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Proinflammatory activation of Toll-like receptor-2 during exposure of penicillin-resistant Streptococcus pneumoniae to beta-lactam antibiotics

Proinflammatory activation of Toll-like receptor-2 during exposure of penicillin-resistant Streptococcus pneumoniae to beta-lactam antibiotics
Proinflammatory activation of Toll-like receptor-2 during exposure of penicillin-resistant Streptococcus pneumoniae to beta-lactam antibiotics

OBJECTIVES: Disease caused by penicillin-resistant Streptococcus pneumoniae (PRSP) is associated with more suppurative complications than disease caused by penicillin-susceptible S. pneumoniae (PSSP). Exposure of S. pneumoniae to beta-lactam antibiotics enhances the proinflammatory activation of human cells by pneumococci via Toll-like receptor-2 (TLR2). To test the hypothesis that penicillin resistance influences cellular TLR2 activation by beta-lactam-exposed pneumococci, we compared TLR2 induction by PSSP (MIC 0.06 mg/L) and a high-level PRSP clinical isolate (159; MIC 16 mg/L) following exposure to penicillin and cefotaxime.

METHODS: Both organisms were treated with penicillin or cefotaxime at and around the MIC. TLR2 signalling was measured as relative IL-8 promoter activation in transfected HeLa cells.

RESULTS: On exposure to penicillin, log-phase PSSP and PRSP induced TLR2-proinflammatory activation at levels significantly higher than unexposed bacteria, and maximal in each case at the MIC. Transformants containing low-affinity penicillin-binding proteins (PBP) 2x, 1a and 2b exhibited stepwise resistance to cefotaxime and penicillin. TLR2 activation following penicillin treatment was dependent on an abnormal cell wall (PBP1a and 2x) and autolysis (PBP2b). High affinity PBP2x was required for this effect to be observed in log-phase pneumococci exposed to cefotaxime at the MIC. Cefotaxime-mediated TLR2 activation was not observed in lag-phase transformants exposed to sub-lethal concentrations.

CONCLUSIONS: These data show that PRSP have similar TLR2-proinflammatory effects to PSSP when exposed to beta-lactam antibiotics but the antibiotic concentration relative to the MIC is critical. This has implications for treatment of pneumococcal disease when tissue concentrations of antibiotic are close to the MIC.

Anti-Bacterial Agents, Cefotaxime, HeLa Cells, Humans, Lipopolysaccharide Receptors, Microbial Sensitivity Tests, Penicillin Resistance, Penicillin-Binding Proteins, Penicillins, Streptococcus pneumoniae, Toll-Like Receptor 2, beta-Lactams, Journal Article, Research Support, Non-U.S. Gov't
0305-7453
35-42
Moore, Lisa J.
13095db5-12ee-47f4-ae09-b1deca4881d3
Gilbey, Andrea M.
74fae8ef-5eec-440a-9a64-6bc5988bcf49
Dowson, Christopher G.
2d7d6f39-96da-4927-bea4-e25e80146b55
Pridmore, Alison C.
b704c202-afcc-4fde-9169-48e51f9fa0b0
Dower, Steven K.
c59b6ed1-57d4-49cb-815c-038a96601ecc
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Moore, Lisa J.
13095db5-12ee-47f4-ae09-b1deca4881d3
Gilbey, Andrea M.
74fae8ef-5eec-440a-9a64-6bc5988bcf49
Dowson, Christopher G.
2d7d6f39-96da-4927-bea4-e25e80146b55
Pridmore, Alison C.
b704c202-afcc-4fde-9169-48e51f9fa0b0
Dower, Steven K.
c59b6ed1-57d4-49cb-815c-038a96601ecc
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51

Moore, Lisa J., Gilbey, Andrea M., Dowson, Christopher G., Pridmore, Alison C., Dower, Steven K. and Read, Robert C. (2007) Proinflammatory activation of Toll-like receptor-2 during exposure of penicillin-resistant Streptococcus pneumoniae to beta-lactam antibiotics. Journal of Antimicrobial Chemotherapy, 59 (1), 35-42. (doi:10.1093/jac/dkl442).

Record type: Article

Abstract

OBJECTIVES: Disease caused by penicillin-resistant Streptococcus pneumoniae (PRSP) is associated with more suppurative complications than disease caused by penicillin-susceptible S. pneumoniae (PSSP). Exposure of S. pneumoniae to beta-lactam antibiotics enhances the proinflammatory activation of human cells by pneumococci via Toll-like receptor-2 (TLR2). To test the hypothesis that penicillin resistance influences cellular TLR2 activation by beta-lactam-exposed pneumococci, we compared TLR2 induction by PSSP (MIC 0.06 mg/L) and a high-level PRSP clinical isolate (159; MIC 16 mg/L) following exposure to penicillin and cefotaxime.

METHODS: Both organisms were treated with penicillin or cefotaxime at and around the MIC. TLR2 signalling was measured as relative IL-8 promoter activation in transfected HeLa cells.

RESULTS: On exposure to penicillin, log-phase PSSP and PRSP induced TLR2-proinflammatory activation at levels significantly higher than unexposed bacteria, and maximal in each case at the MIC. Transformants containing low-affinity penicillin-binding proteins (PBP) 2x, 1a and 2b exhibited stepwise resistance to cefotaxime and penicillin. TLR2 activation following penicillin treatment was dependent on an abnormal cell wall (PBP1a and 2x) and autolysis (PBP2b). High affinity PBP2x was required for this effect to be observed in log-phase pneumococci exposed to cefotaxime at the MIC. Cefotaxime-mediated TLR2 activation was not observed in lag-phase transformants exposed to sub-lethal concentrations.

CONCLUSIONS: These data show that PRSP have similar TLR2-proinflammatory effects to PSSP when exposed to beta-lactam antibiotics but the antibiotic concentration relative to the MIC is critical. This has implications for treatment of pneumococcal disease when tissue concentrations of antibiotic are close to the MIC.

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More information

Accepted/In Press date: 4 October 2006
e-pub ahead of print date: 1 November 2006
Published date: January 2007
Keywords: Anti-Bacterial Agents, Cefotaxime, HeLa Cells, Humans, Lipopolysaccharide Receptors, Microbial Sensitivity Tests, Penicillin Resistance, Penicillin-Binding Proteins, Penicillins, Streptococcus pneumoniae, Toll-Like Receptor 2, beta-Lactams, Journal Article, Research Support, Non-U.S. Gov't

Identifiers

Local EPrints ID: 416315
URI: https://eprints.soton.ac.uk/id/eprint/416315
ISSN: 0305-7453
PURE UUID: c36a4eea-1dac-4166-8c29-10f81933adfb
ORCID for Robert C. Read: ORCID iD orcid.org/0000-0002-4297-6728

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Date deposited: 12 Dec 2017 17:30
Last modified: 14 Mar 2019 01:36

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Contributors

Author: Lisa J. Moore
Author: Andrea M. Gilbey
Author: Christopher G. Dowson
Author: Alison C. Pridmore
Author: Steven K. Dower
Author: Robert C. Read ORCID iD

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