The Fulani ethnic group has relatively better protection from Plasmodium falciparum malaria, as reflected by fewer symptomatic cases of malaria, lower infection rates, and lower parasite densities compared to sympatric ethnic groups. However, the basis for this lower susceptibility to malaria by the Fulani is unknown. The incidence of classic malaria resistance genes are lower in the Fulani than in other sympatric ethnic populations, and targeted SNP analyses of other candidate genes involved in the immune response to malaria have not been able to account for the observed difference in the Fulani susceptibility to P.falciparum. Therefore, we have performed a pilot study to examine global transcription and DNA methylation patterns in specific immune cell populations in the Fulani to elucidate the mechanisms that confer the lower susceptibility to P.falciparum malaria. When we compared uninfected and infected Fulani individuals, in contrast to uninfected and infected individuals from the sympatric ethnic group Mossi, we observed a key difference: a strong transcriptional response was only detected in the monocyte fraction of the Fulani, where over 1000 genes were significantly differentially expressed upon P.falciparum infection.

Central European Institute of Technology Brno Czech Republic

Centre National de Recherche et de Formation sur le Paludisme Ouagadougou Burkina Faso

Department of Biosciences and Nutrition Karolinska Institute Stockholm Sweden

Department of Molecular Biosciences The Wenner Gren Institute Stockholm University Stockholm Sweden

Unit of Infectious Diseases Department of Medicine Karolinska Institute Stockholm Sweden

Université Polytechnique de Bobo Dioulasso Bobo Dioulasso Burkina Faso

See more in PubMed

Allison AC. Genetic control of resistance to human malaria. Current Opinion in Immunology. 2009;21:499–505. doi: 10.1016/j.coi.2009.04.001. PubMed DOI

Arama C, Giusti P, Boström S, Dara V, Traore B, Dolo A, Doumbo O, Varani S, Troye-Blomberg M. Interethnic differences in antigen-presenting cell activation and TLR responses in Malian children during Plasmodium falciparum malaria. PLoS One. 2011;6:e18319. doi: 10.1371/journal.pone.0018319. PubMed DOI PMC

Arama C, Maiga B, Dolo A, Kouriba B, Traoré B, Crompton PD, Pierce SK, Troye-Blomberg M, Miller LH, Doumbo OK. Ethnic differences in susceptibility to malaria: what have we learned from immuno-epidemiological studies in West Africa? Acta Tropica. 2015a;146:152–156. doi: 10.1016/j.actatropica.2015.03.023. PubMed DOI

Arama C, Skinner J, Doumtabe D, Portugal S, Tran TM, Jain A, Traore B, Doumbo OK, Davies DH, Troye-Blomberg M, Dolo A, Felgner PL, Crompton PD. Genetic Resistance to Malaria Is Associated With Greater Enhancement of Immunoglobulin (Ig)M Than IgG Responses to a Broad Array of Plasmodium falciparum Antigens. Open Forum Infectious Diseases. 2015b;2:ofv118. doi: 10.1093/ofid/ofv118. PubMed DOI PMC

Ataide MA, Andrade WA, Zamboni DS, Wang D, Souza MC, Franklin BS, Elian S, Martins FS, Pereira D, Reed G, Fitzgerald KA, Golenbock DT, Gazzinelli RT. Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS Pathogens. 2014;10:e1003885. doi: 10.1371/journal.ppat.1003885. PubMed DOI PMC

Bolad A, Farouk SE, Israelsson E, Dolo A, Doumbo OK, Nebié I, Maiga B, Kouriba B, Luoni G, Sirima BS, Modiano D, Berzins K, Troye-Blomberg M. Distinct interethnic differences in immunoglobulin G class/subclass and immunoglobulin M antibody responses to malaria antigens but not in immunoglobulin G responses to nonmalarial antigens in sympatric tribes living in West Africa. Scandinavian Journal of Immunology. 2005;61:380–386. doi: 10.1111/j.1365-3083.2005.01587.x. PubMed DOI

Boraschi D, Tagliabue A. The interleukin-1 receptor family. Seminars in Immunology. 2013;25:394–407. doi: 10.1016/j.smim.2013.10.023. PubMed DOI

Boström S, Giusti P, Arama C, Persson JO, Dara V, Traore B, Dolo A, Doumbo O, Troye-Blomberg M. Changes in the levels of cytokines, chemokines and malaria-specific antibodies in response to Plasmodium falciparum infection in children living in sympatry in Mali. Malaria Journal. 2012;11:109. doi: 10.1186/1475-2875-11-109. PubMed DOI PMC

Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, Giamarellos-Bourboulis EJ, Martens JH, Rao NA, Aghajanirefah A, Manjeri GR, Li Y, Ifrim DC, Arts RJ, van der Veer BM, van der Meer BM, Deen PM, Logie C, O'Neill LA, Willems P, van de Veerdonk FL, van der Meer JW, Ng A, Joosten LA, Wijmenga C, Stunnenberg HG, Xavier RJ, Netea MG. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345:1250684. doi: 10.1126/science.1250684. PubMed DOI PMC

Cherif M, Amoako-Sakyi D, Dolo A, Pearson JO, Gyan B, Obiri-Yeboah D, Nebie I, Sirima SB, Doumbo O, Troye-Blomberg M, Bakary M. Distribution of FcγR gene polymorphisms among two sympatric populations in Mali: differing allele frequencies, associations with malariometric indices and implications for genetic susceptibility to malaria. Malaria Journal. 2016;15:29. doi: 10.1186/s12936-015-1082-8. PubMed DOI PMC

Cherif MK, Sanou GS, Bougouma EC, Diarra A, Ouédraogo A, Dolo A, Troye-Blomberg M, Cavanagh DR, Theisen M, Modiano D, Sirima SB, Nebié I. Is Fc gamma receptor IIA (FcγRIIA) polymorphism associated with clinical malaria and Plasmodium falciparum specific antibody levels in children from Burkina Faso? Acta Tropica. 2015;142:41–46. doi: 10.1016/j.actatropica.2014.09.019. PubMed DOI

Cherif MK, Sanou GS, Maiga B, Israelsson E, Ouédraogo AL, Bougouma EC, Diarra A, Ouédraogo A, Ouattara AS, Troye-Blomberg M, Dolo A, Cavanagh DR, Theisen M, Modiano D, Sirima SB, Nebié I. FcγRIIa polymorphism and anti-malaria-specific IgG and IgG subclass responses in populations differing in susceptibility to malaria in Burkina Faso. Scandinavian Journal of Immunology. 2012;75:606–613. doi: 10.1111/j.1365-3083.2012.02690.x. PubMed DOI

Davis BK, Roberts RA, Huang MT, Willingham SB, Conti BJ, Brickey WJ, Barker BR, Kwan M, Taxman DJ, Accavitti-Loper MA, Duncan JA, Ting JP. Cutting edge: NLRC5-dependent activation of the inflammasome. The Journal of Immunology. 2011;186:1333–1337. doi: 10.4049/jimmunol.1003111. PubMed DOI PMC

Dev A, Iyer S, Razani B, Cheng G. NF-κB and innate immunity. Current Topics in Microbiology and Immunology. 2011;349:115–143. doi: 10.1007/82_2010_102. PubMed DOI

Esposito F, Lombardi S, Modiano D, Zavala F, Reeme J, Lamizana L, Coluzzi M, Nussenzweig RS. Prevalence and levels of antibodies to the circumsporozoite protein of Plasmodium falciparum in an endemic area and their relationship to resistance against malaria infection. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1988;82:827–832. doi: 10.1016/0035-9203(88)90007-7. PubMed DOI

Farouk SE, Dolo A, Bereczky S, Kouriba B, Maiga B, Färnert A, Perlmann H, Hayano M, Montgomery SM, Doumbo OK, Troye-Blomberg M. Different antibody- and cytokine-mediated responses to Plasmodium falciparum parasite in two sympatric ethnic tribes living in Mali. Microbes and Infection. 2005;7:110–117. doi: 10.1016/j.micinf.2004.09.012. PubMed DOI

Foster SL, Hargreaves DC, Medzhitov R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature. 2007;447:972–978. doi: 10.1038/nature05836. PubMed DOI

Galli GG, Carrara M, Francavilla C, de Lichtenberg KH, Olsen JV, Calogero RA, Lund AH. Genomic and proteomic analyses of Prdm5 reveal interactions with insulator binding proteins in embryonic stem cells. Molecular and Cellular Biology. 2013;33:4504–4516. doi: 10.1128/MCB.00545-13. PubMed DOI PMC

Glass CK, Natoli G. Molecular control of activation and priming in macrophages. Nature Immunology. 2016;17:26–33. doi: 10.1038/ni.3306. PubMed DOI PMC

Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nature Medicine. 2015;21:677–687. doi: 10.1038/nm.3893. PubMed DOI PMC

He Y, Hara H, Núñez G. Mechanism and Regulation of NLRP3 Inflammasome Activation. Trends in Biochemical Sciences. 2016;41:1012–1021. doi: 10.1016/j.tibs.2016.09.002. PubMed DOI PMC

Hirako IC, Gallego-Marin C, Ataide MA, Andrade WA, Gravina H, Rocha BC, de Oliveira RB, Pereira DB, Vinetz J, Diamond B, Ram S, Golenbock DT, Gazzinelli RT. DNA-Containing Immunocomplexes Promote Inflammasome Assembly and Release of Pyrogenic Cytokines by CD14+ CD16+ CD64high CD32low Inflammatory Monocytes from Malaria Patients. mBio. 2015;6:e01605-15–01615. doi: 10.1128/mBio.01605-15. PubMed DOI PMC

Hoeksema MA, de Winther MP. Epigenetic Regulation of Monocyte and Macrophage Function. Antioxidants & Redox Signaling. 2016;25:758–774. doi: 10.1089/ars.2016.6695. PubMed DOI PMC

Kalantari P, DeOliveira RB, Chan J, Corbett Y, Rathinam V, Stutz A, Latz E, Gazzinelli RT, Golenbock DT, Fitzgerald KA. Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria. Cell Reports. 2014;6:196–210. doi: 10.1016/j.celrep.2013.12.014. PubMed DOI PMC

Kobayashi E, Suzuki T, Yamamoto M. Roles nrf2 plays in myeloid cells and related disorders. Oxidative Medicine and Cellular Longevity. 2013;2013:529219. doi: 10.1155/2013/529219. PubMed DOI PMC

Lachmandas E, Beigier-Bompadre M, Cheng SC, Kumar V, van Laarhoven A, Wang X, Ammerdorffer A, Boutens L, de Jong D, Kanneganti TD, Gresnigt MS, Ottenhoff TH, Joosten LA, Stienstra R, Wijmenga C, Kaufmann SH, van Crevel R, Netea MG. Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells. European Journal of Immunology. 2016;46:2574–2586. doi: 10.1002/eji.201546259. PubMed DOI PMC

Liang H, Liu Y. Gasdermins pore cell membrane to pyroptosis. Science China Life Sciences. 2016;59:1090–1092. doi: 10.1007/s11427-016-0243-4. PubMed DOI

Lulli P, Mangano VD, Onori A, Batini C, Luoni G, Sirima BS, Nebie I, Chessa L, Petrarca V, Modiano D. HLA-DRB1 and -DQB1 loci in three west African ethnic groups: genetic relationship with sub-Saharan African and European populations. Human Immunology. 2009;70:903–909. doi: 10.1016/j.humimm.2009.07.025. PubMed DOI

Maiga B, Dolo A, Touré O, Dara V, Tapily A, Campino S, Sepulveda N, Corran P, Rockett K, Clark TG, Blomberg MT, Doumbo OK. Fc gamma receptor IIa-H131R polymorphism and malaria susceptibility in sympatric ethnic groups, Fulani and Dogon of Mali. Scandinavian Journal of Immunology. 2014;79:43–50. doi: 10.1111/sji.12122. PubMed DOI PMC

Malaria Genomic Epidemiology Network. Band G, Rockett KA, Spencer CC, Kwiatkowski DP. A novel locus of resistance to severe malaria in a region of ancient balancing selection. Nature. 2015;526:253–257. doi: 10.1038/nature15390. PubMed DOI PMC

Mangano VD, Kabore Y, Bougouma EC, Verra F, Sepulveda N, Bisseye C, Santolamazza F, Avellino P, Tiono AB, Diarra A, Nebie I, Rockett KA, Sirima SB, Modiano D, MalariaGEN Consortium Novel Insights Into the Protective Role of Hemoglobin S and C Against Plasmodium falciparum Parasitemia. Journal of Infectious Diseases. 2015;212:626–634. doi: 10.1093/infdis/jiv098. PubMed DOI PMC

Martens JH, Mandoli A, Simmer F, Wierenga BJ, Saeed S, Singh AA, Altucci L, Vellenga E, Stunnenberg HG. ERG and FLI1 binding sites demarcate targets for aberrant epigenetic regulation by AML1-ETO in acute myeloid leukemia. Blood. 2012;120:4038–4048. doi: 10.1182/blood-2012-05-429050. PubMed DOI PMC

McCall CE, El Gazzar M, Liu T, Vachharajani V, Yoza B. Epigenetics, bioenergetics, and microRNA coordinate gene-specific reprogramming during acute systemic inflammation. Journal of Leukocyte Biology. 2011;90:439–446. doi: 10.1189/jlb.0211075. PubMed DOI PMC

McCall MB, Hopman J, Daou M, Maiga B, Dara V, Ploemen I, Nganou-Makamdop K, Niangaly A, Tolo Y, Arama C, Bousema JT, van der Meer JW, van der Ven AJ, Troye-Blomberg M, Dolo A, Doumbo OK, Sauerwein RW. Early interferon-gamma response against Plasmodium falciparum correlates with interethnic differences in susceptibility to parasitemia between sympatric Fulani and Dogon in Mali. The Journal of Infectious Diseases. 2010;201:142–152. doi: 10.1086/648596. PubMed DOI

Modiano D, Luoni G, Sirima BS, Lanfrancotti A, Petrarca V, Cruciani F, Simporé J, Ciminelli BM, Foglietta E, Grisanti P, Bianco I, Modiano G, Coluzzi M. The lower susceptibility to Plasmodium falciparum malaria of Fulani of Burkina Faso (west Africa) is associated with low frequencies of classic malaria-resistance genes. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2001;95:149-+ doi: 10.1016/S0035-9203(01)90141-5. PubMed DOI

Modiano D, Petrarca V, Sirima BS, Nebié I, Diallo D, Esposito F, Coluzzi M. Different response to Plasmodium falciparum malaria in west African sympatric ethnic groups. PNAS. 1996;93:13206–13211. doi: 10.1073/pnas.93.23.13206. PubMed DOI PMC

Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, O'Neill LA, Xavier RJ, L. A. O'Neill, R. J. Trained immunity: A program of innate immune memory in health and disease. Science. 2016;352:aaf1098. doi: 10.1126/science.aaf1098. PubMed DOI PMC

Netea MG, van der Meer JW. Trained Immunity: An Ancient Way of Remembering. Cell Host & Microbe. 2017;21:297–300. doi: 10.1016/j.chom.2017.02.003. PubMed DOI

Novakovic B, Habibi E, Wang SY, Arts RJ, Davar R, Megchelenbrink W, Kim B, Kuznetsova T, Kox M, Zwaag J, Matarese F, van Heeringen SJ, Janssen-Megens EM, Sharifi N, Wang C, Keramati F, Schoonenberg V, Flicek P, Clarke L, Pickkers P, Heath S, Gut I, Netea MG, Martens JH, Logie C, Stunnenberg HG. β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance. Cell. 2016;167:e1314. doi: 10.1016/j.cell.2016.09.034. PubMed DOI PMC

Perdijk O, Arama C, Giusti P, Maiga B, Troye-Blomberg M, Dolo A, Doumbo O, Persson JO, Boström S. Haptoglobin phenotype prevalence and cytokine profiles during Plasmodium falciparum infection in Dogon and Fulani ethnic groups living in Mali. Malaria Journal. 2013;12:432. doi: 10.1186/1475-2875-12-432. PubMed DOI PMC

Petrarca V, Petrangeli G, Rossi P, Sabatinelli G. [Chromosomal study of Anopheles gambiae and Anopheles arabiensis in Ouagadougou (Burkina Faso) and various neighboring villages] Parassitologia. 1986;28:41–61. PubMed

Portugal S, Doumtabe D, Traore B, Miller LH, Troye-Blomberg M, Doumbo OK, Dolo A, Pierce SK, Crompton PD. B cell analysis of ethnic groups in Mali with differential susceptibility to malaria. Malaria Journal. 2012;11:162. doi: 10.1186/1475-2875-11-162. PubMed DOI PMC

Quintin J, Cheng SC, van der Meer JW, Netea MG. Innate immune memory: towards a better understanding of host defense mechanisms. Current Opinion in Immunology. 2014;29:1–7. doi: 10.1016/j.coi.2014.02.006. PubMed DOI

Riddell J, Gazit R, Garrison BS, Guo G, Saadatpour A, Mandal PK, Ebina W, Volchkov P, Yuan GC, Orkin SH, Rossi DJ. Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell. 2014;157:549–564. doi: 10.1016/j.cell.2014.04.006. PubMed DOI PMC

Rizzetto L, Ifrim DC, Moretti S, Tocci N, Cheng SC, Quintin J, Renga G, Oikonomou V, De Filippo C, Weil T, Blok BA, Lenucci MS, Santos MA, Romani L, Netea MG, Cavalieri D. Fungal Chitin Induces Trained Immunity in Human Monocytes during Cross-talk of the Host with Saccharomyces cerevisiae. Journal of Biological Chemistry. 2016;291:7961–7972. doi: 10.1074/jbc.M115.699645. PubMed DOI PMC

Rizzo C, Ronca R, Fiorentino G, Verra F, Mangano V, Poinsignon A, Sirima SB, Nèbiè I, Lombardo F, Remoue F, Coluzzi M, Petrarca V, Modiano D, Arcà B. Humoral response to the Anopheles gambiae salivary protein gSG6: a serological indicator of exposure to Afrotropical malaria vectors. PLoS One. 2011;6:e17980. doi: 10.1371/journal.pone.0017980. PubMed DOI PMC

Rutenberg-Schoenberg M, Sexton AN, Simon MD. The Properties of Long Noncoding RNAs That Regulate Chromatin. Annual Review of Genomics and Human Genetics. 2016;17:69–94. doi: 10.1146/annurev-genom-090314-024939. PubMed DOI

Saeed S, Logie C, Francoijs KJ, Frigè G, Romanenghi M, Nielsen FG, Raats L, Shahhoseini M, Huynen M, Altucci L, Minucci S, Martens JH, Stunnenberg HG. Chromatin accessibility, p300, and histone acetylation define PML-RARα and AML1-ETO binding sites in acute myeloid leukemia. Blood. 2012;120:3058–3068. doi: 10.1182/blood-2011-10-386086. PubMed DOI

Saeed S, Quintin J, Kerstens HH, Rao NA, Aghajanirefah A, Matarese F, Cheng SC, Ratter J, Berentsen K, van der Ent MA, Sharifi N, Janssen-Megens EM, Ter Huurne M, Mandoli A, van Schaik T, Ng A, Burden F, Downes K, Frontini M, Kumar V, Giamarellos-Bourboulis EJ, Ouwehand WH, van der Meer JW, Joosten LA, Wijmenga C, Martens JH, Xavier RJ, Logie C, Netea MG, Stunnenberg HG. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345:1251086. doi: 10.1126/science.1251086. PubMed DOI PMC

Schultze JL. Chromatin Remodeling in Monocyte and Macrophage Activation. Advances in Protein Chemistry and Structural Biology. 2017;106:1–15. doi: 10.1016/bs.apcsb.2016.09.001. PubMed DOI

Sharma D, Kanneganti TD. The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation. The Journal of Cell Biology. 2016;213:617–629. doi: 10.1083/jcb.201602089. PubMed DOI PMC

Shokoples SE, Ndao M, Kowalewska-Grochowska K, Yanow SK. Multiplexed real-time PCR assay for discrimination of Plasmodium species with improved sensitivity for mixed infections. Journal of Clinical Microbiology. 2009;47:975–980. doi: 10.1128/JCM.01858-08. PubMed DOI PMC

Torcia MG, Santarlasci V, Cosmi L, Clemente A, Maggi L, Mangano VD, Verra F, Bancone G, Nebie I, Sirima BS, Liotta F, Frosali F, Angeli R, Severini C, Sannella AR, Bonini P, Lucibello M, Maggi E, Garaci E, Coluzzi M, Cozzolino F, Annunziato F, Romagnani S, Modiano D. Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria. PNAS. 2008;105:646–651. doi: 10.1073/pnas.0709969105. PubMed DOI PMC

Vafa M, Israelsson E, Maiga B, Dolo A, Doumbo OK, Troye-Blomberg M. Relationship between immunoglobulin isotype response to Plasmodium falciparum blood stage antigens and parasitological indexes as well as splenomegaly in sympatric ethnic groups living in Mali. Acta Tropica. 2009;109:12–16. doi: 10.1016/j.actatropica.2008.09.001. PubMed DOI

Wiley JS, Sluyter R, Gu BJ, Stokes L, Fuller SJ. The human P2X7 receptor and its role in innate immunity. Tissue Antigens. 2011;78:321–332. doi: 10.1111/j.1399-0039.2011.01780.x. PubMed DOI

Yang W, Ernst P. SET/MLL family proteins in hematopoiesis and leukemia. International Journal of Hematology. 2017;105:7–16. doi: 10.1007/s12185-016-2118-8. PubMed DOI

Yordy JS, Muise-Helmericks RC. Signal transduction and the Ets family of transcription factors. Oncogene. 2000;19:6503–6513. doi: 10.1038/sj.onc.1204036. PubMed DOI

Zhou J, Ludlow LE, Hasang W, Rogerson SJ, Jaworowski A. Opsonization of malaria-infected erythrocytes activates the inflammasome and enhances inflammatory cytokine secretion by human macrophages. Malaria Journal. 2012;11:343. doi: 10.1186/1475-2875-11-343. PubMed DOI PMC

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What will studies of Fulani individuals naturally exposed to malaria teach us about protective immunity to malaria?