title: Brucella abortus induces the secretion of proinflammatory mediators from glial cells leading to astrocyte apoptosis.
abstract: Central nervous system (CNS) invasion by bacteria of the genus Brucella results in an inflammatory disorder called neurobrucellosis. In this study we present in vivo and in vitro evidence that B. abortus and its lipoproteins activate the innate immunity of the CNS, eliciting an inflammatory response that leads to astrogliosis, a characteristic feature of neurobrucellosis. Intracranial injection of heat-killed B. abortus (HKBA) or outer membrane protein 19 (Omp19), a B. abortus lipoprotein model, induced astrogliosis in mouse striatum. Moreover, infection of astrocytes and microglia with B. abortus induced the secretion of interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, macrophage chemoattractant protein-1, and KC (CXCL1). HKBA also induced these inflammatory mediators, suggesting the involvement of a structural component of the bacterium. Accordingly, Omp19 induced the same cytokine and chemokine secretion pattern. B. abortus infection induced astrocyte, but not microglia, apoptosis. Indeed, HKBA and Omp19 elicited not only astrocyte apoptosis but also proliferation, two features observed during astrogliosis. Apoptosis induced by HKBA and L-Omp19 was completely suppressed in cells of TNF receptor p55-/- mice or when the general caspase inhibitor Z-VAD-FMK was added to cultures. Hence, TNF-alpha signaling via TNF receptor (TNFR) 1 through the coupling of caspases determines apoptosis. Our results provide proof of the principle that Brucella lipoproteins could be key virulence factors in neurobrucellosis and that astrogliosis might contribute to neurobrucellosis pathogenesis.
authors.affiliation: Instituto de Estudios de la Inmunidad Humoral (IDEHU), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires. Junín 956 4 Piso. (1113) Buenos Aires, Argentina.
authors.forename: Clara
authors.initials: C
authors.lastname: García Samartino
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Delpino
authors.forename: Clara
authors.initials: C
authors.lastname: Pott Godoy
authors.forename: María Silvia
authors.initials: MS
authors.lastname: Di Genaro
authors.forename: Karina A
authors.initials: KA
authors.lastname: Pasquevich
authors.forename: Astrid
authors.initials: A
authors.lastname: Zwerdling
authors.forename: Paula
authors.initials: P
authors.lastname: Barrionuevo
authors.forename: Patricia
authors.initials: P
authors.lastname: Mathieu
authors.forename: Juliana
authors.initials: J
authors.lastname: Cassataro
authors.forename: Fernando
authors.initials: F
authors.lastname: Pitossi
authors.forename: Guillermo H
authors.initials: GH
authors.lastname: Giambartolomei
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D001425:Bacterial Outer Membrane Proteins / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D002003:Brucella abortus / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D005260:Female; D006358:Hot Temperature; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D018925:Chemokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008074:Lipoproteins; C097319:OMP19 protein, Brucella abortus; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases