Adjuvant TACE inhibitor treatment improves the outcome of TLR2-/- mice with experimental pneumococcal meningitis.
BACKGROUND
Streptococcus (S.) pneumoniae meningitis has a high lethality despite antibiotic treatment. Inflammation is a major pathogenetic factor, which is unresponsive to antibiotics. Therefore adjunctive therapies with antiinflammatory compounds have been developed. TNF484 is a TNF-alpha converting enzyme (TACE) inhibitor and has been found efficacious in experimental meningitis. Toll-like receptor 2 (TLR2) contributes to host response in pneumococcal meningitis by enhancing bacterial clearing and downmodulating inflammation. In this study, TNF484 was applied in mice, which lacked TLR2 and exhibited a strong meningeal inflammation.


METHODS
103 CFU S. pneumoniae serotype 3 was inoculated subarachnoidally into C57BL/6 wild type (wt) mice or TLR2-/-, CD14-/- and CD14-/-/TLR2-/- mice. Severity of disease and survival was followed over 9 days. Response to antibiotics (80 mg/kg ceftriaxone i.p. for 5 days) and/or TACE inhibitor treatment (1 mg/kg s.c. twice daily for 4 days) was evaluated. Animals were sacrificed after 12, 24, and 48 h for analysis of bacterial load in cerebrospinal fluid (CSF) and brain and for TNF and leukocyte measurements in CSF.


RESULTS
TLR2-/- mice were significantly sicker than the other mouse strains 24 h after infection. All knockout mice showed higher disease severity after 48 h and died earlier than wt mice. TNF release into CSF was significantly more elevated in TLR2-/- than in the other strains after 24 h. Brain bacterial numbers were significantly higher in all knockout than wt mice after 24 h. Modulation of outcome by antibiotic and TACE inhibitor treatment was evaluated. With antibiotic therapy all wt, CD14-/- and TLR2-/-/CD14-/- mice, but only 79% of TLR2-/- mice, were rescued. TACE inhibitor treatment alone did not rescue, but prolonged survival in wt mice, and in TLR2-/- and CD14-/- mice to the values observed in untreated wt mice. By combined antibiotic and TACE inhibitor treatment 95% of TLR2-/- mice were rescued.


CONCLUSIONS
During pneumococcal meningitis strong inflammation in TLR2-deficiency was associated with incomplete responsiveness to antibiotics and complete response to combined antibiotic and TACE inhibitor treatment. TACE inhibitor treatment offers a promising adjuvant therapeutic strategy in pneumococcal meningitis.
Echchannaoui
Hakim
H
Division of Infectious Diseases, Department of Research, University Hospitals, Basel, Switzerland. Hakim.echchannaoui@unibas.ch <Hakim.echchannaoui@unibas.ch>
Leib
Stephen L
SL
Neumann
Ulf
U
Landmann
Regine M A
RM
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002443:Ceftriaxone / Q000494:pharmacology; D017024:Chemotherapy, Adjuvant; D005260:Female; D006877:Hydroxamic Acids / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008297:Male; D008586:Meningitis, Pneumococcal / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011008:Pneumococcal Infections / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000254:growth & development; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000900:Anti-Bacterial Agents; D006877:Hydroxamic Acids; D018950:Lipopolysaccharide Receptors; C455823:N(4)-(2,2-dimethyl-1-methylcarbamoylpropyl)-N(1)-hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)succinamide; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D002443:Ceftriaxone; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse