Plasmodium falciparum malaria drives epigenetic reprogramming of human monocytes toward a regulatory phenotype
Rajan Guha, Anna Mathioudaki, Safiatou Doumbo, Didier Doumtabe, Jeff Skinner, Gunjan Arora, Shafiuddin Siddiqui, Shanping Li, Kassoum Kayentao, Aissata Ongoiba, Judith Zaugg, Boubacar Traore, Peter D Crompton, Rajan Guha, Anna Mathioudaki, Safiatou Doumbo, Didier Doumtabe, Jeff Skinner, Gunjan Arora, Shafiuddin Siddiqui, Shanping Li, Kassoum Kayentao, Aissata Ongoiba, Judith Zaugg, Boubacar Traore, Peter D Crompton
Abstract
In malaria-naïve children and adults, Plasmodium falciparum-infected red blood cells (Pf-iRBCs) trigger fever and other symptoms of systemic inflammation. However, in endemic areas where individuals experience repeated Pf infections over many years, the risk of Pf-iRBC-triggered inflammatory symptoms decreases with cumulative Pf exposure. The molecular mechanisms underlying these clinical observations remain unclear. Age-stratified analyses of uninfected, asymptomatic Malian individuals before the malaria season revealed that monocytes of adults produced lower levels of inflammatory cytokines (IL-1β, IL-6 and TNF) in response to Pf-iRBC stimulation compared to monocytes of Malian children and malaria-naïve U.S. adults. Moreover, monocytes of Malian children produced lower levels of IL-1β and IL-6 following Pf-iRBC stimulation compared to 4-6-month-old infants. Accordingly, monocytes of Malian adults produced more IL-10 and expressed higher levels of the regulatory molecules CD163, CD206, Arginase-1 and TGM2. These observations were recapitulated in an in vitro system of monocyte to macrophage differentiation wherein macrophages re-exposed to Pf-iRBCs exhibited attenuated inflammatory cytokine responses and a corresponding decrease in the epigenetic marker of active gene transcription, H3K4me3, at inflammatory cytokine gene loci. Together these data indicate that Pf induces epigenetic reprogramming of monocytes/macrophages toward a regulatory phenotype that attenuates inflammatory responses during subsequent Pf exposure. Trial Registration: ClinicalTrials.gov NCT01322581.
Conflict of interest statement
The authors have declared that no competing interests exist.
Figures
![Fig 1. Monocytes of Malian adults exhibit…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8023468/bin/ppat.1009430.g001.jpg)
![Fig 2. Monocytes of Malian adults upregulate…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8023468/bin/ppat.1009430.g002.jpg)
![Fig 3. RNA-seq analysis of monocytes after…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8023468/bin/ppat.1009430.g003.jpg)
![Fig 4. In vitro model of monocyte…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8023468/bin/ppat.1009430.g004.jpg)
![Fig 5. Pre-exposure of monocytes to P…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8023468/bin/ppat.1009430.g005.jpg)
![Fig 6. P . falciparum exposure drives…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8023468/bin/ppat.1009430.g006.jpg)
References
- Lyke KE, Burges R, Cissoko Y, Sangare L, Dao M, Diarra I, et al.. Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. Infect Immun. 2004;72(10):5630–7. Epub 2004/09/24. 10.1128/IAI.72.10.5630-5637.2004
- Walther M, Woodruff J, Edele F, Jeffries D, Tongren JE, King E, et al.. Innate immune responses to human malaria: heterogeneous cytokine responses to blood-stage Plasmodium falciparum correlate with parasitological and clinical outcomes. J Immunol. 2006;177(8):5736–45. Epub 2006/10/04. 10.4049/jimmunol.177.8.5736 .
- Smith JD, Rowe JA, Higgins MK, Lavstsen T. Malaria’s deadly grip: cytoadhesion of Plasmodium falciparum-infected erythrocytes. Cell Microbiol. 2013;15(12):1976–83. Epub 2013/08/21. 10.1111/cmi.12183
- Portugal S, Tran TM, Ongoiba A, Bathily A, Li S, Doumbo S, et al.. Treatment of Chronic Asymptomatic Plasmodium falciparum Infection Does Not Increase the Risk of Clinical Malaria Upon Reinfection. Clin Infect Dis. 2017;64(5):645–53. Epub 2017/04/01. 10.1093/cid/ciw849
- Kurup SP, Butler NS, Harty JT. T cell-mediated immunity to malaria. Nat Rev Immunol. 2019;19(7):457–71. Epub 2019/04/04. 10.1038/s41577-019-0158-z
- Perez-Mazliah D, Ndungu FM, Aye R, Langhorne J. B-cell memory in malaria: Myths and realities. Immunol Rev. 2020;293(1):57–69. Epub 2019/11/17. 10.1111/imr.12822
- Takala SL, Plowe CV. Genetic diversity and malaria vaccine design, testing and efficacy: preventing and overcoming ’vaccine resistant malaria’. Parasite Immunol. 2009;31(9):560–73. Epub 2009/08/21. PIM1138 [pii] 10.1111/j.1365-3024.2009.01138.x .
- Scherf A, Lopez-Rubio JJ, Riviere L. Antigenic variation in Plasmodium falciparum. Annu Rev Microbiol. 2008;62:445–70. Epub 2008/09/13. 10.1146/annurev.micro.61.080706.093134 .
- Portugal S, Obeng-Adjei N, Moir S, Crompton PD, Pierce SK. Atypical memory B cells in human chronic infectious diseases: An interim report. Cell Immunol. 2017;321:18–25. Epub 2017/07/25. 10.1016/j.cellimm.2017.07.003
- Kumar R, Loughland JR, Ng SS, Boyle MJ, Engwerda CR. The regulation of CD4(+) T cells during malaria. Immunol Rev. 2020;293(1):70–87. Epub 2019/11/02. 10.1111/imr.12804 .
- Dobbs KR, Crabtree JN, Dent AE. Innate immunity to malaria-The role of monocytes. Immunol Rev. 2020;293(1):8–24. Epub 2019/12/17. 10.1111/imr.12830
- Stanisic DI, Cutts J, Eriksson E, Fowkes FJ, Rosanas-Urgell A, Siba P, et al.. gammadelta T cells and CD14+ monocytes are predominant cellular sources of cytokines and chemokines associated with severe malaria. J Infect Dis. 2014;210(2):295–305. Epub 2014/02/14. 10.1093/infdis/jiu083 .
- Netea MG, Dominguez-Andres J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, et al.. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020;20(6):375–88. Epub 2020/03/07. 10.1038/s41577-020-0285-6
- Chavakis T, Mitroulis I, Hajishengallis G. Hematopoietic progenitor cells as integrative hubs for adaptation to and fine-tuning of inflammation. Nat Immunol. 2019;20(7):802–11. Epub 2019/06/20. 10.1038/s41590-019-0402-5
- Patel AA, Zhang Y, Fullerton JN, Boelen L, Rongvaux A, Maini AA, et al.. The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J Exp Med. 2017;214(7):1913–23. Epub 2017/06/14. 10.1084/jem.20170355
- Boutlis CS, Yeo TW, Anstey NM. Malaria tolerance—for whom the cell tolls? Trends Parasitol. 2006;22(8):371–7. Epub 2006/06/21. S1471-4922(06)00131-0 [pii] 10.1016/j.pt.2006.06.002 .
- Tran TM, Li S, Doumbo S, Doumtabe D, Huang CY, Dia S, et al.. An intensive longitudinal cohort study of Malian children and adults reveals no evidence of acquired immunity to Plasmodium falciparum infection. Clin Infect Dis. 2013;57(1):40–7. Epub 2013/03/15. 10.1093/cid/cit174
- Andrade CM, Fleckenstein H, Thomson-Luque R, Doumbo S, Lima NF, Anderson C, et al.. Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season. Nat Med. 2020. Epub 2020/10/28. 10.1038/s41591-020-1084-0 .
- Portugal S, Moebius J, Skinner J, Doumbo S, Doumtabe D, Kone Y, et al.. Exposure-dependent control of malaria-induced inflammation in children. PLoS Pathog. 2014;10(4):e1004079. 10.1371/journal.ppat.1004079
- Langhorne J, Ndungu FM, Sponaas AM, Marsh K. Immunity to malaria: more questions than answers. Nat Immunol. 2008;9(7):725–32. Epub 2008/06/20. ni.f.205 [pii] 10.1038/ni.f.205 .
- Kapellos TS, Bonaguro L, Gemund I, Reusch N, Saglam A, Hinkley ER, et al.. Human Monocyte Subsets and Phenotypes in Major Chronic Inflammatory Diseases. Front Immunol. 2019;10:2035. Epub 2019/09/24. 10.3389/fimmu.2019.02035
- van der Maaten L, Hinton G. Visualizing Data using t-SNE. J Mach Learn Res. 2008;9:2579–605.
- Shrivastava R, Shukla N. Attributes of alternatively activated (M2) macrophages. Life Sci. 2019;224:222–31. Epub 2019/04/01. 10.1016/j.lfs.2019.03.062 .
- Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86. Epub 2004/11/09. 10.1016/j.it.2004.09.015 .
- Saeed S, Quintin J, Kerstens HH, Rao NA, Aghajanirefah A, Matarese F, et al.. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345(6204):1251086. Epub 2014/09/27. 10.1126/science.1251086
- Fanucchi S, Mhlanga MM. Lnc-ing Trained Immunity to Chromatin Architecture. Front Cell Dev Biol. 2019;7:2. Epub 2019/02/09. 10.3389/fcell.2019.00002
- Crompton PD, Moebius J, Portugal S, Waisberg M, Hart G, Garver LS, et al.. Malaria immunity in man and mosquito: insights into unsolved mysteries of a deadly infectious disease. Annu Rev Immunol. 2014;32:157–87. 10.1146/annurev-immunol-032713-120220
- Etzerodt A, Moestrup SK. CD163 and inflammation: biological, diagnostic, and therapeutic aspects. Antioxid Redox Signal. 2013;18(17):2352–63. Epub 2012/08/21. 10.1089/ars.2012.4834
- Gordon S, Pluddemann A, Martinez Estrada F. Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunol Rev. 2014;262(1):36–55. Epub 2014/10/17. 10.1111/imr.12223
- Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958–69. Epub 2008/11/26. 10.1038/nri2448
- Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95. Epub 2012/03/02. 10.1172/JCI59643
- Martinez FO, Helming L, Milde R, Varin A, Melgert BN, Draijer C, et al.. Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences. Blood. 2013;121(9):e57–69. Epub 2013/01/08. 10.1182/blood-2012-06-436212 .
- Mitroulis I, Ruppova K, Wang B, Chen LS, Grzybek M, Grinenko T, et al.. Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity. Cell. 2018;172(1–2):147–61 e12. Epub 2018/01/13. 10.1016/j.cell.2017.11.034
- Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonca LE, Pacis A, et al.. BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis. Cell. 2018;172(1–2):176–90 e19. Epub 2018/01/13. 10.1016/j.cell.2017.12.031 .
- Venugopal K, Hentzschel F, Valkiunas G, Marti M. Plasmodium asexual growth and sexual development in the haematopoietic niche of the host. Nat Rev Microbiol. 2020;18(3):177–89. Epub 2020/01/11. 10.1038/s41579-019-0306-2
- Nahrendorf W, Ivens A, Spence PJ. Inducible mechanisms of disease tolerance provide an alternative strategy of acquired immunity to malaria. bioRxiv. 2020. 10.1101/2020.10.01.322180.
- Tran TM, Guha R, Portugal S, Skinner J, Ongoiba A, Bhardwaj J, et al.. A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation. Immunity. 2019;51(4):750–65 e10. Epub 2019/09/08. 10.1016/j.immuni.2019.08.009
- Farrington L, Vance H, Rek J, Prahl M, Jagannathan P, Katureebe A, et al.. Both inflammatory and regulatory cytokine responses to malaria are blunted with increasing age in highly exposed children. Malar J. 2017;16(1):499. Epub 2017/12/30. 10.1186/s12936-017-2148-6
- Tran TM, Jones MB, Ongoiba A, Bijker EM, Schats R, Venepally P, et al.. Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria. Sci Rep. 2016;6:31291. Epub 2016/08/11. 10.1038/srep31291
- Walk J, de Bree LCJ, Graumans W, Stoter R, van Gemert GJ, van de Vegte-Bolmer M, et al.. Outcomes of controlled human malaria infection after BCG vaccination. Nat Commun. 2019;10(1):874. Epub 2019/02/23. 10.1038/s41467-019-08659-3
- Schrum JE, Crabtree JN, Dobbs KR, Kiritsy MC, Reed GW, Gazzinelli RT, et al.. Cutting Edge: Plasmodium falciparum Induces Trained Innate Immunity. J Immunol. 2018;200(4):1243–8. Epub 2018/01/14. 10.4049/jimmunol.1701010
- Jongo SA, Church LWP, Mtoro AT, Chakravarty S, Ruben AJ, Swanson PA, et al.. Safety and Differential Antibody and T-Cell Responses to the Plasmodium falciparum Sporozoite Malaria Vaccine, PfSPZ Vaccine, by Age in Tanzanian Adults, Adolescents, Children, and Infants. Am J Trop Med Hyg. 2019;100(6):1433–44. Epub 2019/04/18. 10.4269/ajtmh.18-0835
- Jongo SA, Shekalaghe SA, Church LWP, Ruben AJ, Schindler T, Zenklusen I, et al.. Safety, Immunogenicity, and Protective Efficacy against Controlled Human Malaria Infection of Plasmodium falciparum Sporozoite Vaccine in Tanzanian Adults. Am J Trop Med Hyg. 2018;99(2):338–49. Epub 2018/06/27. 10.4269/ajtmh.17-1014
- Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20(6):355–62. Epub 2020/05/08. 10.1038/s41577-020-0331-4
- Mbow M, Lell B, Jochems SP, Cisse B, Mboup S, Dewals BG, et al.. COVID-19 in Africa: Dampening the storm? Science. 2020;369(6504):624–6. Epub 2020/08/09. 10.1126/science.abd3902 .
- Lalaoui R, Bakour S, Raoult D, Verger P, Sokhna C, Devaux C, et al.. What could explain the late emergence of COVID-19 in Africa? New Microbes New Infect. 2020;38:100760. Epub 2020/09/29. 10.1016/j.nmni.2020.100760
- Ataide MA, Andrade WA, Zamboni DS, Wang D, Souza Mdo C, Franklin BS, et al.. Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS Pathog. 2014;10(1):e1003885. Epub 2014/01/24. 10.1371/journal.ppat.1003885
- McCall MB, Netea MG, Hermsen CC, Jansen T, Jacobs L, Golenbock D, et al.. Plasmodium falciparum infection causes proinflammatory priming of human TLR responses. J Immunol. 2007;179(1):162–71. . 10.4049/jimmunol.179.1.162
- Jaillon S, Berthenet K, Garlanda C. Sexual Dimorphism in Innate Immunity. Clin Rev Allergy Immunol. 2019;56(3):308–21. Epub 2017/10/01. 10.1007/s12016-017-8648-x .
- Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, 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):17537–42. Epub 2012/09/19. 10.1073/pnas.1202870109
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