title: Resistance of the brain to Escherichia coli K1 infection depends on MyD88 signaling and the contribution of neutrophils and monocytes.
abstract: Escherichia coli is the leading cause of Gram-negative neonatal bacterial meningitis and also causes meningitis and meningoencephalitis in older and immunocompromised patients. Here, we determined the contribution of granulocytes, monocytes, and TLR signaling cascades in the resistance of adult mice to Escherichia coli K1 brain infection. Deficiency in MyD88 (myd88(-/-)) but not in TRIF (trif(lps2)) adaptor proteins dramatically reduced the survival of animals. Depletion of CD11b(+) Ly-6G(+) Ly-6C(int) neutrophils by application of the anti-Ly-6G (1A8) monoclonal antibody (MAb) led to higher bacterial loads in cerebellum and spleen tissue and resulted in increased mortality compared to those of isotype-treated controls. Depletion of CD11b(+) Ly-6G(+) Ly-6C(int) neutrophils and CD11b(+) Ly-6G(-) Ly-6C(high) monocytes by administration of the anti-Gr-1 (RB6-8C5) MAb rendered mice even more susceptible to the infection, with higher central nervous system (CNS) and spleen bacterial burdens than anti-Ly-6G-treated animals. Depletion of ∼50% of CD11b(+) Ly-6G(-) Ly-6C(high) monocytes by injection of the anti-CCR2 (MC-21) MAb resulted in a trend toward higher mortality compared to that with isotype treatment. Production of interleukin 1β (IL-1β), IL-6, KC, and MIP-2 in the CNS strongly depended on the bacterial load: increased levels of these cytokines/chemokines were found after depletion of CD11b(+) Ly-6G(+) Ly-6C(int) neutrophils alone or together with CD11b(+) Ly-6G(-) Ly-6C(high) monocytes. These findings identify Toll-like receptor (TLR)-MyD88 signaling and neutrophil and monocyte activity as critical elements in the early host defense against E. coli meningitis.
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany. sandragottingen@gmail.com
authors.forename: Sandra
authors.initials: S
authors.lastname: Ribes
authors.forename: Tommy
authors.initials: T
authors.lastname: Regen
authors.forename: Tanja
authors.initials: T
authors.lastname: Meister
authors.forename: Simone C
authors.initials: SC
authors.lastname: Tauber
authors.forename: Sandra
authors.initials: S
authors.lastname: Schütze
authors.forename: Alexander
authors.initials: A
authors.lastname: Mildner
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.forename: Uwe-Karsten
authors.initials: UK
authors.lastname: Hanisch
authors.forename: Roland
authors.initials: R
authors.lastname: Nau
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000818:Animals; D001921:Brain / Q000276:immunology*; D018925:Chemokines / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000472:pathogenicity*; D006098:Granulocytes / Q000276:immunology; D007113:Immunity, Innate / Q000502:physiology; D020814:Meningitis, Escherichia coli / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology; D009000:Monocytes / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D009504:Neutrophils / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018925:Chemokines; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse