Resistance of the Brain to Escherichia coli K1 Infection Depends on MyD88 Signaling and the Contribution of Neutrophils and Monocytes

Ribes, Sandra; Regen, Tommy; Meister, Tanja; Tauber, Simone C.; Schütze, Sandra; Mildner, Alexander; Mack, Matthias; Hanisch, Uwe‐Karsten; Nau, Roland

doi:10.1128/iai.01349-12

Cited by 35 publications

(68 citation statements)

References 36 publications

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“…CAE staining confirmed the low amount of infiltrating leukocytes as previously reported [22] and showed no differences between scores in CpG- and buffer-treated animals (median 0.43 (0.16/0.68) versus 0.65 (0.16/1.29), P = 0.5).…”

Section: Resultssupporting

confidence: 88%

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

Ribes

Meister

Ott

et al. 2014

J Neuroinflammation

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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.

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Section: Resultssupporting

confidence: 88%

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

Ribes

Meister

Ott

et al. 2014

J Neuroinflammation

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“…The addition of the B220 marker enabled normalization of cell counts to the B cell population (Fig. 3B), which is not affected by the depletion treatment (44). We confirmed the phenotype of every gated cell population with the CD11b, Ly6C, and Ly6G markers.…”

Section: Neutrophils Are Eliminated From the Circulation Of Eae Mice supporting

confidence: 57%

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Aubé

Lévesque

Paré

et al. 2014

The Journal of Immunology

183

159

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Disruption of the blood–brain and blood–spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP+ myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP+ cells into the CNS and lasted for ∼4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1R type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB.

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“…CD11b + Ly-6G + Ly-6C int granulocytes and CD11b + Ly-6G - Ly-6C high monocytes in the bloodstream were required for the control of intracerebrally injected E. coli K1 (Ribes et al, 2013). Animals that received intraperitoneally an anti-Gr-1 antibody (clone RB6-8C5) showed an earlier and higher mortality than anti-IgG 2b -treated mice (92.3 vs. 11.1%, P = 0.0002).…”

Section: The Efficiency Of Microglia To Prevent Cns Infections Dependmentioning

confidence: 99%

Strategies to increase the activity of microglia as efficient protectors of the brain against infections

Nau

Ribes²,

Djukic

et al. 2014

Front. Cell. Neurosci.

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In healthy individuals, infections of the central nervous system (CNS) are comparatively rare. Based on the ability of microglial cells to phagocytose and kill pathogens and on clinical findings in immunocompromised patients with CNS infections, we hypothesize that an intact microglial function is crucial to protect the brain from infections. Phagocytosis of pathogens by microglial cells can be stimulated by agonists of receptors of the innate immune system. Enhancing this pathway to increase the resistance of the brain to infections entails the risk of inducing collateral damage to the nervous tissue. The diversity of microglial cells opens avenue to selectively stimulate sub-populations responsible for the defence against pathogens without stimulating sub-populations which are responsible for collateral damage to the nervous tissue. Palmitoylethanolamide (PEA), an endogenous lipid, increased phagocytosis of bacteria by microglial cells in vitro without a measurable proinflammatory effect. It was tested clinically apparently without severe side effects. Glatiramer acetate increased phagocytosis of latex beads by microglia and monocytes, and dimethyl fumarate enhanced elimination of human immunodeficiency virus from infected macrophages without inducing a release of proinflammatory compounds. Therefore, the discovery of compounds which stimulate the elimination of pathogens without collateral damage of neuronal structures appears an achievable goal. PEA and, with limitations, glatiramer acetate and dimethyl fumarate appear promising candidates.

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Resistance of the Brain to Escherichia coli K1 Infection Depends on MyD88 Signaling and the Contribution of Neutrophils and Monocytes

Cited by 35 publications

References 36 publications

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

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

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Strategies to increase the activity of microglia as efficient protectors of the brain against infections

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