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Role of Neutrophils and Innate Immune Mechanisms in Urinary Tract Infections

Frendéus, Björn LU (2001)
Abstract (Swedish)
Popular Abstract in Swedish

Hur börjar en infektion och vad avgör vem som drabbas? Hur ser den sjukdomsframkallande bakterien ut, och hur försvarar vi oss mot dess angrepp? Vi studerar dessa frågor med urinvägsinfektioner som modell.



De flesta urinvägsinfektioner orsakas av E. coli bakterier med speciella ytstrukturer som de använder för att angripa slemhinnan i urinvägarna. Genom sin starka förmåga att binda till epitelceller i urinvägarnas slemhinnor kan bakterierna angripa olika delar av urinvägarna, till exempel urinblåsan eller njurbäckenet. Vidhäftningen tillåter bakterierna att hålla sig kvar och sprida sig till nya infektionsställen, men är också viktig för det direkta angreppet på mukosan som... (More)
Popular Abstract in Swedish

Hur börjar en infektion och vad avgör vem som drabbas? Hur ser den sjukdomsframkallande bakterien ut, och hur försvarar vi oss mot dess angrepp? Vi studerar dessa frågor med urinvägsinfektioner som modell.



De flesta urinvägsinfektioner orsakas av E. coli bakterier med speciella ytstrukturer som de använder för att angripa slemhinnan i urinvägarna. Genom sin starka förmåga att binda till epitelceller i urinvägarnas slemhinnor kan bakterierna angripa olika delar av urinvägarna, till exempel urinblåsan eller njurbäckenet. Vidhäftningen tillåter bakterierna att hålla sig kvar och sprida sig till nya infektionsställen, men är också viktig för det direkta angreppet på mukosan som leder till sjukdom.



De E. coli som sprider sig till njurarna orsakar pyelonefrit (njurbäcken-inflammation). De bär på sin yta så kallade P fimbrier, som binder till särskilda socker-strukturer (receptorer) på epitelcellerna. I denna avhandling visas hur P fimbrierna aktiverar inflammation. Detta har tidigare varit oklart, eftersom receptorerna endast är fästa i cellmembranets yttre del och därmed inte direkt kan leda en signal in i cellen. Vi visar nu att P fimbrierna aktiverar inflammation med en s.k. hjälp-receptor, (Toll-like receptor 4, TLR4). Genom att först fästa vid till sockerreceptorerna och sedan aktivera TLR4 stimulerar de P fimbrierade bakterierna ett mukosa svar som leder till inflammation.



P fimbrierade E. coli aktiverar epitelcellerna att producera inflammatoriska proteiner. En undergrupp av dessa kallas kemokiner, och har till uppgift att rekrytera kroppens försvarsceller till den infekterade mukosan. Tidigare studier har visat att kemokinet interleukin-8 (IL-8) produceras av epitelcellerna vid UVI, och signalerar till neutrofila granulocyter (en viss sorts blodkroppar) att vandra till infektionsplatsen. Våra studier visar att IL-8 och de receptorer som IL-8 binder till på både neutrofier och epitelceller är nödvändiga för att neutrofilerna skall ta sig igenom mukosan och hitta bakterierna. (Less)
Abstract
Urinary tract infections (UTI) are among the most common infections in man. Despite their prevalence, information on the molecular mechanisms defects that explain the increased susceptibility to disease are lacking. This study focused on mucosal inflammation and the molecular mechanisms by which uropathogenic Escherichia coli activate this response.



P fimbriae are expressed by most E. coli strains that cause acute pyelonephritis. By binding to Gala1-4Galb containing motifs in the globoseries of glycosphingolipids P fimbriae trigger inflammatory responses that underlie disease pathology. P fimbriae were shown here to utilize the Toll-like receptor 4 (TLR4) pathway to activate inflammation. P fimbriated E. coli induced a... (More)
Urinary tract infections (UTI) are among the most common infections in man. Despite their prevalence, information on the molecular mechanisms defects that explain the increased susceptibility to disease are lacking. This study focused on mucosal inflammation and the molecular mechanisms by which uropathogenic Escherichia coli activate this response.



P fimbriae are expressed by most E. coli strains that cause acute pyelonephritis. By binding to Gala1-4Galb containing motifs in the globoseries of glycosphingolipids P fimbriae trigger inflammatory responses that underlie disease pathology. P fimbriae were shown here to utilize the Toll-like receptor 4 (TLR4) pathway to activate inflammation. P fimbriated E. coli induced a strong inflammatory response in TLR4+ mice, but not in TLR4- mice. In contrast to previously described activation of TLR4, the P fimbriae induced signal was independent of the LPS/LBP/CD14 pathway.



The TLR4 deficiency was shown to impair resistance to UTI through an effect on neutrophil recruitment. Uropathogenic E. coli induced a rapid and strong neutrophil recruitment in TLR4+ mice, but only a weak response in TLR4- mice. TLR4+ mice cleared infection, while in TLR4- mice bacterial numbers increased with time. Neutrophil depletion converted the TLR4+ mice to the TLR4- susceptible phenotype.



Neutrophil recruitment was shown to depend on IL-8 and IL-8 receptors. In vitro neutrophil transepithelial migration was blocked by antibodies to the interleukin-8 receptor CXCR1, and neutrophils of IL-8R knockout mice failed to cross the urinary tract epithelium and accumulated in subepithelial tissue compartments. mIL-8Rh knock-out mice failed to clear infection, developed symptoms of disease, and showed evidence of renal scarring. Subsequent studies showed that children prone to acute pyelonephritis have decreased neutrophil CXCR1 expression. The results suggest that TLR and CXCR expression determine neutrophil recruitment to the infected urinary tract, and suggest that a CXCR1 deficiency might underlie increased susceptibility to acute pyelonephritis. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Professor Sansonetti, Philippe
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Mikrobiologi, mycology, virology, bacteriology, Microbiology, Mucosal immunology, Infection Resistance, Neutrophils, Toll-like receptors, Urinary Tract Infections, Chemokine receptors, bakteriologi, virologi, mykologi
pages
159 pages
defense location
Rune Grubb salen, Sölvegatan 21, Lund
defense date
2001-03-10 10:15
external identifiers
  • other:ISRN: LUMED/MEMG-0100-SE
ISBN
91-628-4665-5
language
English
LU publication?
yes
id
843df7be-21cd-4819-8613-8de0f1062531 (old id 41383)
date added to LUP
2007-06-20 16:01:45
date last changed
2016-09-19 08:45:16
@phdthesis{843df7be-21cd-4819-8613-8de0f1062531,
  abstract     = {Urinary tract infections (UTI) are among the most common infections in man. Despite their prevalence, information on the molecular mechanisms defects that explain the increased susceptibility to disease are lacking. This study focused on mucosal inflammation and the molecular mechanisms by which uropathogenic Escherichia coli activate this response.<br/><br>
<br/><br>
P fimbriae are expressed by most E. coli strains that cause acute pyelonephritis. By binding to Gala1-4Galb containing motifs in the globoseries of glycosphingolipids P fimbriae trigger inflammatory responses that underlie disease pathology. P fimbriae were shown here to utilize the Toll-like receptor 4 (TLR4) pathway to activate inflammation. P fimbriated E. coli induced a strong inflammatory response in TLR4+ mice, but not in TLR4- mice. In contrast to previously described activation of TLR4, the P fimbriae induced signal was independent of the LPS/LBP/CD14 pathway.<br/><br>
<br/><br>
The TLR4 deficiency was shown to impair resistance to UTI through an effect on neutrophil recruitment. Uropathogenic E. coli induced a rapid and strong neutrophil recruitment in TLR4+ mice, but only a weak response in TLR4- mice. TLR4+ mice cleared infection, while in TLR4- mice bacterial numbers increased with time. Neutrophil depletion converted the TLR4+ mice to the TLR4- susceptible phenotype.<br/><br>
<br/><br>
Neutrophil recruitment was shown to depend on IL-8 and IL-8 receptors. In vitro neutrophil transepithelial migration was blocked by antibodies to the interleukin-8 receptor CXCR1, and neutrophils of IL-8R knockout mice failed to cross the urinary tract epithelium and accumulated in subepithelial tissue compartments. mIL-8Rh knock-out mice failed to clear infection, developed symptoms of disease, and showed evidence of renal scarring. Subsequent studies showed that children prone to acute pyelonephritis have decreased neutrophil CXCR1 expression. The results suggest that TLR and CXCR expression determine neutrophil recruitment to the infected urinary tract, and suggest that a CXCR1 deficiency might underlie increased susceptibility to acute pyelonephritis.},
  author       = {Frendéus, Björn},
  isbn         = {91-628-4665-5},
  keyword      = {Mikrobiologi,mycology,virology,bacteriology,Microbiology,Mucosal immunology,Infection Resistance,Neutrophils,Toll-like receptors,Urinary Tract Infections,Chemokine receptors,bakteriologi,virologi,mykologi},
  language     = {eng},
  pages        = {159},
  school       = {Lund University},
  title        = {Role of Neutrophils and Innate Immune Mechanisms in Urinary Tract Infections},
  year         = {2001},
}