Supplement 2): p. S33-S40. https://doi.org/1016/j.jaci.2009.09.017

  21. Nutt, S.L., et al., The generation of antibody-secreting plasma cells. Nature Reviews Immunology, 2015. 15(3): p. 160-171. https://doi.org/1038/nri3795.

  22. Evavold, C.L. and J.C. Kagan, How Inflammasomes Inform Adaptive Immunity. Journal of Molecular Biology, 2018. 430(2): p. 217-237. https://doi.org/1016/j.jmb.2017.09.019.

  23. Gourbal, B., et al., Innate immune memory: An evolutionary perspective. 283(1): p. 21-40. https://doi.org/10.1111/imr.12647.

  24. Ratajczak, W., et al., Immunological memory cells. Central-European journal of immunology, 2018. 43(2): p. 194-203. https://doi.org/5114/ceji.2018.77390

  25. Sallusto, F., et al., From Vaccines to Memory and Back. Immunity, 2010. 33(4): p. 451-463. https://doi.org/1016/j.immuni.2010.10.008.

  26. Ahmed, R. and D. Gray, Immunological Memory and Protective Immunity: Understanding Their Relation. 272(5258): p. 54-60. https://doi.org/10.1126/science.272.5258.54

  27. Campos, M. and D.L. Godson, The effectiveness and limitations of immune memory: understanding protective immune responses. International Journal for Parasitology, 2003. 33(5): p. 655-661. https://doi.org/1016/s0020-7519(03)00066-3

  28. Mulder, W.J.M., et al., Therapeutic targeting of trained immunity. Nature Reviews Drug Discovery, 2019. 18(7): p. 553-566. https://doi.org/1038/s41573-019-0025-4.

  29. Netea, M.G. and J.W.M. van der Meer, Trained Immunity: An Ancient Way of Remembering. Cell Host & Microbe, 2017. 21(3): p. 297-300. doi: 10.1016/j.chom.2017.02.003.

  30. Buchmann, K., Evolution of Innate Immunity: Clues from Invertebrates via Fish to Mammals. Frontiers in immunology, 2014. 5: p. 459-459. https://doi.org/3389/fimmu.2014.00459.

  31. Medzhitov, R. and C.A. Janeway, An ancient system of host defense. Current Opinion in Immunology, 1998. 10(1): p. 12-15. https://doi.org/1016/s0952-7915(98)80024-1

  32. Kurtz, J., Specific memory within innate immune systems. Trends in Immunology, 2005. 26(4): p. 186-192. https://doi.org/1016/j.it.2005.02.001

  33. Boman, H.G., I. Nilsson, and B. Rasmuson, Inducible Antibacterial Defence System in Drosophila. Nature, 1972. 237(5352): p. 232-235. https://doi.org/1038/237232a0

  34. Lemaitre, B., J.M. Reichhart, and J.A. Hoffmann, Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms. Proceedings of the National Academy of Sciences of the United States of America, 1997. 94(26): p. 14614-14619. https://doi.org/1073/pnas.94.26.14614

  35. Milutinović, B. and J. Kurtz, Immune memory in invertebrates. Seminars in Immunology, 2016. 28(4): p. 328-342. https://doi.org/1016/j.smim.2016.05.004.

  36. Reimer-Michalski, E.-M. and U. Conrath, Innate immune memory in plants. Seminars in Immunology, 2016. 28(4): p. 319-327. https://doi.org/1016/j.smim.2016.05.006

  37. Netea, Mihai , J. Quintin, and Jos W.M. van der Meer, Trained Immunity: A Memory for Innate Host Defense. Cell Host & Microbe, 2011. 9(5): p. 355-361. https://doi.org/10.1016/j.chom.2011.04.006.

  38. Sun, J.C., J.N. Beilke, and L.L. Lanier, Adaptive immune features of natural killer cells. Nature, 2009. 457(7229): p. 557-561. https://doi.org/1038/nature07665.

  39. Netea, M.G. and R. van Crevel, BCG-induced protection: Effects on innate immune memory. Seminars in Immunology, 2014. 26(6): p. 512-517. https://doi.org/1016/j.smim.2014.09.006.

  40. Kleinnijenhuis, J., et al., BCG-induced trained immunity in NK cells: Role for non-specific protection to infection. Clinical Immunology, 2014. 155(2): p. 213-219. https://doi.org/1016/j.clim.2014.10.005

  41. Netea, M.G., et al., Trained immunity: A program of innate immune memory in health and disease. Science, 2016. 352(6284): p. aaf1098. https://doi.org/1126/science.aaf1098

  42. Ganeshan, K. and A. Chawla, Metabolic Regulation of Immune Responses. 32(1): p. 609-634. https://doi.org/10.1146/annurev-immunol-032713-120236.

  43. Pearce, E.L. and E.J. Pearce, Metabolic pathways in immune cell activation and quiescence. Immunity, 2013. 38(4): p. 633-643. https://doi.org/1016/j.immuni.2013.04.005.

  44. du Plessis, S.S., et al., Oxidative phosphorylation versus glycolysis: what fuel do spermatozoa use? Asian journal of andrology, 2015. 17(2): p. 230-235. https://doi.org/4103/1008-682X.135123

  45. Dominguez-Andres, J. and M.G. Netea, Long-term reprogramming of the innate immune system. 105(2): p. 329-338. https://doi.org/10.1002/JLB.MR0318-104R.

  46. Kelly, B. and L.A.J. O'Neill, Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell research, 2015. 25(7): p. 771-784. https://doi.org/1038/cr.2015.68

  47. O'Neill, L.A.J. and E.J. Pearce, Immunometabolism governs dendritic cell and macrophage function. The Journal of experimental medicine, 2016. 213(1): p. 15-23. https://doi.org/1084/jem.20151570.

  48. Arts, R.J.W., L.A.B. Joosten, and M.G. Netea, Immunometabolic circuits in trained immunity. Seminars in Immunology, 2016. 28(5): p. 425-430. https://doi.org/1016/j.smim.2016.09.002

  49. Cheng, S.-C., et al., mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity. 345(6204): p. 1250684. https://doi.org/10.1126/science.1250684.

  50. Arts, R.J.W., et al., Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. Cell Metabolism, 2016. 24(6): p. 807-819. https://doi.org/1016/j.cmet.2016.10.008.

  51. Domínguez-Andrés, J., L.A.B. Joosten, and M.G. Netea, Induction of innate immune memory: the role of cellular metabolism. Current Opinion in Immunology, 2019. 56: p. 10-16. doi: 10.1016/j.coi.2018.09.001.

  52. Yahya Sohrabi, R.G., Hannes M. Findeisen, Altered Cellular Metabolism Drives Trained Immunity. Trends in Endocrinology and Metabolism, 2018. 29 (9): p. 602-605. https://doi.org/1016/j.tem.2018.03.012.

  53. Chen, S., et al., Epigenetic regulation of macrophages: from homeostasis maintenance to host defense. Cellular & Molecular Immunology, 2020. 17(1): p. 36-49. https://doi.org/10.1038/s41423-019-0315-0

  54. Samuel T. Keating, A.E.-O., Epigenetic and Metabolism. Circulation Research, 2015. 116: p. 715-736. https://doi.org/10.1161/CIRCRESAHA.116.303936

  55. Rodriguez, R.M., B. Suarez-Alvarez, and C. Lopez-Larrea, Therapeutic Epigenetic Reprogramming of Trained Immunity in Myeloid Cells. Trends in Immunology, 2019. 40(1): p. 66-80. https://doi.org/1016/j.it.2018.11.006.

  56. Quintin, J., et al., Candida albicans Infection Affords Protection against Reinfection via Functional Reprogramming of Monocytes. Cell Host & Microbe, 2012. 12(2): p. 223-232. https://doi.org/1016/j.chom.2012.06.006.

  57. van der Heijden, C.D.C.C., et al., Epigenetics and Trained Immunity. Antioxidants & redox signaling, 2018. 29(11): p. 1023-1040. https://doi.org/1089/ars.2017.7310.

  58. Sánchez-Ramón, S., et al., Trained Immunity-Based Vaccines: A New Paradigm for the Development of Broad-Spectrum Anti-infectious 2018. 9(2936). https://doi.org/10.3389/fimmu.2018.02936

  59. Oliveira, T.L., et al., Recombinant BCG strains expressing chimeric proteins derived from Leptospira protect hamsters against leptospirosis. Vaccine, 2019. 37(6): p. 776-782. https://doi.org/1016/j.vaccine.2018.12.050.

  60. Kleinnijenhuis, J., et al., Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. 109(43): p. 17537-17542. https://doi.org/10.1073/pnas.1202870109

  61. Parra, M., et al., Molecular Analysis of Non-Specific Protection against Murine Malaria Induced by BCG Vaccination. PLOS ONE, 2013. 8(7): p. e66115. https://doi.org/1371/journal.pone.0066115

  62. dos Santos, J.C., et al., Non-specific effects of BCG in protozoal infections: tegumentary leishmaniasis and malaria. Clinical Microbiology and Infection, 2019. 25(12): p. 1479-1483. https://doi.org/10.1016/j.cmi.2019.06.002

  63. Blok, B.A., et al., Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. 98(3): p. 347-356. https://doi.org/10.1189/jlb.5RI0315-096R

  64. de Bree, L.C.J., et al., Non-specific effects of vaccines: Current evidence and potential implications. Seminars in Immunology, 2018. 39: p. 35-43. https://doi.org/10.1016/j.smim.2018.06.002

  65. Babjuk, M., et al., EAU Guidelines on Non-Muscle-Invasive Urothelial Carcinoma of the Bladder. European Urology, 2008. 54(2): p. 303-314. https://doi.org/10.1016/j.eururo.2008.04.051

  66. Mitroulis, I., et al., Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity. Cell, 2018. 172: p. 147-161.e12. https://doi.org/10.1016/j.cell.2017.11.034

  67. Gillard, G.O., et al., Thy1+ Nk Cells from Vaccinia Virus-Primed Mice Confer Protection against Vaccinia Virus Challenge in the Absence of Adaptive Lymphocytes. PLOS Pathogens, 2011. 7(8): p. e1002141. https://doi.org/10.1371/annotation/b29086ef-e08d-444c-8113-18a6dd429a7c

  68. Tai, L.-H., et al., Perioperative Influenza Vaccination Reduces Postoperative Metastatic Disease by Reversing Surgery-Induced Dysfunction in Natural Killer Cells. 19(18): p. 5104-5115. https://doi.org/10.1158/1078-0432.CCR-13-0246

  69. Gyssens, I.C. and M.G. Netea, Heterologous effects of vaccination and trained immunity. Clinical Microbiology and Infection, 2019. 25(12): p. 1457-1458. https://doi.org/10.1016/j.cmi.2019.05.024

  70. Gardiner, C.M. and K.H.G. Mills, The cells that mediate innate immune memory and their functional significance in inflammatory and infectious diseases. Seminars in Immunology, 2016. 28(4): p. 343-350. https://doi.org/10.1016/j.smim.2016.03.001

  71. Oberbarnscheidt, M.H., et al., Non-self recognition by monocytes initiates allograft rejection. The Journal of clinical investigation, 2014. 124(8): p. 3579-3589. https://doi.org/1172/JCI74370

  72. Ochando, J., et al., “Trained immunity in organ transplantation” Am J Transplant. 20: 10– 18, 2020. https://doi.org/10.1111/ajt.15620

  73. Zecher, D., et al., An Innate Response to Allogeneic Nonself Mediated by Monocytes. 183(12): p. 7810-7816. https://doi.org/10.4049/jimmunol.0902194

  74. Gisterå, A. and G.K. Hansson, The immunology of atherosclerosis. Nature Reviews Nephrology, 2017. 13(6): p. 368-380. https://doi.org/10.1038/nrneph.2017.51

  75. Libby, P., et al., Nature Reviews Disease Primers, 2019. 5(1): p. 56. https://doi.org/10.1161/CIRCRESAHA.116.308334

  76. Siroon Bekkering , J.Q., Leo A.B. Joosten , Jos W.M. van der Meer , Mihai G. Netea , Niels P. Riksen, Oxidized Low-Density Lipoprotein Induces Long-Term Proinflammatory Cytokine Production and Foam Cell Formation via Epigenetic Reprogramming of Monocytes. Arteriosclerosis, Thrombosis, and Vascular Biology, 2014. 34: p. 1731–1738. https://doi.org/10.1161/ATVBAHA.114.303887

  77. van der Valk, F.M., et al., Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans. Circulation, 2016. 134(8): p. 611-624. https://doi.org/10.1161/CIRCULATIONAHA.116.020838

  78. van Tuijl, J., et al., Immunometabolism orchestrates training of innate immunity in atherosclerosis. Cardiovascular Research, 2019. 115(9): p. 1416-1424. https://doi.org/10.1093/cvr/cvz107

  79. Wentowski, C., N. Mewada, and N.D. Nielsen, Sepsis in 2018: a review. Anaesthesia & Intensive Care Medicine, 2019. 20(1): p. 6-13. https://doi.org/10.1016/j.mpaic.2018.11.009

  80. Bomans, K., et al., Sepsis Induces a Long-Lasting State of Trained Immunity in Bone Marrow Monocytes. Frontiers in immunology, 2018. 9: p. 2685-2685. https://doi.org/10.3389/fimmu.2018.02685

  81. Zhang, H., et al., Sepsis Induces Hematopoietic Stem Cell Exhaustion and Myelosuppression through Distinct Contributions of TRIF and MYD88. Stem cell reports, 2016. 6(6): p. 940-956. https://doi.org/10.1016/j.stemcr.2016.05.002

  82. van der Meer, J.W.M., et al., Trained immunity: A smart way to enhance innate immune defence. Molecular Immunology, 2015. 68(1): p. 40-44. https://doi.org/10.1016/j.molimm.2015.06.019

Published
2020-04-25
How to Cite
[1]
S. Incalcaterra and J. Dominguez, “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., vol. 8, no. 1, pp. 68-81, Apr. 2020.