title: Transcriptional profiling of the circulating immune response to lassa virus in an aerosol model of exposure.
abstract: Lassa virus (LASV) is a significant human pathogen that is endemic to several countries in West Africa. Infection with LASV leads to the development of hemorrhagic fever in a significant number of cases, and it is estimated that thousands die each year from the disease. Little is known about the complex immune mechanisms governing the response to LASV or the genetic determinants of susceptibility and resistance to infection. In the study presented here, we have used a whole-genome, microarray-based approach to determine the temporal host response in the peripheral blood mononuclear cells (PBMCs) of non-human primates (NHP) following aerosol exposure to LASV. Sequential sampling over the entire disease course showed that there are strong transcriptional changes of the immune response to LASV exposure, including the early induction of interferon-responsive genes and Toll-like receptor signaling pathways. However, this increase in early innate responses was coupled with a lack of pro-inflammatory cytokine response in LASV exposed NHPs. There was a distinct lack of cytokines such as IL1β and IL23α, while immunosuppressive cytokines such as IL27 and IL6 were upregulated. Comparison of IRF/STAT1-stimulated gene expression with the viral load in LASV exposed NHPs suggests that mRNA expression significantly precedes viremia, and thus might be used for early diagnostics of the disease. Our results provide a transcriptomic survey of the circulating immune response to hemorrhagic LASV exposure and provide a foundation for biomarker identification to allow clinical diagnosis of LASV infection through analysis of the host response.
authors: Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: Shikha
authors: S
authors: Malhotra
authors: Judy Y
authors: JY
authors: Yen
authors: Anna N
authors: AN
authors: Honko
authors: Sara
authors: S
authors: Garamszegi
authors: Ignacio S
authors: IS
authors: Caballero
authors: Joshua C
authors: JC
authors: Johnson
authors: Eric M
authors: EM
authors: Mucker
authors: John C
authors: JC
authors: Trefry
authors: Lisa E
authors: LE
authors: Hensley
authors: John H
authors: JH
authors: Connor
mesh_terms: D000818:Animals; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D007113:Immunity, Innate / Q000276:immunology; D007835:Lassa Fever / Q000235:genetics* / Q000821:virology; D007836:Lassa virus / Q000276:immunology* / Q000472:pathogenicity; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008251:Macaca / Q000276:immunology* / Q000821:virology*; D008297:Male; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D051193:Toll-Like Receptors
references: J Virol. 2007 Aug;81(15):7960-73
references: 17522210
references: Sci Transl Med. 2011 Nov 30;3(111):111ra120
references: 22133721
references: J Virol. 2011 Sep;85(17):9060-8
references: 21734050
references: Curr Top Microbiol Immunol. 1987;133:89-113
references: 3030664
references: J Infect Dis. 1980 May;141(5):580-9
references: 6768812
references: Virol J. 2011 May 06;8:205
references: 21548931
references: Bull World Health Organ. 1975;52(4-6):535-45
references: 1085209
references: PLoS One. 2013;8(1):e52198
references: 23326326
references: J Infect Dis. 1987 Mar;155(3):437-44
references: 3805771
references: Immunology. 2003 Sep;110(1):38-47
references: 12941139
references: Infect Immun. 1982 Aug;37(2):771-8
references: 6749685
references: J Infect Dis. 2011 Aug 15;204(4):592-600
references: 21791661
references: Arthritis Rheum. 2004 Jun;50(6):1806-14
references: 15188357
references: Mediators Inflamm. 2012;2012:503128
references: 22791937
references: Bioinformatics. 2004 Jun 12;20(9):1453-4
references: 14871861
references: Nat Protoc. 2009;4(1):44-57
references: 19131956
references: Immunity. 2005 Feb;22(2):247-57
references: 15723812
references: Philos Trans R Soc Lond B Biol Sci. 2012 Mar 19;367(1590):868-77
references: 22312054
references: J Infect Dis. 2001 Jun 15;183(12):1713-21
references: 11372023
references: Am J Trop Med Hyg. 1983 Jul;32(4):829-37
references: 6881432
references: Science. 2009 Jun 19;324(5934):1569-72
references: 19423777
references: Biochem Pharmacol. 2012 Jul 1;84(1):11-20
references: 22402301
references: Nat Med. 2004 Dec;10(12 Suppl):S110-21
references: 15577929
references: Am J Trop Med Hyg. 2010 May;82(5):954-60
references: 20439981
references: Pan Afr Med J. 2012;11:55
references: 22593791
references: J Virol. 2012 Jul;86(13):7216-26
references: 22532679
references: Emerg Infect Dis. 2010 Dec;16(12):2009-11
references: 21122249
references: J Infect Dis. 1984 Mar;149(3):420-7
references: 6715898
references: Bioinformatics. 2004 Nov 22;20(17):3246-8
references: 15180930
references: J Immunol. 2006 Apr 1;176(7):4284-95
references: 16547266
references: J Infect Dis. 2011 Nov;204 Suppl 3:S1043-52
references: 21987740
references: J Virol. 2012 Mar;86(6):3389-92
references: 22238311
references: FASEB J. 2004 Sep;18(12):1439-41
references: 15247147
references: Bull World Health Organ. 1975;52(4-6):523-34
references: 821625
references: J Immunol. 2004 Mar 1;172(5):2861-9
references: 14978087
references: BMJ. 1995 Sep 30;311(7009):857-9
references: 7580496
references: J Virol. 2002 Jun;76(11):5532-9
references: 11991981
references: J Thromb Haemost. 2009 Oct;7(10):1718-26
references: 19682241
references: Vopr Virusol. 1991 Mar-Apr;36(2):150-2
references: 1882523
references: Science. 1974 Jul 19;185(4147):263-5
references: 4833828
references: Infect Immun. 1984 May;44(2):528-33
references: 6715049
references: Immunity. 2012 Jun 29;36(6):1017-30
references: 22726954
references: Immunity. 2001 Jul;15(1):23-34
references: 11485735
references: PLoS One. 2012;7(8):e41387
references: 22916107
references: J Virol. 2007 Jun;81(12):6482-90
references: 17409137
references: J Virol. 2001 Jul;75(13):5965-76
references: 11390598
references: Curr Top Microbiol Immunol. 1987;134:5-68
references: 3034512
references: Genome Biol. 2007;8(8):R174
references: 17725815
references: PLoS Pathog. 2010 Mar 26;6(3):e1000836
references: 20360949
references: Immunol Rev. 2009 Nov;232(1):273-85
references: 19909370
references: J Gen Virol. 2008 Oct;89(Pt 10):2569-2579
references: 18796726
references: Microbes Infect. 2002 Jan;4(1):43-50
references: 11825774
references: J Virol. 2009 Jun;83(11):5890-903
references: 19297492
references: Vaccine. 2008 Sep 26;26(41):5246-54
references: 18692539
references: N Engl J Med. 1986 Jan 2;314(1):20-6
references: 3940312
references: J Med Virol. 1984;14(4):295-303
references: 6512508
references: Cell. 2006 Sep 22;126(6):1121-33
references: 16990136