{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T14:12:45Z","timestamp":1770041565815,"version":"3.49.0"},"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T00:00:00Z","timestamp":1640649600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p><jats:italic>Plasmodium falciparum<\/jats:italic>Malaria and Epstein-Barr Virus (EBV) infection are risk factors in the development of Burkitt\u2019s lymphoma. In Indonesia, 100% of the population is persistently infected with EBV early in life and at risk of developing EBV-linked cancers. Currently, 10.7 million people in Indonesia are living in Malaria-endemic areas. This cross-sectional study was initiated to investigate how acute Malaria dysregulates immune control over latent EBV infection. Using blood and plasma samples of 68 patients with acute Malaria and 27 healthy controls, we measured the level of parasitemia for each plasmodium type (<jats:italic>P<\/jats:italic>.<jats:italic>falciparum<\/jats:italic>,<jats:italic>P<\/jats:italic>.<jats:italic>vivax<\/jats:italic>, and mixed) by microscopy and rapid test. The level of 4 regulatory cytokines was determined by quantitative ELISA and the level of circulating EBV genome by real-time PCR targeting the single copy EBNA-1 sequence. All Plasmodium-infected cases had high-level parasitemia (&gt;1000 parasites\/ul blood) except for one case. EBV-DNA levels were significantly more elevated in<jats:italic>P<\/jats:italic>.<jats:italic>falciparum<\/jats:italic>and<jats:italic>P<\/jats:italic>.<jats:italic>vivax<\/jats:italic>infections (P&lt;0.05) compared to controls. EBV-DNA levels were not related to age, gender, Malaria symptoms, or plasmodium type. TNF-\u03b1 and IL-10 levels were increased in Malaria cases versus controls, but IFN-\u03b3 and TGF- \u03b2 levels were comparable between the groups. Only TNF-\u03b1 levels in<jats:italic>P<\/jats:italic>.<jats:italic>falciparum<\/jats:italic>cases showed a clear correlation with elevated EBV DNA levels (R<jats:sup>2<\/jats:sup>= 0.8915). This is the first study addressing the relation between EBV (re)activation and cytokine responses during acute Malaria, revealing a clear correlation between pro-inflammatory cytokine TNF-\u03b1 and EBV-DNA levels, specifically in<jats:italic>P<\/jats:italic>.<jats:italic>falciparum<\/jats:italic>cases, suggesting this cytokine to be key in dysregulating EBV homeostasis during acute<jats:italic>P<\/jats:italic>.<jats:italic>falciparum<\/jats:italic>Malaria.<\/jats:p>","DOI":"10.1371\/journal.pone.0261923","type":"journal-article","created":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T19:01:39Z","timestamp":1640718099000},"page":"e0261923","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Quantitative cytokine level of TNF-\u03b1, IFN-\u03b3, IL-10, TGF-\u03b2 and circulating Epstein-Barr virus DNA load in individuals with acute Malaria due to P. falciparum or P. vivax or double infection in a Malaria endemic region in Indonesia"],"prefix":"10.1371","volume":"16","author":[{"given":"Insani","family":"Budiningsih","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoes Prijatna","family":"Dachlan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Usman","family":"Hadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0765-4125","authenticated-orcid":true,"given":"Jaap Michiel","family":"Middeldorp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,12,28]]},"reference":[{"issue":"1","key":"pone.0261923.ref001","first-page":"151","article-title":"Epstein-Barr Virus: Introducing the virus","volume":"390","author":"DA Thorley-Lawson","year":"2015","journal-title":"Curr Top Microbiol Immunol"},{"issue":"1","key":"pone.0261923.ref002","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1128\/CMR.00044-10","article-title":"Progress and problems in understanding and managing primary Epstein-Barr Virus infections","volume":"24","author":"OA Odumade","year":"2011","journal-title":"Clin Microbiol Rev"},{"issue":"1","key":"pone.0261923.ref003","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1073\/pnas.2237267100","article-title":"Demonstration of the Burkitt\u2019s lymphoma Epstein-Barr Virus phenotype in dividing latently infected memory cells in vivo","volume":"101","author":"D Hochberg","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"pone.0261923.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1040-8428(02)00078-1","article-title":"Pathogenic roles for Epstein-Barr Virus (EBV) gene products in EBV-associated proliferative disorders","volume":"45","author":"JM Middeldorp","year":"2003","journal-title":"Crit Rev Oncol Hematol"},{"key":"pone.0261923.ref005","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1146\/annurev.pathol.1.110304.100209","article-title":"Spectrum of Epstein-Barr virus-associated diseases","volume":"1","author":"JL Kutok","year":"2006","journal-title":"Annu Rev Pathol"},{"issue":"6","key":"pone.0261923.ref006","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1189\/jlb.0313173","article-title":"Innate immune responses against Epstein Barr virus infection","volume":"94","author":"O Chijioke","year":"2013","journal-title":"J Leukoc Biol"},{"key":"pone.0261923.ref007","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1146\/annurev-immunol-032414-112326","article-title":"The immunology of Epstein- Barr Virus-induced disease","volume":"33","author":"GS Taylor","year":"2015","journal-title":"Annu Rev Immunol"},{"issue":"12","key":"pone.0261923.ref008","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/nrmicro2015","article-title":"The curious case of the tumour virus: 50 years of Burkitt\u2019s lymphoma","volume":"6","author":"DA Thorley-Lawson","year":"2008","journal-title":"Nat Rev Microbiol"},{"issue":"9822","key":"pone.0261923.ref009","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1016\/S0140-6736(11)61177-X","article-title":"Burkitt\u2019s lymphoma","volume":"379","author":"EM Molyneux","year":"2012","journal-title":"Lancet"},{"issue":"3","key":"pone.0261923.ref010","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1179\/146532805X58120","article-title":"Burkitt lymphoma in Papua New Guinea\u201440 years on","volume":"25","author":"E Lavu","year":"2005","journal-title":"Ann Trop Paediatr"},{"issue":"6","key":"pone.0261923.ref011","doi-asserted-by":"crossref","first-page":"e80","DOI":"10.1371\/journal.ppat.0030080","article-title":"A molecular link between Malaria and Epstein-Barr Virus reactivation","volume":"3","author":"A Ch\u00eane","year":"2007","journal-title":"PLoS Pathog"},{"issue":"1","key":"pone.0261923.ref012","doi-asserted-by":"crossref","first-page":"e1005331","DOI":"10.1371\/journal.ppat.1005331","article-title":"The Link between Plasmodium falciparum Malaria and Endemic Burkitt\u2019s Lymphoma\u2014New Insight into a 50-Year-Old Enigma","volume":"12","author":"D Thorley-Lawson","year":"2016","journal-title":"PLoS Pathog"},{"key":"pone.0261923.ref013","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ebiom.2016.11.034","article-title":"Parasite Infection, Carcinogenesis and Human Malignancy","volume":"15","author":"H van Tong","year":"2017","journal-title":"EBioMedicine"},{"issue":"6","key":"pone.0261923.ref014","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1093\/infdis\/jir872","article-title":"Early age at time of primary Epstein-Barr Virus infection results in poorly controlled viral infection in infants from western Kenya: Clues to the etiology of endemic Burkitt lymphoma","volume":"205","author":"E Piriou","year":"2012","journal-title":"J Infect Dis"},{"issue":"6","key":"pone.0261923.ref015","doi-asserted-by":"crossref","first-page":"e604","DOI":"10.1016\/S2214-109X(18)30198-0","article-title":"Malaria elimination in Indonesia: halfway there","volume":"6","author":"V Sitohang","year":"2018","journal-title":"Lancet Glob Health"},{"issue":"4","key":"pone.0261923.ref016","doi-asserted-by":"crossref","first-page":"185","DOI":"10.5732\/cjc.011.10328","article-title":"Nasopharyngeal carcinoma in Indonesia: Epidemiology, incidence, signs, and symptoms at presentation","volume":"31","author":"M Adham","year":"2012","journal-title":"Chin J Cancer"},{"issue":"1","key":"pone.0261923.ref017","doi-asserted-by":"crossref","first-page":"62","DOI":"10.35816\/jiskh.v11i1.220","article-title":"Konsumsi Ikan Asin dan Daging Asap dengan Kejadian Karsinoma Nasofaring","volume":"9","author":"M Kasim","year":"2020","journal-title":"Jurnal Ilmiah Kesehatan Sandi Husada"},{"issue":"1","key":"pone.0261923.ref018","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13027-021-00391-2","article-title":"Interplay between Epstein-Barr virus infection and environmental xenobiotic exposure in cancer","volume":"16","author":"F Aguayo","year":"2021","journal-title":"Infect Agent Cancer"},{"issue":"8","key":"pone.0261923.ref019","doi-asserted-by":"crossref","first-page":"e12628","DOI":"10.1111\/pim.12628","article-title":"Immune effector mechanisms in malaria: An update focusing on human immunity","volume":"41","author":"AM Moormann","year":"2019","journal-title":"Parasite Immunol"},{"key":"pone.0261923.ref020","volume-title":"Book: Immune Response Activation and Immunomodulation","author":"JL Mu\u00f1oz-Carrillo","year":"2019"},{"issue":"6","key":"pone.0261923.ref021","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1002\/ijc.29127","article-title":"AID expression in peripheral blood of children living in a Malaria holoendemic region is associated with changes in B cell subsets and Epstein-Barr Virus","volume":"136","author":"JR Wilmore","year":"2015","journal-title":"Int J Cancer"},{"issue":"3","key":"pone.0261923.ref022","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1007\/s10995-014-1546-4","article-title":"Plasmodium falciparum Infection is Associated with Epstein\u2013Barr Virus Reactivation in Pregnant Women Living in Malaria Holoendemic Area of Western Kenya","volume":"19","author":"II Daud","year":"2015","journal-title":"Matern Child Health J"},{"key":"pone.0261923.ref023","volume-title":"Cancer, Burkitt Lymphoma. StatPearls Treasure Island (FL)","author":"BS Graham","year":"2019"},{"key":"pone.0261923.ref024","volume-title":"Basic Malaria microscopy-training manual","author":"World Health Organization","year":"2010"},{"issue":"4","key":"pone.0261923.ref025","doi-asserted-by":"crossref","first-page":"e94193","DOI":"10.1371\/journal.pone.0094193","article-title":"Assumed white blood cell count of 8,000 cells\/ml overestimates Malaria parasite density in the Brazilian amazon","volume":"9","author":"ER Alves-Junior","year":"2014","journal-title":"PLoS One"},{"issue":"2","key":"pone.0261923.ref026","first-page":"1","article-title":"Submicroscopic malaria cases play role in local transmission in Trenggalek district, East Java Province, Indonesia","volume":"17","author":"H Arwati","year":"2018","journal-title":"Malaria J"},{"issue":"6","key":"pone.0261923.ref027","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1093\/infdis\/jiv525","article-title":"Impact of Plasmodium falciparum Coinfection on Longitudinal Epstein-Barr Virus Kinetics in Kenyan Children","volume":"213","author":"A Reynaldi","year":"2016","journal-title":"J Infect Dis"},{"key":"pone.0261923.ref028","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.coviro.2016.09.006","article-title":"Malaria: how this parasitic infection aids and abets EBV-associated Burkitt lymphomagenesis","volume":"20","author":"AM Moormann","year":"2016","journal-title":"Curr Opin Virol"},{"issue":"2","key":"pone.0261923.ref029","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/apm.13018","article-title":"Endemic Burkitt lymphoma\u2013an aggressive childhood cancer linked to Plasmodium falciparum exposure, but not to exposure to other Malaria parasites","volume":"128","author":"M del P Quintana","year":"2020","journal-title":"APMIS"},{"issue":"1","key":"pone.0261923.ref030","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/imr.12816","article-title":"The immunology of Plasmodium vivax Malaria","volume":"293","author":"LR Antonelli","year":"2020","journal-title":"Immunol Rev"},{"issue":"1","key":"pone.0261923.ref031","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1186\/s12916-020-01759-8","article-title":"Malaria and risk of lymphoid neoplasms and other cancer: a nationwide population-based cohort study","volume":"18","author":"K Wyss","year":"2020","journal-title":"BMC Med"},{"issue":"8","key":"pone.0261923.ref032","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1158\/1078-0432.CCR-12-2897","article-title":"Epstein-Barr Virus DNA load in nasopharyngeal brushings and whole blood in nasopharyngeal carcinoma patients before and after treatment","volume":"19","author":"M Adham","year":"2013","journal-title":"Clin Cancer Res"},{"issue":"4","key":"pone.0261923.ref033","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1128\/JCM.39.4.1211-1216.2001","article-title":"Toward standardization of Epstein-Barr Virus DNA load monitoring: Unfractionated whole blood as preferred clinical specimen","volume":"39","author":"SJC Stevens","year":"2001","journal-title":"J Clin Microbiol"},{"issue":"7","key":"pone.0261923.ref034","doi-asserted-by":"crossref","first-page":"3066","DOI":"10.1128\/JCM.43.7.3066-3073.2005","article-title":"Diagnostic value of measuring Epstein-Barr Virus (EBV) DNA load and carcinoma-specific viral mRNA in relation to anti-EBV immunoglobulin A (IgA) and IgG antibody levels in blood of nasopharyngeal carcinoma patients from Indonesia","volume":"43","author":"SJC Stevens","year":"2005","journal-title":"J Clin Microbiol"},{"issue":"8","key":"pone.0261923.ref035","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1086\/428910","article-title":"Exposure to holoendemic malaria results in elevated Epstein-Barr virus loads in children","volume":"191","author":"AM Moormann","year":"2005","journal-title":"J Infect Dis"},{"key":"pone.0261923.ref036","first-page":"24327424","article-title":"Epstein-Barr Virus antibody titer and its association with the domain scores from the World Health Organization\u2019s Quality of Life questionnaire: Findings from Rural Hainan Province, China","author":"Y Inoue","year":"2014","journal-title":"Am J Hum Biol"},{"key":"pone.0261923.ref037","first-page":"18040814","article-title":"Stress-induced immune dysregulation: Implications for wound healing, infectious disease and cancer","author":"JP Godbout","year":"2006","journal-title":"J Neuroimmune Pharmacol"},{"key":"pone.0261923.ref038","unstructured":"Newswire\u2014Bisnis.com. 2018. Access internet 2021. Available from: https:\/\/surabaya.bisnis.com\/read\/20180517\/531\/796232\/produksi-ikan-asin-probolinggo-meningkat-drastis."},{"issue":"2","key":"pone.0261923.ref039","doi-asserted-by":"crossref","first-page":"e12763","DOI":"10.1111\/pim.12763","article-title":"Host-pathogen interaction in the tissue environment during Plasmodium blood-stage infection","volume":"43","author":"K Yui","year":"2021","journal-title":"Parasite Immunol"},{"issue":"1","key":"pone.0261923.ref040","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/imr.12830","article-title":"Innate immunity to malaria-The role of monocytes","volume":"293","author":"KR Dobbs","year":"2020","journal-title":"Immunol Rev"},{"issue":"3","key":"pone.0261923.ref041","doi-asserted-by":"crossref","first-page":"e58488","DOI":"10.1371\/journal.pone.0058488","article-title":"Prolonged restraint stress increases IL-6, reduces IL-10, and causes persistent depressive-like behavior that is reversed by recombinant IL-10","volume":"8","author":"JL Voorhees","year":"2013","journal-title":"PLoS One"},{"issue":"3","key":"pone.0261923.ref042","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/j.0141-9838.2004.00678.x","article-title":"Higher IL-10 levels are associated with less effective clearance of Plasmodium falciparum parasites","volume":"26","author":"E Hugosson","year":"2004","journal-title":"Parasite Immunol"},{"key":"pone.0261923.ref043","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3389\/fimmu.2019.00229","article-title":"The role of IL-10 in Malaria: A double edged sword","volume":"10","author":"R Kumar","year":"2019","journal-title":"Front Immunol"},{"issue":"2","key":"pone.0261923.ref044","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/BF01541734","article-title":"Decreased serum levels of TGF-\u03b2 in patients with acute Plasmodium falciparum Malaria","volume":"15","author":"C Wenisch","year":"1995","journal-title":"J Clin Immunol"},{"issue":"1","key":"pone.0261923.ref045","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1080\/21505594.2020.1726569","article-title":"Balancing in a black box: Potential immunomodulatory roles for TGF-\u03b2 signaling during blood-stage Malaria","volume":"11","author":"LL Drewry","year":"2020","journal-title":"Virulence"},{"key":"pone.0261923.ref046","doi-asserted-by":"crossref","first-page":"391","DOI":"10.3389\/fncel.2014.00391","article-title":"IFN-\u03b3 differentially modulates memory-related processes under basal and chronic stressor conditions","volume":"8","author":"D Litteljohn","year":"2014","journal-title":"Front Cell Neurosci"},{"issue":"1","key":"pone.0261923.ref047","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1186\/s12879-020-05107-2","article-title":"Association of cerebral Malaria and TNF-\u03b1 levels: A systematic review","volume":"20","author":"L Le\u00e3o","year":"2020","journal-title":"BMC Infect Dis"},{"issue":"1","key":"pone.0261923.ref048","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1179\/2047773212Y.0000000069","article-title":"Association of high plasma TNF-alpha levels and TNF-alpha\/IL-10 ratios with TNF2 allele in severe P. falciparum malaria patients in Sri Lanka","volume":"107","author":"MK Perera","year":"2013","journal-title":"Pathog Glob Health"},{"issue":"4","key":"pone.0261923.ref049","first-page":"645","article-title":"Serum TNF alpha levels: A prognostic marker for assessment of severity of Malaria","volume":"30","author":"P Kinra","year":"2013","journal-title":"Trop Biomed"},{"key":"pone.0261923.ref050","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.coi.2014.02.009","article-title":"From the regulatory functions of B cells to the identification of cytokine-producing plasma cell subsets","volume":"28","author":"VD Dang","year":"2014","journal-title":"Curr Opin Immunol"},{"issue":"8","key":"pone.0261923.ref051","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/0145-2126(96)00029-X","article-title":"Promotion of IL8, IL10, TNF-alpha and TNF-beta production by EBV infection","volume":"20","author":"SC Klein","year":"1996","journal-title":"Leuk Res"},{"issue":"5","key":"pone.0261923.ref052","doi-asserted-by":"crossref","first-page":"e1004170","DOI":"10.1371\/journal.ppat.1004170","article-title":"A Multifactorial Role for P. falciparum Malaria in Endemic Burkitt\u2019s Lymphoma Pathogenesis","volume":"10","author":"C Torgbor","year":"2014","journal-title":"PLoS Pathog"},{"issue":"10","key":"pone.0261923.ref053","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1002\/jmv.23988","article-title":"Epstein-Barr Virus viral load and serology in childhood non-Hodgkin\u2019s lymphoma and chronic inflammatory conditions in Uganda: implications for disease risk and characteristics","volume":"86","author":"J Orem","year":"2014","journal-title":"J Med Virol"},{"issue":"8","key":"pone.0261923.ref054","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1002\/ijc.22857","article-title":"Epstein-Barr virus infection and risk of lymphoma: immunoblot analysis of antibody responses against EBV-related proteins in a large series of lymphoma subjects and matched controls","volume":"121","author":"Sanjos\u00e9 Sd","year":"2007","journal-title":"Int J Cancer"},{"issue":"1","key":"pone.0261923.ref055","doi-asserted-by":"crossref","first-page":"373","DOI":"10.4103\/jfmpc.jfmpc_1594_20","article-title":"A three year Seroepidemiological and molecular study of Epstein -Barr virus infection among different age groups with hematological malignancies in a Tertiary care centre of North India (2017\u20132019)","volume":"10","author":"SS Patel","year":"2021","journal-title":"J Family Med Prim Care"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0261923","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T22:55:48Z","timestamp":1700002548000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0261923"}},"subtitle":[],"editor":[{"given":"Luzia Helena","family":"Carvalho","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,12,28]]},"references-count":55,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0261923","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,28]]}}}