Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection.
BACKGROUND
Prophylaxis with unmethylated cytosine phosphate guanidine (CpG) oligodeoxynucleotides (ODN) protects against several systemic experimental infections. Escherichia coli is a major cause of Gram-negative neonatal bacterial meningitis and also causes meningitis and meningoencephalitis in older and immunocompromised patients.


METHODS
Wild-type (wt) and Toll-like receptor 9 (TLR9)-deficient mice were rendered neutropenic by intraperitoneal administration of the anti-Ly-6G monoclonal antibody. Immunocompetent and neutropenic mice received intraperitoneal CpG ODN or vehicle 72 h prior to induction of E. coli K1 meningoencephalitis.


RESULTS
Pre-treatment with CpG ODN significantly increased survival of neutropenic wt mice from 33% to 75% (P = 0.0003) but did not protect neutropenic TLR9-/- mice. The protective effect of CpG ODN was associated with an enhanced production of interleukin (IL)-12/IL-23p40 with sustained increased levels in serum and spleen at least for 17 days after conditioning compared to buffer-treated animals. CpG-treated neutropenic wt mice showed reduced bacterial concentrations and increased recruitment of Ly6ChighCCR2+ monocytes in brain and spleen 42 h after infection. The levels of macrophage inflammatory protein 1α (MIP-1α) and interferon gamma (IFN-γ) in spleen were higher 42 h after infection in CpG-treated compared to buffer-treated neutropenic animals. In immunocompetent mice, prophylaxis with CpG ODN did not significantly increase survival compared to the buffer group (60% vs. 45%, P = 0.2).


CONCLUSIONS
These findings suggest that systemic administration of CpG ODN may help to prevent bacterial CNS infections in immunocompromised individuals.
Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany. sandragottingen@gmail.com.
Sandra
S
Ribes
Tanja
T
Meister
Martina
M
Ott
Sandra
S
Redlich
Hana
H
Janova
Uwe-Karsten
UK
Hanisch
Stefan
S
Nessler
Roland
R
Nau
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004926:Escherichia coli / Q000502:physiology; D004927:Escherichia coli Infections / Q000517:prevention & control*; D005434:Flow Cytometry; D019791:Guanidine / Q000737:chemistry*; D008590:Meningoencephalitis / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000172:deficiency
D015703:Antigens, CD; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D019791:Guanidine