title: Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding.
abstract: Noroviruses (NoV) are the most common cause of epidemic gastroenteritis world-wide. NoV infections are often asymptomatic, although individuals still shed large amounts of NoV in their stool. Understanding the differences between asymptomatic and symptomatic individuals would help in elucidating mechanisms of NoV pathogenesis. Our goal was to compare the serum cytokine responses and faecal viral RNA titres of asymptomatic and symptomatic NoV-infected individuals. We tested serum samples from infected subjects (n = 26; 19 symptomatic, seven asymptomatic) from two human challenge studies of GI.1 NoV for 16 cytokines. Samples from prechallenge and days 1-4 post-challenge were tested for these cytokines. Cytokine levels were compared to stool NoV RNA titres quantified previously by reverse transcription-polymerase chain reaction (RT-qPCR). While both symptomatic and asymptomatic groups had similar patterns of cytokine responses, the symptomatic group generally exhibited a greater elevation of T helper type 1 (Th1) and Th2 cytokines and IL-8 post-challenge compared to the asymptomatic group (all P < 0·01). Daily viral RNA titre was associated positively with daily IL-6 concentration and negatively with daily IL-12p40 concentration (all P < 0·05). Symptoms were not associated significantly with daily viral RNA titre, duration of viral shedding or cumulative shedding. Symptomatic individuals, compared to asymptomatic, have greater immune system activation, as measured by serum cytokines, but they do not have greater viral burden, as measured by titre and shedding, suggesting that symptoms may be immune-mediated in NoV infection.
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.|Medical Scientist Training Program, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Newman
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.|Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Moe
authors.affiliation: Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Kirby
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
authors.forename: W D
authors.initials: WD
authors.lastname: Flanders
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Parkos
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.|Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Leon
mesh_terms: D000293:Adolescent; D000328:Adult; D058070:Asymptomatic Diseases; D005243:Feces / Q000737:chemistry / Q000821:virology; D005260:Female; D005759:Gastroenteritis / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D053762:Interleukin-12 Subunit p40 / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood*; D016209:Interleukin-8 / Q000097:blood*; D008297:Male; D029322:Norovirus / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology / Q000821:virology; D058408:Th1-Th2 Balance; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology / Q000821:virology; D019562:Viral Load / Q000276:immunology; D017201:Virus Shedding / Q000276:immunology*
chemical_list: C508600:IL6 protein, human; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D016209:Interleukin-8; D012367:RNA, Viral
keywords: adaptive immunity; caliciviruses; gastroenteritis; innate immunity; symptoms
references.citation: Clin Diagn Lab Immunol. 2003 Nov;10(6):995-1001
references.pmid: 14607858
references.citation: Clin Infect Dis. 2012 Jul;55(2):189-93
references.pmid: 22491335
references.citation: PLoS Pathog. 2011 Dec;7(12):e1002413
references.pmid: 22174679
references.citation: Appl Environ Microbiol. 2011 Aug;77(15):5476-82
references.pmid: 21705552
references.citation: J Med Virol. 2014 Dec;86(12):2055-64
references.pmid: 24531909
references.citation: Science. 2014 Aug 1;345(6196):578-82
references.pmid: 25082704
references.citation: J Virol. 2008 Jul;82(13):6610-7
references.pmid: 18417579
references.citation: Clin Microbiol Infect. 2014 Aug;20(8):717-23
references.pmid: 25040790
references.citation: J Exp Med. 2014 Nov 17;211(12):2397-410
references.pmid: 25366965
references.citation: Sci Prog. 2014;97(Pt 3):197-214
references.pmid: 25549406
references.citation: Eur J Immunol. 2015 Oct;45(10 ):2742-57
references.pmid: 26256101
references.citation: Nat Clin Pract Gastroenterol Hepatol. 2005 May;2(5):216-22
references.pmid: 16265204
references.citation: Clin Exp Immunol. 2015 Nov;182(2):195-203
references.pmid: 26178578
references.citation: Epidemiol Infect. 2015 Jun;143(8):1710-7
references.pmid: 25336060
references.citation: Expert Opin Ther Targets. 2013 Dec;17(12):1439-60
references.pmid: 24090198
references.citation: PLoS One. 2014 Apr 11;9(4):e92240
references.pmid: 24727912
references.citation: J Med Virol. 2010 Sep;82(9):1612-6
references.pmid: 20648618
references.citation: Science. 2015 Jan 16;347(6219):266-9
references.pmid: 25431490
references.citation: J Virol. 2005 Mar;79(5):2900-9
references.pmid: 15709009
references.citation: J Virol. 2007 Apr;81(7):3251-63
references.pmid: 17229692
references.citation: Hepat Mon. 2014 Jun 07;14(6):e18892
references.pmid: 24976843
references.citation: J Med Virol. 2003 Feb;69(2):286-95
references.pmid: 12683420
references.citation: Appl Environ Microbiol. 2011 Oct;77(19):6884-8
references.pmid: 21856841
references.citation: J Virol. 2006 Nov;80(21):10372-81
references.pmid: 17041218
references.citation: Clin Infect Dis. 2012 Apr;54(7):931-7
references.pmid: 22291099
references.citation: Gut. 2009 Aug;58(8):1070-7
references.pmid: 19036950
references.citation: J Virol. 2008 Feb;82(4):1777-86
references.pmid: 18045944
references.citation: Lancet Infect Dis. 2014 Aug;14(8):725-30
references.pmid: 24981041
references.citation: Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3450-6
references.pmid: 19064561
references.citation: Nat Med. 2003 May;9(5):548-53
references.pmid: 12692541
references.citation: Pediatr Transplant. 2011 Aug;15(5):505-9
references.pmid: 21504523
references.citation: Science. 2003 Mar 7;299(5612):1575-8
references.pmid: 12624267
references.citation: PLoS One. 2013 Jul 24;8(7):e68413
references.pmid: 23894302
references.citation: Cytokine. 2013 Jan;61(1):205-9
references.pmid: 23107825
references.citation: PLoS Pathog. 2008 Dec;4(12):e1000236
references.pmid: 19079577
references.citation: J Virol. 2010 Feb;84(4):1800-15
references.pmid: 20007270
references.citation: Emerg Infect Dis. 2008 Oct;14(10):1553-7
references.pmid: 18826818
references.citation: J Clin Virol. 2015 Aug;69:133-7
references.pmid: 26209395
references.citation: J Infect Dis. 2015 Mar 15;211(6):870-8
references.pmid: 25210140
references.citation: J Hosp Infect. 2011 Sep;79(1):27-31
references.pmid: 21764172
references.citation: N Engl J Med. 2011 Dec 8;365(23):2178-87
references.pmid: 22150036
references.citation: Nat Clin Pract Gastroenterol Hepatol. 2008 Nov;5(11):637-47
references.pmid: 18813221