title: Lack of clinical manifestations in asymptomatic dengue infection is attributed to broad down-regulation and selective up-regulation of host defence response genes.
abstract: OBJECTIVE
  Dengue represents one of the most serious life-threatening vector-borne infectious diseases that afflicts approximately 50 million people across the globe annually. Whilst symptomatic infections are frequently reported, asymptomatic dengue remains largely unnoticed. Therefore, we sought to investigate the immune correlates conferring protection to individuals that remain clinically asymptomatic.
  
  
  METHODS
  We determined the levels of neutralizing antibodies (nAbs) and gene expression profiles of host immune factors in individuals with asymptomatic infections, and whose cognate household members showed symptoms consistent to clinical dengue infection.
  
  
  RESULTS
  We observed broad down-regulation of host defense response (innate, adaptive and matrix metalloprotease) genes in asymptomatic individuals as against symptomatic patients, with selective up-regulation of distinct genes that have been associated with protection. Selected down-regulated genes include: TNF α (TNF), IL8, C1S, factor B (CFB), IL2, IL3, IL4, IL5, IL8, IL9, IL10 and IL13, CD80, CD28, and IL18, MMP8, MMP10, MMP12, MMP15, MMP16, and MMP24. Selected up-regulated genes include: RANTES (CCL5), MIP-1α (CCL3L1/CCL3L3), MIP-1β (CCL4L1), TGFβ (TGFB), and TIMP1.
  
  
  CONCLUSIONS
  Our findings highlight the potential association of certain host genes conferring protection against clinical dengue. These data are valuable to better explore the mysteries behind the hitherto poorly understood immunopathogenesis of subclinical dengue infection.
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia.
authors.forename: Adeline S L
authors.initials: AS
authors.lastname: Yeo
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia; Perdana University Graduate School of Medicine & Centre for Bioinformatics, MARDI Complex, Jalan MAEPS Perdana, Serdang, Selangor Darul Ehsan, Malaysia.
authors.forename: Nur Atiqah
authors.initials: NA
authors.lastname: Azhar
authors.affiliation: Perdana University Graduate School of Medicine & Centre for Bioinformatics, MARDI Complex, Jalan MAEPS Perdana, Serdang, Selangor Darul Ehsan, Malaysia.
authors.forename: Wanyi
authors.initials: W
authors.lastname: Yeow
authors.affiliation: Institute for Basic Biomedical Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: C Conover
authors.initials: CC
authors.lastname: Talbot
authors.affiliation: Perdana University Graduate School of Medicine & Centre for Bioinformatics, MARDI Complex, Jalan MAEPS Perdana, Serdang, Selangor Darul Ehsan, Malaysia; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Mohammad Asif
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia.
authors.forename: Esaki M
authors.initials: EM
authors.lastname: Shankar
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia.
authors.forename: Anusyah
authors.initials: A
authors.lastname: Rathakrishnan
authors.affiliation: Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Azliyati
authors.initials: A
authors.lastname: Azizan
authors.affiliation: Institute for Medical Molecular Biotechnology, Universiti Teknologi MARA, Sungai Buloh Campus, Jalan Hospital, Sungai Buloh, Selangor, Malaysia.
authors.forename: Seok Mui
authors.initials: SM
authors.lastname: Wang
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia.
authors.forename: Siew Kim
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Department of Parasitology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia.
authors.forename: Mun Yik
authors.initials: MY
authors.lastname: Fong
authors.affiliation: Department of Trauma and Emergency Medicine, University of Malaya Medical Centre, Lembah Pantai, Kuala Lumpur, Malaysia.
authors.forename: Rishya
authors.initials: R
authors.lastname: Manikam
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia.
authors.forename: Shamala
authors.initials: S
authors.lastname: Devi Sekaran
mesh_terms: D057134:Antibodies, Neutralizing / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003715:Dengue / Q000821:virology*; D003716:Dengue Virus / Q000472:pathogenicity*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D020782:Matrix Metalloproteinases
references.citation: Immunol Rev. 2010 Nov;238(1):247-62
references.pmid: 20969597
references.citation: J Infect Dis. 2004 Jan 15;189(2):221-32
references.pmid: 14722886
references.citation: Cell Microbiol. 2009 Apr;11(4):604-15
references.pmid: 19134117
references.citation: J Virol. 2001 Apr;75(8):3501-8
references.pmid: 11264339
references.citation: Am J Trop Med Hyg. 1978 May;27(3):581-9
references.pmid: 677371
references.citation: Nat Rev Immunol. 2011 Jul 15;11(8):532-43
references.pmid: 21760609
references.citation: Immunol Cell Biol. 2003 Jun;81(3):196-206
references.pmid: 12752684
references.citation: Dig Dis Sci. 2005 Oct;50(10):1793-803
references.pmid: 16187176
references.citation: Nat Immunol. 2011 Jun 20;12(7):597-606
references.pmid: 21685955
references.citation: Hum Immunol. 2010 Nov;71(11):1135-40
references.pmid: 20732366
references.citation: J Gen Virol. 2004 Jul;85(Pt 7):1801-1813
references.pmid: 15218164
references.citation: J Med Virol. 1999 Nov;59(3):335-40
references.pmid: 10502266
references.citation: J Infect Dis. 1999 Apr;179(4):755-62
references.pmid: 10068569
references.citation: Trans R Soc Trop Med Hyg. 1998 Nov-Dec;92(6):654-6
references.pmid: 10326113
references.citation: FEMS Immunol Med Microbiol. 2005 Jan 1;43(1):99-102
references.pmid: 15607642
references.citation: Trends Immunol. 2002 Jun;23(6):273-5
references.pmid: 12072358
references.citation: J Exp Med. 2010 Apr 12;207(4):793-806
references.pmid: 20308361
references.citation: Clin Vaccine Immunol. 2007 Aug;14(8):969-77
references.pmid: 17567768
references.citation: Arch Med Res. 2005 Sep-Oct;36(5):425-35
references.pmid: 16099317
references.citation: Nature. 2013 Apr 25;496(7446):504-7
references.pmid: 23563266
references.citation: Virology. 2008 Oct 25;380(2):296-303
references.pmid: 18774583
references.citation: J Infect Dis. 2006 Apr 15;193(8):1078-88
references.pmid: 16544248
references.citation: EMBO Rep. 2006 Nov;7(11):1176-81
references.pmid: 17028575
references.citation: J Gen Virol. 1990 Dec;71 ( Pt 12):2909-14
references.pmid: 2273390
references.citation: Nature. 2008 Jul 24;454(7203):428-35
references.pmid: 18650913
references.citation: PLoS One. 2012;7(7):e38527
references.pmid: 22815692
references.citation: J Infect Dis. 2000 Jan;181(1):2-9
references.pmid: 10608744
references.citation: J Virol. 2004 Dec;78(24):13779-92
references.pmid: 15564486
references.citation: Am J Trop Med Hyg. 1993 Mar;48(3):324-31
references.pmid: 8470771
references.citation: Am J Trop Med Hyg. 1958 Sep;7(5):561-73
references.pmid: 13571577
references.citation: Mem Inst Oswaldo Cruz. 2001 Feb;96(2):229-32
references.pmid: 11285501
references.citation: PLoS Negl Trop Dis. 2011 Mar 01;5(3):e975
references.pmid: 21390158
references.citation: J Med Virol. 1998 Nov;56(3):280-5
references.pmid: 9783699
references.citation: Vaccine. 2009 Jan 14;27(3):355-68
references.pmid: 19022321
references.citation: Am J Trop Med Hyg. 2012 Nov;87(5):936-42
references.pmid: 22987650
references.citation: J Biomed Sci. 2001 Sep;8(5):377-88
references.pmid: 11549879
references.citation: Jpn J Infect Dis. 2008 Jul;61(4):298-301
references.pmid: 18653973
references.citation: Int J Exp Pathol. 1999 Jun;80(3):143-9
references.pmid: 10469270
references.citation: J Clin Immunol. 2013 Apr;33(3):613-8
references.pmid: 23274801
references.citation: Adv Drug Deliv Rev. 2008 Apr 29;60(7):805-12
references.pmid: 18262679
references.citation: J Immunol. 2006 Sep 15;177(6):3848-56
references.pmid: 16951347
references.citation: Am J Trop Med Hyg. 1997 Aug;57(2):119-25
references.pmid: 9288801
references.citation: FEMS Immunol Med Microbiol. 2000 Jul;28(3):183-8
references.pmid: 10865168
references.citation: Lancet. 1969 Aug 9;2(7615):327
references.pmid: 4184246
references.citation: PLoS One. 2010 Jun 23;5(6):e11267
references.pmid: 20585645
references.citation: Am J Physiol. 1989 Dec;257(6 Pt 1):L399-410
references.pmid: 2610269
references.citation: J Exp Med. 1983 Jul 1;158(1):258-63
references.pmid: 6864163
references.citation: Indian J Med Res. 2006 Jan;123(1):25-30
references.pmid: 16567864
references.citation: Microbiol Mol Biol Rev. 2012 Mar;76(1):16-32
references.pmid: 22390970
references.citation: mBio. 2012 Feb 07;3(1):
references.pmid: 22318317
references.citation: Tissue Antigens. 2003 Mar;61(3):189-202
references.pmid: 12694568
references.citation: J Immunol. 1999 May 1;162(9):5609-15
references.pmid: 10228044
references.citation: Am J Trop Med Hyg. 2010 Jun;82(6):1153-6
references.pmid: 20519616
references.citation: FEMS Immunol Med Microbiol. 2001 Apr;30(3):229-33
references.pmid: 11335143
references.citation: Southeast Asian J Trop Med Public Health. 1987 Sep;18(3):316-20
references.pmid: 3501613
references.citation: J Immunol. 1967 Aug;99(2):285-90
references.pmid: 6031202
references.citation: Am J Trop Med Hyg. 1995 Mar;52(3):225-7
references.pmid: 7694963
references.citation: J Virol Methods. 2006 Dec;138(1-2):123-30
references.pmid: 17000012
references.citation: Am J Trop Med Hyg. 1976 Mar;25(2):318-25
references.pmid: 1259091
references.citation: PLoS One. 2012;7(12):e52215
references.pmid: 23284941
references.citation: PLoS Negl Trop Dis. 2011 Jan 04;5(1):e926
references.pmid: 21245912
references.citation: Tissue Antigens. 2004 Oct;64(4):469-72
references.pmid: 15361124
references.citation: PLoS One. 2011;6(8):e23346
references.pmid: 21829730
references.citation: J Infect Dis. 2008 Aug 15;198(4):516-24
references.pmid: 18598189
references.citation: J Clin Invest. 1991 Nov;88(5):1473-80
references.pmid: 1939640
references.citation: Infect Immun. 2000 Feb;68(2):702-7
references.pmid: 10639436
references.citation: Southeast Asian J Trop Med Public Health. 1987 Dec;18(4):532-8
references.pmid: 3329413
references.citation: BMC Infect Dis. 2008 Jun 25;8:86
references.pmid: 18578883
references.citation: Immunol Rev. 2008 Oct;225:300-13
references.pmid: 18837790
references.citation: J Infect Dis. 2008 May 15;197(10):1459-67
references.pmid: 18444802
references.citation: Rev Med Virol. 2006 Jul-Aug;16(4):263-75
references.pmid: 16791836
references.citation: Viruses. 2010 Dec;2(12):2649-62
references.pmid: 21994635
references.citation: Trans R Soc Trop Med Hyg. 1987;81(5):816-20
references.pmid: 3450004