Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces.
The epithelial surfaces of the upper respiratory tract are continuously exposed to a wide variety of commensal microorganisms. In addition to acting as a physical barrier, epithelial cells respond to specific microbial products with the generation of signals, such as cytokines, that trigger inflammation. Because they are common components of the nasopharyngeal flora that share the potential to cause disease, we investigated the effects of Haemophilus influenzae and Streptococcus pneumoniae, alone and in combination, on human respiratory epithelial cells in culture and in a murine model of nasopharyngeal colonization. Exposure of A549 or Detroit 562 epithelial cells to both S. pneumoniae and H. influenzae led to a synergistic increase in production of IL-8, the major neutrophil chemokine in the airway, through an NF-kappaB-dependent mechanism. Likewise, nasal cocolonization of mice caused a synergistic rise in local production of macrophage inflammatory protein 2 in nasal lavage fluid and subsequent recruitment of neutrophils. This synergistic effect depended on production of the pore-forming cytolytic toxin, pneumolysin, by S. pneumoniae and activation of host p38 mitogen-activated protein kinase. Although both H. influenzae and S. pneumoniae have ligands for Toll-like receptors (TLRs) TLR2 and TLR4, synergistic activation was TLR2- and TLR4-independent. Thus, epithelial surfaces are capable of amplifying proinflammatory responses during concurrent stimulation by multiple microbial species. These synergistic responses, demonstrated both in vitro and in vivo, may contribute to inflammation of heavily colonized mucosal barriers.
Ratner
Adam J
AJ
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Lysenko
Elena S
ES
Paul
Marina N
MN
Weiser
Jeffrey N
JN
D015153:Blotting, Western; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000382:microbiology*; D006193:Haemophilus influenzae / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000382:microbiology*; D012137:Respiratory System / Q000382:microbiology*; D013296:Streptococcus pneumoniae / Q000302:isolation & purification / Q000502:physiology
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1966-71
12569171
Infect Immun. 2003 Oct;71(10):5523-30
14500470
J Leukoc Biol. 2002 Nov;72(5):847-55
12429706
Science. 2000 Sep 1;289(5484):1560-3
10968793
Am J Physiol Lung Cell Mol Physiol. 2004 Jul;287(1):L143-52
15047567
J Exp Med. 1944 Feb 1;79(2):137-58
19871359
J Infect Dis. 2000 Apr;181(4):1330-6
10762564
Nat Immunol. 2004 Nov;5(11):1166-74
15489856
Infect Immun. 2003 Feb;71(2):850-6
12540566
Infect Immun. 1989 Jul;57(7):2037-42
2731982
J Immunol. 2004 Mar 1;172(5):3132-8
14978119
Science. 2003 Jun 6;300(5625):1584-7
12791997
Infect Immun. 1991 Jul;59(7):2297-304
2050399
J Immunol. 2003 Jan 1;170(1):438-44
12496429
J Infect Dis. 1993 Feb;167(2):464-8
8421183
Infect Immun. 2000 Aug;68(8):4430-40
10899840
Microb Drug Resist. 2003 Spring;9(1):99-108
12705689
Immunity. 1999 Oct;11(4):443-51
10549626
J Immunol. 1999 Jul 1;163(1):1-5
10384090
Pediatr Infect Dis J. 1997 Nov;16(11):1060-4
9384340
J Biol Chem. 2002 Jan 11;277(2):949-57
11698399
J Immunol. 2002 Jan 15;168(2):810-5
11777976
J Infect Dis. 1994 Dec;170(6):1532-8
7995993
Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3563-8
14993593
J Exp Med. 2003 Aug 18;198(4):521-31
12925671
Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8774-9
11438700
Mol Microbiol. 2000 Jan;35(1):234-45
10632893
J Immunol. 2001 Aug 15;167(4):1882-5
11489966
J Clin Invest. 1995 Nov;96(5):2204-10
7593606
J Clin Invest. 1998 Jun 1;101(11):2598-605
9616231
J Infect Dis. 2001 Oct 1;184(7):926-30
11528597
Exp Lung Res. 1991 Jan-Feb;17(1):17-23
2013270
Am J Respir Cell Mol Biol. 1991 Nov;5(5):416-23
1834101
Science. 2002 Nov 8;298(5596):1241-5
12424381
Infect Immun. 2004 Feb;72(2):1204-9
14742577
Cell. 2001 Jan 12;104(1):143-52
11163247
J Pediatr. 1993 Apr;122(4):517-23
8463894
J Exp Med. 2002 Feb 4;195(3):359-65
11828011
J Infect Dis. 2002 Aug 1;186(3):361-71
12134232
Science. 2003 Mar 28;299(5615):2076-9
12637671
J Exp Med. 1998 Dec 7;188(11):2091-7
9841923
J Bacteriol. 2001 Jun;183(12):3770-83
11371542
J Biol Chem. 2003 May 2;278(18):15587-94
12594207