title: The robust and modulated biomarker network elicited by the Plasmodium vivax infection is mainly mediated by the IL-6/IL-10 axis and is associated with the parasite load.
abstract: BACKGROUND
  Recent studies have shown that the inflammatory process, including the biomarker production, and the intense activation of innate immune responses are greater in the malaria caused by Plasmodium vivax than other species. Here, we examined the levels of serum biomarkers and their interaction during acute malaria.
  
  
  METHODS
  Blood samples were collected from P. vivax-infected patients at admission and from healthy donors. Levels of serum biomarkers were measured by Cytometric Bead Assay or ELISA.
  
  
  RESULTS
  P. vivax infection triggered the production of both inflammatory and regulatory biomarkers. Levels of IL-6, CXCL-8, IFN-γ, IL-5, and IL-10 were higher in P. vivax-infected patients than in healthy donors. On the other hand, malaria patients produced lower levels of TNF-α, IL-12p70, and IL-2 than healthy individuals. While the levels of IL-10 and IL-6 were found independent on the number of malaria episodes, higher levels of these cytokines were seen in patients with higher parasite load.
  
  
  CONCLUSIONS
  A mixed pattern of proinflammatory and regulatory biomarkers is produced in P. vivax malaria. Analysis of biomarker network suggests that IL-10 and IL-6 are a robust axis in malaria patients and that this interaction seems to be associated with the parasite load.
authors.affiliation: Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), 69077-000 Manaus, AM, Brazil ; Departamento de Ensino e Pesquisa, Fundação de Hematologia e Hemoterapia do Amazonas (HEMOAM), 69050-001 Manaus, AM, Brazil.
authors.forename: Allyson Guimarães
authors.initials: AG
authors.lastname: da Costa
authors.affiliation: Laboratório de Imunopatologia, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), 30190-002 Belo Horizonte, MG, Brazil.
authors.forename: Lis Ribeiro do Valle
authors.initials: LR
authors.lastname: Antonelli
authors.affiliation: Laboratório de Imunopatologia, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), 30190-002 Belo Horizonte, MG, Brazil.
authors.forename: Pedro Augusto Carvalho
authors.initials: PA
authors.lastname: Costa
authors.affiliation: Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), 69077-000 Manaus, AM, Brazil ; Centro de Pesquisas Leônidas e Maria Deane, Fundação Oswaldo Cruz (FIOCRUZ), 69057-070 Manaus, AM, Brazil.
authors.forename: João Paulo Diniz
authors.initials: JP
authors.lastname: Pimentel
authors.affiliation: Departamento de Ensino e Pesquisa, Fundação de Hematologia e Hemoterapia do Amazonas (HEMOAM), 69050-001 Manaus, AM, Brazil.
authors.forename: Nadja Pinto
authors.initials: NP
authors.lastname: Garcia
authors.affiliation: Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), 69077-000 Manaus, AM, Brazil ; Departamento de Ensino e Pesquisa, Fundação de Hematologia e Hemoterapia do Amazonas (HEMOAM), 69050-001 Manaus, AM, Brazil.
authors.forename: Andréa Monteiro
authors.initials: AM
authors.lastname: Tarragô
authors.affiliation: Instituto de Medicina Tropical de Coari, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), 69460-000 Coari, AM, Brazil.
authors.forename: Maria do Perpétuo Socorro Lopes
authors.initials: Mdo P
authors.lastname: dos Santos
authors.affiliation: Centro de Pesquisas Leônidas e Maria Deane, Fundação Oswaldo Cruz (FIOCRUZ), 69057-070 Manaus, AM, Brazil.
authors.forename: Paulo Afonso
authors.initials: PA
authors.lastname: Nogueira
authors.affiliation: Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), 69077-000 Manaus, AM, Brazil.
authors.forename: Maria Izabel Ovellar
authors.initials: MI
authors.lastname: Hekcmann
authors.affiliation: Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), 69077-000 Manaus, AM, Brazil.
authors.forename: Aya
authors.initials: A
authors.lastname: Sadahiro
authors.affiliation: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), 30190-002 Belo Horizonte, MG, Brazil.
authors.forename: Andréa
authors.initials: A
authors.lastname: Teixeira-Carvalho
authors.affiliation: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), 30190-002 Belo Horizonte, MG, Brazil.
authors.forename: Olindo Assis
authors.initials: OA
authors.lastname: Martins-Filho
authors.affiliation: Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), 69077-000 Manaus, AM, Brazil ; Departamento de Ensino e Pesquisa, Fundação de Hematologia e Hemoterapia do Amazonas (HEMOAM), 69050-001 Manaus, AM, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: Malheiro
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016000:Cluster Analysis; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D016753:Interleukin-10 / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood*; D016780:Malaria, Vivax / Q000097:blood* / Q000276:immunology / Q000469:parasitology*; D008297:Male; D008875:Middle Aged; D059208:Parasite Load; D010966:Plasmodium vivax / Q000276:immunology*; D040901:Proteomics; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D016753:Interleukin-10
references.citation: Clin Infect Dis. 2009 Aug 1;49(3):336-43
references.pmid: 19548833
references.citation: PLoS One. 2010 Mar 10;5(3):e9623
references.pmid: 20224778
references.citation: Science. 1991 Oct 4;254(5028):99-102
references.pmid: 1718038
references.citation: J Immunol. 1985 Nov;135(5):3498-504
references.pmid: 3930605
references.citation: PLoS Pathog. 2010 Feb 19;6(2):e1000770
references.pmid: 20174609
references.citation: Lancet Infect Dis. 2009 Sep;9(9):555-66
references.pmid: 19695492
references.citation: PLoS Med. 2008 Jun 17;5(6):e127
references.pmid: 18563961
references.citation: Am J Trop Med Hyg. 2007 Dec;77(6 Suppl):79-87
references.pmid: 18165478
references.citation: J Neuroinflammation. 2012 Feb 27;9:40
references.pmid: 22369693
references.citation: Am J Trop Med Hyg. 2010 Feb;82(2):185-93
references.pmid: 20133990
references.citation: Parasite Immunol. 2007 Sep;29(9):435-44
references.pmid: 17727567
references.citation: Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8097-101
references.pmid: 8058763
references.citation: Lancet. 1987 Oct 17;2(8564):921
references.pmid: 2889120
references.citation: J Infect Dis. 2011 Sep 15;204(6):873-83
references.pmid: 21849284
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10700-2
references.pmid: 7938013
references.citation: PLoS Pathog. 2009 Apr;5(4):e1000364
references.pmid: 19343213
references.citation: Science. 1988 Jan 29;239(4839):502-4
references.pmid: 2829354
references.citation: Malar J. 2013 Feb 21;12:69
references.pmid: 23433077
references.citation: PLoS One. 2013;8(2):e55756
references.pmid: 23437061
references.citation: PLoS One. 2012;7(9):e44394
references.pmid: 22973442
references.citation: Nat Med. 1997 Jan;3(1):80-3
references.pmid: 8986746
references.citation: Parasite Immunol. 2006 May;28(5):201-7
references.pmid: 16629705
references.citation: Trop Med Int Health. 2006 Jun;11(6):817-23
references.pmid: 16772003
references.citation: Malar J. 2010 Jan 13;9:13
references.pmid: 20070895
references.citation: Clin Exp Immunol. 2003 Jun;132(3):467-72
references.pmid: 12780694
references.citation: J Immunol. 2010 Jun 1;184(11):6043-52
references.pmid: 20427769
references.citation: J Immunol. 2011 Aug 1;187(3):1157-65
references.pmid: 21709158
references.citation: Mem Inst Oswaldo Cruz. 2013 Feb;108(1):98-105
references.pmid: 23440122
references.citation: Am J Trop Med Hyg. 2007 Nov;77(5):984-91
references.pmid: 17984364
references.citation: J Immunol. 1995 Sep 1;155(5):2545-56
references.pmid: 7650384
references.citation: Malar J. 2012 Jan 09;11:12
references.pmid: 22230294
references.citation: J Immunol. 2008 Dec 15;181(12):8344-55
references.pmid: 19050251
references.citation: PLoS Negl Trop Dis. 2012;6(6):e1710
references.pmid: 22745844
references.citation: Infect Immun. 2000 Aug;68(8):4399-406
references.pmid: 10899836
references.citation: Lancet Infect Dis. 2004 Jun;4(6):327-36
references.pmid: 15172341
references.citation: Neurosci Lett. 1994 Sep 26;179(1-2):53-6
references.pmid: 7845624
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3200-3
references.pmid: 1565611
references.citation: J Exp Med. 1991 Nov 1;174(5):1209-20
references.pmid: 1940799
references.citation: Infect Immun. 2010 Nov;78(11):4763-72
references.pmid: 20713627
references.citation: Bull Soc Pathol Exot. 2008 Jun;101(3):243-8
references.pmid: 18683322
references.citation: PLoS Negl Trop Dis. 2012;6(9):e1814
references.pmid: 22970336
references.citation: J Immunol. 2012 May 15;188(10):5054-62
references.pmid: 22504653
references.citation: J Immunol. 1991 Dec 1;147(11):3736-44
references.pmid: 1682383