title: Intrauterine group A streptococcal infections are exacerbated by prostaglandin E2.
abstract: Streptococcus pyogenes (Group A Streptococcus; GAS) is a major cause of severe postpartum sepsis, a re-emerging cause of maternal morbidity and mortality worldwide. Immunological alterations occur during pregnancy to promote maternofetal tolerance, which may increase the risk for puerperal infection. PGE2 is an immunomodulatory lipid that regulates maternofetal tolerance, parturition, and innate immunity. The extent to which PGE2 regulates host immune responses to GAS infections in the context of endometritis is unknown. To address this, both an in vivo mouse intrauterine (i.u.) GAS infection model and an in vitro human macrophage-GAS interaction model were used. In C57BL/6 mice, i.u. GAS inoculation resulted in local and systemic inflammatory responses and triggered extensive changes in the expression of eicosanoid pathway genes. The i.u. administration of PGE2 increased the mortality of infected mice, suppressed local IL-6 and IL-17A levels, enhanced neutrophilic inflammation, reduced uterine macrophage populations, and increased bacterial dissemination. A role for endogenous PGE2 in the modulation of antistreptococcal host defense was suggested, because mice lacking the genes encoding the microsomal PGE2 synthase-1 or the EP2 receptor were protected from death, as were mice treated with the EP4 receptor antagonist, GW627368X. PGE2 also regulated GAS-macrophage interactions. In GAS-infected human THP-1 (macrophage-like) cells, PGE2 inhibited the production of MCP-1 and TNF-α while augmenting IL-10 expression. PGE2 also impaired the phagocytic ability of human placental macrophages, THP-1 cells, and mouse peritoneal macrophages in vitro. Exploring the targeted disruption of PGE2 synthesis and signaling to optimize existing antimicrobial therapies against GAS may be warranted.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Mason
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rogers
authors.forename: Elyara M
authors.initials: EM
authors.lastname: Soares
authors.forename: Tara
authors.initials: T
authors.lastname: Bani-Hashemi
authors.forename: John
authors.initials: J
authors.lastname: Erb Downward
authors.forename: Dalen
authors.initials: D
authors.lastname: Agnew
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
authors.forename: Jason B
authors.initials: JB
authors.lastname: Weinberg
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Crofford
authors.forename: David M
authors.initials: DM
authors.lastname: Aronoff
mesh_terms: D000818:Animals; D002460:Cell Line; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011645:Puerperal Infection / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013290:Streptococcal Infections / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013297:Streptococcus pyogenes; D014599:Uterus / Q000382:microbiology
chemical_list: D015232:Dinoprostone
references.citation: Blood. 2010 Oct 21;116(16):2950-9
references.pmid: 20606163
references.citation: J Investig Med. 2009 Aug;57(6):703-8
references.pmid: 19240648
references.citation: J Exp Med. 2004 Jul 19;200(2):267-72
references.pmid: 15263032
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):9044-9
references.pmid: 12835414
references.citation: J Nutr. 1997 Oct;127(10):1989-92
references.pmid: 9311955
references.citation: J Infect Dis. 2008 Dec 1;198(11):1692-8
references.pmid: 18939933
references.citation: J Immunol. 2013 Feb 15;190(4):1614-22
references.pmid: 23325886
references.citation: Genes Immun. 2007 Jul;8(5):404-15
references.pmid: 17525705
references.citation: PLoS Pathog. 2008 Apr 18;4(4):e1000042
references.pmid: 18421376
references.citation: Am J Obstet Gynecol. 2010 Mar;202(3):308.e1-8
references.pmid: 20207250
references.citation: J Immunol. 2011 Dec 1;187(11):6022-31
references.pmid: 22025550
references.citation: Infect Immun. 2009 Jan;77(1):85-97
references.pmid: 18852237
references.citation: Prostaglandins. 1973 Feb;3(2):223-7
references.pmid: 4729571
references.citation: PLoS Med. 2006 Mar;3(3):e53
references.pmid: 16401174
references.citation: Cell Immunol. 1990 May;127(2):352-67
references.pmid: 2139365
references.citation: Arterioscler Thromb Vasc Biol. 2011 May;31(5):986-1000
references.pmid: 21508345
references.citation: Infect Dis Obstet Gynecol. 2008;2008:796892
references.pmid: 19125207
references.citation: Clin Exp Immunol. 2002 Feb;127(2):263-9
references.pmid: 11876748
references.citation: J R Coll Physicians Edinb. 2011 Dec;41(4):339-46
references.pmid: 22184573
references.citation: J Infect Dis. 2006 Jun 15;193(12):1685-92
references.pmid: 16703512
references.citation: J Immunol. 2007 Oct 15;179(8):5454-61
references.pmid: 17911632
references.citation: J Leukoc Biol. 2000 May;67(5):615-21
references.pmid: 10811000
references.citation: J Leukoc Biol. 2003 Sep;74(3):395-402
references.pmid: 12949243
references.citation: Eur J Immunol. 2007 Apr;37(4):1001-9
references.pmid: 17330822
references.citation: Am J Reprod Immunol. 2010 Jun;63(6):425-33
references.pmid: 20367629
references.citation: Microbes Infect. 2006 Feb;8(2):478-86
references.pmid: 16297651
references.citation: Prostaglandins Other Lipid Mediat. 2012 May;98(1-2):23-30
references.pmid: 22575745
references.citation: Front Biosci. 2007 Jan 01;12:1329-43
references.pmid: 17127385
references.citation: J Cell Mol Med. 2013 Jan;17(1):90-102
references.pmid: 23205502
references.citation: J Immunol. 1997 Jul 1;159(1):28-35
references.pmid: 9200435
references.citation: Infect Immun. 2008 Aug;76(8):3399-404
references.pmid: 18490458
references.citation: J Immunol. 2009 Aug 15;183(4):2642-9
references.pmid: 19635910
references.citation: J Immunol. 2000 Apr 1;164(7):3733-40
references.pmid: 10725732
references.citation: J Immunol. 2010 Jan 15;184(2):677-84
references.pmid: 20018632
references.citation: N Engl J Med. 1987 Jul 16;317(3):146-9
references.pmid: 3299086
references.citation: J Immunol. 2009 Jan 1;182(1):530-7
references.pmid: 19109185
references.citation: J Immunol. 2008 Jun 15;180(12):8222-30
references.pmid: 18523288
references.citation: Infect Immun. 2004 May;72(5):2956-63
references.pmid: 15102808
references.citation: J Leukoc Biol. 1988 Dec;44(6):474-84
references.pmid: 2973508
references.citation: Curr Opin Infect Dis. 2010 Jun;23(3):249-54
references.pmid: 20375891
references.citation: PLoS One. 2010 Jan 13;5(1):e8668
references.pmid: 20084270
references.citation: Mol Microbiol. 2004 Jan;51(1):123-34
references.pmid: 14651616
references.citation: J Immunol. 2004 Jul 1;173(1):559-65
references.pmid: 15210817
references.citation: J Immunol. 2002 Mar 1;168(5):2255-63
references.pmid: 11859113
references.citation: J Immunol. 2006 Oct 15;177(8):5499-508
references.pmid: 17015736
references.citation: J Exp Med. 2009 Jan 16;206(1):61-8
references.pmid: 19124657
references.citation: PLoS One. 2009;4(3):e4902
references.pmid: 19295914
references.citation: Nature. 2012 Oct 4;490(7418):107-11
references.pmid: 22902502
references.citation: Am J Obstet Gynecol. 1987 Mar;156(3):649-55
references.pmid: 3103451
references.citation: J Immunol. 2010 Aug 15;185(4):2372-81
references.pmid: 20644176
references.citation: Pediatrics. 1982 Sep;70(3):343-7
references.pmid: 7050875
references.citation: Infect Immun. 2007 Aug;75(8):4148-57
references.pmid: 17526748
references.citation: FASEB J. 2010 Sep;24(9):3500-10
references.pmid: 20395453
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Clin Infect Dis. 2012 Mar 1;54(5):652-60
references.pmid: 22157172
references.citation: J Matern Fetal Neonatal Med. 2008 Feb;21(2):89-94
references.pmid: 18240075
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1131-8
references.pmid: 16414978
references.citation: Infect Immun. 2000 Jun;68(6):3523-34
references.pmid: 10816507
references.citation: Am J Vet Res. 1992 Sep;53(9):1534-9
references.pmid: 1329587
references.citation: Clin Infect Dis. 2011 Jul 15;53(2):114-23
references.pmid: 21690617
references.citation: J Immunol. 2010 Oct 1;185(7):4328-35
references.pmid: 20810988
references.citation: Am J Reprod Immunol. 2012 Feb;67(2):91-100
references.pmid: 22023345
references.citation: J Immunol. 2005 Nov 15;175(10):6924-30
references.pmid: 16272352
references.citation: J Immunol Methods. 1990 Sep 14;132(2):181-9
references.pmid: 2145368
references.citation: Lancet Infect Dis. 2005 Nov;5(11):685-94
references.pmid: 16253886
references.citation: Am J Reprod Immunol Microbiol. 1986 Dec;12(4):111-7
references.pmid: 2949637