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1.
Infect Immun ; 79(6): 2489-98, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21444667

RESUMO

Intracellular bacterial pathogens manipulate host cell functions by producing enzymes that stimulate or antagonize signal transduction. The Listeria monocytogenes genome contains a gene, lmo1800, encoding a protein with a conserved motif of conventional tyrosine phosphatases. Here, we report that the lmo1800-encoded protein LipA is secreted by Listeria and displays tyrosine as well as lipid phosphatase activity in vitro. Bacteria lacking LipA are severely attenuated in virulence in vivo, thus revealing a so-far-undescribed enzymatic activity involved in Listeria infection.


Assuntos
Proteínas de Bactérias/fisiologia , Listeria monocytogenes/patogenicidade , Listeriose/microbiologia , Fatores de Virulência/fisiologia , Animais , Western Blotting , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Técnica de Placa Hemolítica , Listeria monocytogenes/enzimologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Tirosina Fosfatases/fisiologia
2.
PLoS Pathog ; 5(3): e1000355, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19325882

RESUMO

Production of type I interferons (IFN-I, mainly IFNalpha and IFNbeta) is a hallmark of innate immune responses to all classes of pathogens. When viral infection spreads to lymphoid organs, the majority of systemic IFN-I is produced by a specialized "interferon-producing cell" (IPC) that has been shown to belong to the lineage of plasmacytoid dendritic cells (pDC). It is unclear whether production of systemic IFN-I is generally attributable to pDC irrespective of the nature of the infecting pathogen. We have addressed this question by studying infections of mice with the intracellular bacterium Listeria monocytogenes. Protective innate immunity against this pathogen is weakened by IFN-I activity. In mice infected with L. monocytogenes, systemic IFN-I was amplified via IFN-beta, the IFN-I receptor (IFNAR), and transcription factor interferon regulatory factor 7 (IRF7), a molecular circuitry usually characteristic of non-pDC producers. Synthesis of serum IFN-I did not require TLR9. In contrast, in vitro-differentiated pDC infected with L. monocytogenes needed TLR9 to transcribe IFN-I mRNA. Consistent with the assumption that pDC are not the producers of systemic IFN-I, conditional ablation of the IFN-I receptor in mice showed that most systemic IFN-I is produced by myeloid cells. Furthermore, results obtained with FACS-purified splenic cell populations from infected mice confirmed the assumption that a cell type with surface antigens characteristic of macrophages and not of pDC is responsible for bulk IFN-I synthesis. The amount of IFN-I produced in the investigated mouse lines was inversely correlated to the resistance to lethal infection. Based on these data, we propose that the engagement of pDC, the mode of IFN-I mobilization, as well as the shaping of the antimicrobial innate immune response by IFN-I differ between intracellular pathogens.


Assuntos
Interferon Tipo I/biossíntese , Listeriose/imunologia , Macrófagos/imunologia , Animais , Antígenos CD/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Citometria de Fluxo , Fator Regulador 7 de Interferon/imunologia , Interferon Tipo I/imunologia , Interferon beta/imunologia , Listeria monocytogenes/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/citologia , Baço/imunologia , Receptor Toll-Like 9/imunologia , Receptor Toll-Like 9/metabolismo
3.
Cell Microbiol ; 10(5): 1116-29, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18182083

RESUMO

Type I IFN (IFN-I) increase the sensitivity of cells and mice to lethal infection with Listeria monocytogenes. Therefore the amount of IFN-I produced during infection might be an important factor determining Listeria virulence. Two commonly used strains of L. monocytogenes, EGD and LO28, were identified as, respectively, low and high inducers of IFN-I synthesis in infected macrophages. Increased IFN-I production resulted from the stronger ability of the LO28 strain to trigger the IRF3 signalling pathway and correlated with an increased sensitization of macrophages to lethal infection. In contrast, stimulation of NFkappaB, MAPK, or inflammasome signalling by the LO28 and EGD strains did not differ significantly. The LO28 strain was more virulent in wild-type (wt) C57/BL6 mice than the EGD strain whereas both strains were similarly virulent in IFN-I receptor-deficient C57/BL6 mice. Together our data suggest that isolates of wt L. monocytogenes differ in their ability to trigger the IRF3 signalling pathway and IFN-I production, and that the amount of IFN-I produced during infection is an important determinant of Listeria virulence.


Assuntos
Interferon beta/metabolismo , Listeria monocytogenes/patogenicidade , Animais , Toxinas Bacterianas/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas Hemolisinas/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/genética , Listeria monocytogenes/metabolismo , Listeriose/microbiologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Receptor de Interferon alfa e beta/genética , Transdução de Sinais , Especificidade da Espécie , Virulência
4.
PLoS One ; 8(3): e60476, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23544144

RESUMO

In this study we investigated the role of Bruton's tyrosine kinase (Btk) in the immune response to the Gram-positive intracellular bacterium Listeria monocytogenes (Lm). In response to Lm infection, Btk was activated in bone marrow-derived macrophages (BMMs) and Btk (-/-) BMMs showed enhanced TNF-α, IL-6 and IL-12p40 secretion, while type I interferons were produced at levels similar to wild-type (wt) BMMs. Although Btk-deficient BMMs displayed reduced phagocytosis of E. coli fragments, there was no difference between wt and Btk (-/-) BMMs in the uptake of Lm upon infection. Moreover, there was no difference in the response to heat-killed Lm between wt and Btk (-/-) BMMs, suggesting a role for Btk in signaling pathways that are induced by intracellular Lm. Finally, Btk (-/-) mice displayed enhanced resistance and an increased mean survival time upon Lm infection in comparison to wt mice. This correlated with elevated IFN-γ and IL-12p70 serum levels in Btk (-/-) mice at day 1 after infection. Taken together, our data suggest an important regulatory role for Btk in macrophages during Lm infection.


Assuntos
Listeria monocytogenes/fisiologia , Listeriose/enzimologia , Listeriose/microbiologia , Macrófagos/enzimologia , Macrófagos/microbiologia , Proteínas Tirosina Quinases/metabolismo , Tirosina Quinase da Agamaglobulinemia , Animais , Células da Medula Óssea/patologia , Citocinas/biossíntese , Suscetibilidade a Doenças , Ativação Enzimática/efeitos dos fármacos , Immunoblotting , Lipopeptídeos/farmacologia , Listeria monocytogenes/efeitos dos fármacos , Listeriose/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Fagocitose/efeitos dos fármacos , Fagossomos/efeitos dos fármacos , Fagossomos/microbiologia , Proteínas Tirosina Quinases/deficiência
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