Administration of capsule-selective endosialidase E minimizes upregulation of organ gene expression induced by experimental systemic infection with Escherichia coli K1.
Many neurotropic strains of Escherichia coli cause potentially lethal bacteraemia and meningitis in newborn infants by virtue of their capacity to elaborate the protective polysialic acid (polySia) K1 capsule. Recombinant capsule depolymerase, endosialidase E (endoE), selectively removes polySia from the bacterial surface; when administered intraperitoneally to infected neonatal rats, the enzyme interrupts the transit of E. coli K1 from gut to brain via the blood circulation and prevents death from systemic infection. We now show that experimental E. coli K1 infection is accompanied by extensive modulation of host gene expression in the liver, spleen and brain tissues of neonatal rats. Bacterial invasion of the brain resulted in a threefold or greater upregulation of approximately 400 genes, a large number of which were associated with the induction of inflammation and the immune and stress responses: these included genes encoding C-X-C and C-C chemokines, lipocalins, cytokines, apolipoproteins and enzymes involved in the synthesis of low-molecular-mass inflammatory mediators. Administration of a single dose of endoE, 24 h after initiation of systemic infection, markedly reduced, but did not completely abrogate, these changes in gene expression, suggesting that attenuation of E. coli K1 virulence by removal of the polySia capsule may minimize the attendant inflammatory processes that contribute to poor outcome in these severe systemic infections.
Zelmer
Andrea
A
School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
Martin
Melissa J
MJ
London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
Gundogdu
Ozan
O
London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
Birchenough
George
G
School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
Lever
Rebecca
R
School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
Wren
Brendan W
BW
London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
Luzio
J Paul
JP
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
Taylor
Peter W
PW
School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
D000818:Animals; D016667:Bacterial Capsules / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000401:mortality; D015870:Gene Expression; D006801:Humans; D009439:Neuraminidase / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012794:Sialic Acids / Q000378:metabolism; D015854:Up-Regulation; D014774:Virulence
D012794:Sialic Acids; C021319:polysialic acid; C035355:endo-N-acetylneuraminidase; D009439:Neuraminidase
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