Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection

Abstract

BackgroundProphylaxis 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.MethodsWild-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.ResultsPre-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).ConclusionsThese findings suggest that systemic administration of CpG ODN may help to prevent bacterial CNS infections in immunocompromised individuals.

Inhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation

“…Cell-surface nucleolin is the receptor for a 26-mer DNA oligonucleotide (Soundararajan et al, 2009), which is around the same size as the commercial CpGs used in this study. Furthermore, nucleolin mediates the uptake of~8,000-kDa DNA nanoparticles (Chen et al, 2008), which are slightly larger than CpG DNA (Ribes et al, 2014). Collectively, previous reports create a plausible rationale for the importance of cell-surface nucleolin for internalization of immunogenic DNA.…”

“…The function of nucleolin in the heart is poorly understood, but it is up-regulated at the mRNA and protein level in human heart failure (Rosello-Lleti et al, 2012). Furthermore, nucleolin mediates the uptake of~8,000-kDa DNA nanoparticles (Chen et al, 2008), which are slightly larger than CpG DNA (Ribes et al, 2014). Among others, nucleolin is important for the attachment of HIV-1 to the cell surface of CD4+ T cells (Said et al, 2002) and is required for internalization of human parainfluenza virus type 3 to airway epithelial cells (Bose, Basu, & Banerjee, 2004).…”

Trained immunity: A program of innate immune memory in health and disease

“…For example, trained immunity induced by β-glucan (a polysaccharide component of mainly fungal cell walls) induces protection against infection with Staphylococcus aureus (15, 16). Similarly, the peptidoglycan component muramyl dipeptide induces protection against Toxoplasma (17), and prophylactic treatment with TLR9 agonists such as oligodeoxynucleotides containing unmethylated CpG dinucleotides three days before the infection protects against sepsis and Escherichia coli meningitis (18). Furthermore, flagellin can induce protection against S. pneumonia (19) and rotavirus (20), the latter being independent of adaptive immunity and induced by dendritic cell-derived interleukin (IL)-18, which in turn drives production of IL-22 by epithelial cells.…”

Bacterial meningitis: an update of new treatment options

“…In an E. coli mouse meningitis model, pre-treatment with the TLR9 agonist CpG ODN (an oligonucleotide containing an unmethylated cytosine next to a guanine nucleotide) 72 h before infection increased the survival of neutropenic mice from 33 to 75% (p = 0.0003). The protective effect of CpG ODN was associated with an enhanced production of IL-12/ IL-23p40 and an increased recruitment of monocytes in brain and spleen [230].…”