title: Host gene expression profiling and in vivo cytokine studies to characterize the role of linezolid and vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) murine sepsis model.
abstract: Linezolid (L), a potent antibiotic for Methicillin Resistant Staphylococcus aureus (MRSA), inhibits bacterial protein synthesis. By contrast, vancomycin (V) is a cell wall active agent. Here, we used a murine sepsis model to test the hypothesis that L treatment is associated with differences in bacterial and host characteristics as compared to V. Mice were injected with S. aureus USA300, and then intravenously treated with 25 mg/kg of either L or V at 2 hours post infection (hpi). In vivo alpha-hemolysin production was reduced in both L and V-treated mice compared to untreated mice but the reduction did not reach the statistical significance [P = 0.12 for L; P = 0.70 for V). PVL was significantly reduced in L-treated mice compared to untreated mice (P = 0.02). However the reduction of in vivo PVL did not reach the statistical significance in V- treated mice compared to untreated mice (P = 0.27). Both antibiotics significantly reduced IL-1β production [P = 0.001 for L; P = 0.006 for V]. IL-6 was significantly reduced with L but not V antibiotic treatment [P<0.001 for L; P = 0.11 for V]. Neither treatment significantly reduced production of TNF-α. Whole-blood gene expression profiling showed no significant effect of L and V on uninfected mice. In S. aureus-infected mice, L altered the expression of a greater number of genes than V (95 vs. 42; P = 0.001). Pathway analysis for the differentially expressed genes identified toll-like receptor signaling pathway to be common to each S. aureus-infected comparison. Expression of immunomodulatory genes like Cxcl9, Cxcl10, Il1r2, Cd14 and Nfkbia was different among the treatment groups. Glycerolipid metabolism pathway was uniquely associated with L treatment in S. aureus infection. This study demonstrates that, as compared to V, treatment with L is associated with reduced levels of toxin production, differences in host inflammatory response, and distinct host gene expression characteristics in MRSA sepsis.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, USA. batu.sharma@duke.edu
authors.forename: Batu K
authors.initials: BK
authors.lastname: Sharma-Kuinkel
authors.forename: Yurong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Ahn
authors.forename: Vance G
authors.initials: VG
authors.lastname: Fowler
mesh_terms: D000081:Acetamides / Q000627:therapeutic use*; D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods*; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity*; D051379:Mice; D023303:Oxazolidinones / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology; D014640:Vancomycin / Q000627:therapeutic use*
chemical_list: D000081:Acetamides; D023303:Oxazolidinones; D014640:Vancomycin; D000069349:Linezolid
references.citation: Rev Med Interne. 2009 Oct;30(10):907-10
references.pmid: 19299049
references.citation: J Infect Dis. 2008 Oct 15;198(8):1166-70
references.pmid: 18729780
references.citation: J Infect Dis. 1995 Aug;172(2):410-9
references.pmid: 7542686
references.citation: Antimicrob Agents Chemother. 2003 May;47(5):1752-5
references.pmid: 12709354
references.citation: Antimicrob Agents Chemother. 2000 Dec;44(12):3438-40
references.pmid: 11083654
references.citation: J Infect Dis. 2011 Sep 15;204(6):937-41
references.pmid: 21849291
references.citation: PLoS One. 2009 Sep 25;4(9):e7204
references.pmid: 19779608
references.citation: J Appl Bacteriol. 1993 Aug;75(2):123-8
references.pmid: 8407672
references.citation: Curr Opin Pharmacol. 2009 Oct;9(5):545-51
references.pmid: 19726228
references.citation: J Biol Chem. 1986 May 15;261(14):6338-45
references.pmid: 3634775
references.citation: PLoS Pathog. 2010 Sep 02;6(9):e1001088
references.pmid: 20824097
references.citation: Am J Respir Crit Care Med. 2004 May 15;169(10):1135-43
references.pmid: 15001460
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003 Oct;96(4):492-8
references.pmid: 14561977
references.citation: J Antimicrob Chemother. 2006 Jan;57(1):150-1
references.pmid: 16244085
references.citation: BMC Med Genomics. 2011 Jul 22;4:61
references.pmid: 21781289
references.citation: J Infect Dis. 2012 Nov 15;206(10):1604-11
references.pmid: 22966128
references.citation: J Infect Chemother. 2010 Apr;16(2):94-9
references.pmid: 20094752
references.citation: Cytokine Growth Factor Rev. 2003 Dec;14(6):523-35
references.pmid: 14563354
references.citation: PLoS One. 2009;4(5):e5446
references.pmid: 19424507
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5587-92
references.pmid: 20231457
references.citation: N Engl J Med. 2000 May 4;342(18):1334-49
references.pmid: 10793167
references.citation: Antimicrob Agents Chemother. 2004 May;48(5):1581-5
references.pmid: 15105108
references.citation: Chemotherapy. 2005 Oct;51(6):363-5
references.pmid: 16227692
references.citation: Antimicrob Agents Chemother. 2007 Apr;51(4):1515-9
references.pmid: 17242137
references.citation: Bioinformatics. 2006 Dec 1;22(23):2926-33
references.pmid: 17000751
references.citation: Clin Cancer Res. 2010 Jan 1;16(1):249-59
references.pmid: 20028755
references.citation: PLoS One. 2012;7(4):e34970
references.pmid: 22529963
references.citation: Nat Rev Immunol. 2005 Oct;5(10):749-59
references.pmid: 16175180
references.citation: Pharmacol Ther. 2008 Mar;117(3):393-405
references.pmid: 18289694
references.citation: Antimicrob Agents Chemother. 1998 Nov;42(11):2817-23
references.pmid: 9797209
references.citation: Infect Immun. 2006 Jan;74(1):125-34
references.pmid: 16368965
references.citation: Antimicrob Agents Chemother. 2004 Feb;48(2):546-55
references.pmid: 14742208
references.citation: J Infect Dis. 1987 Feb;155(2):220-8
references.pmid: 2879873
references.citation: N Engl J Med. 2005 Apr 7;352(14):1445-53
references.pmid: 15814880
references.citation: Antimicrob Agents Chemother. 2008 Jun;52(6):2156-62
references.pmid: 18411321
references.citation: N Engl J Med. 1998 Aug 20;339(8):520-32
references.pmid: 9709046
references.citation: J Infect Dis. 1988 Jul;158(1):23-8
references.pmid: 3292661
references.citation: J Antimicrob Chemother. 2002 Dec;50(6):971-4
references.pmid: 12461019
references.citation: Clin Microbiol Rev. 2005 Jul;18(3):521-40
references.pmid: 16020688
references.citation: J Infect Chemother. 2002 Jun;8(2):194-7
references.pmid: 12111578
references.citation: Blood. 2007 Mar 1;109(5):2066-77
references.pmid: 17105821
references.citation: Infect Immun. 1998 Nov;66(11):5183-9
references.pmid: 9784520
references.citation: Science. 2007 Feb 23;315(5815):1130-3
references.pmid: 17234914
references.citation: Pediatr Infect Dis J. 1999 Dec;18(12):1096-100
references.pmid: 10608632
references.citation: Am J Pathol. 2010 Mar;176(3):1346-54
references.pmid: 20093487
references.citation: Infect Immun. 2005 Feb;73(2):722-9
references.pmid: 15664910
references.citation: Arch Med Res. 2006 Jan;37(1):31-5
references.pmid: 16314183
references.citation: Lancet Infect Dis. 2003 Jun;3(6):359-71
references.pmid: 12781508
references.citation: Endocr Rev. 2008 Oct;29(6):647-76
references.pmid: 18606873
references.citation: Int J Antimicrob Agents. 2008 Jan;31(1):12-20
references.pmid: 17935949
references.citation: Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):358-65
references.pmid: 16778563
references.citation: Clin Microbiol Rev. 2010 Jul;23(3):616-87
references.pmid: 20610826
references.citation: Lancet. 2002 Mar 2;359(9308):753-9
references.pmid: 11888586
references.citation: Int J Antimicrob Agents. 2012 Feb;39(2):96-104
references.pmid: 22196394
references.citation: Annu Rev Microbiol. 2010;64:143-62
references.pmid: 20825344
references.citation: Crit Care Med. 2006 Jun;34(6):1589-96
references.pmid: 16625125
references.citation: EMBO J. 1991 Oct;10(10):2821-32
references.pmid: 1833184
references.citation: PLoS One. 2009 Jul 27;4(7):e6387
references.pmid: 19633710
references.citation: Antimicrob Agents Chemother. 2005 Aug;49(8):3513-6
references.pmid: 16048971
references.citation: Antimicrob Agents Chemother. 2012 Apr;56(4):1744-8
references.pmid: 22290944
references.citation: FASEB J. 2010 Mar;24(3):712-22
references.pmid: 19841036
references.citation: J Infect Chemother. 2000 Mar;6(1):1-7
references.pmid: 11810524
references.citation: Antimicrob Agents Chemother. 1994 Jul;38(7):1523-9
references.pmid: 7979283
references.citation: BMC Genomics. 2010 Nov 27;11:672
references.pmid: 21110886
references.citation: Antimicrob Agents Chemother. 2007 Sep;51(9):3434-6
references.pmid: 17606686
references.citation: Clin Infect Dis. 2006 Mar 1;42(5):729-30
references.pmid: 16447124
references.citation: Clin Microbiol Rev. 2010 Jul;23(3):590-615
references.pmid: 20610825
references.citation: J Bacteriol. 2003 Apr;185(8):2635-43
references.pmid: 12670989
references.citation: J Biol Chem. 1984 Jul 10;259(13):8115-21
references.pmid: 6145712
references.citation: Clin Infect Dis. 2005 Jan 1;40(1):100-7
references.pmid: 15614698
references.citation: J Infect Dis. 2007 Jan 15;195(2):202-11
references.pmid: 17191165
references.citation: J Infect Dis. 2006 Dec 15;194(12):1761-70
references.pmid: 17109350
references.citation: PLoS One. 2009 Oct 19;4(10):e7499
references.pmid: 19838303
references.citation: PLoS Med. 2007 Apr;4(4):e106
references.pmid: 17407386
references.citation: Genome Biol. 2009;10(11):R127
references.pmid: 19903332
references.citation: Am J Pathol. 2008 Dec;173(6):1657-68
references.pmid: 18974303
references.citation: J Antimicrob Chemother. 2002 Nov;50(5):665-72
references.pmid: 12407122
references.citation: Annu Rev Biochem. 2006;75:367-401
references.pmid: 16756496
references.citation: J Infect Dis. 2000 Jan;181(1):176-80
references.pmid: 10608764