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1.
Proc Natl Acad Sci U S A ; 117(47): 29811-29822, 2020 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-33177235

RESUMO

Inflammasomes have been implicated in the detection and clearance of a variety of bacterial pathogens, but little is known about whether this innate sensing mechanism has any regulatory effect on the expression of stimulatory ligands by the pathogen. During infection with Salmonella and many other pathogens, flagellin is a major activator of NLRC4 inflammasome-mediated macrophage pyroptosis and pathogen eradication. Salmonella switches to a flagellin-low phenotype as infection progresses to avoid this mechanism of clearance by the host. However, the host cues that Salmonella perceives to undergo this switch remain unclear. Here, we report an unexpected role of the NLRC4 inflammasome in promoting expression of its microbial ligand, flagellin, and identify a role for type 1 IFN signaling in switching of Salmonella to a flagellin-low phenotype. Early in infection, activation of NLRC4 by flagellin initiates pyroptosis and concomitant release of lysophospholipids which in turn enhance expression of flagellin by Salmonella thereby amplifying its ability to elicit cell death. TRIF-dependent production of type 1 IFN, however, later represses NLRC4 and the lysophospholipid biosynthetic enzyme iPLA2, causing a decline in intracellular lysophospholipids that results in down-regulation of flagellin expression by Salmonella These findings reveal a previously unrecognized immune-modulating regulatory cross-talk between endosomal TLR signaling and cytosolic NLR activation with significant implications for the establishment of infection with Salmonella.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Flagelina/metabolismo , Fosfolipases A2 do Grupo VI/metabolismo , Interferon Tipo I/metabolismo , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação ao Cálcio/genética , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Flagelina/imunologia , Fosfolipases A2 do Grupo VI/antagonistas & inibidores , Humanos , Imunidade Inata , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Cetonas/administração & dosagem , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Lisofosfolipídeos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Naftalenos/administração & dosagem , Cultura Primária de Células , Piroptose/imunologia , Infecções por Salmonella/microbiologia , Salmonella typhimurium/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
2.
PLoS Pathog ; 11(8): e1005083, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26248231

RESUMO

Recurrent urinary tract infections (UTIs) caused by uropathogenic E. coli (UPEC) are common and morbid infections with limited therapeutic options. Previous studies have demonstrated that persistent intracellular infection of bladder epithelial cells (BEC) by UPEC contributes to recurrent UTI in mouse models of infection. However, the mechanisms employed by UPEC to survive within BEC are incompletely understood. In this study we aimed to understand the role of host vesicular trafficking proteins in the intracellular survival of UPEC. Using a cell culture model of intracellular UPEC infection, we found that the small GTPase Rab35 facilitates UPEC survival in UPEC-containing vacuoles (UCV) within BEC. Rab35 plays a role in endosomal recycling of transferrin receptor (TfR), the key protein responsible for transferrin-mediated cellular iron uptake. UPEC enhance the expression of both Rab35 and TfR and recruit these proteins to the UCV, thereby supplying UPEC with the essential nutrient iron. Accordingly, Rab35 or TfR depleted cells showed significantly lower intracellular iron levels and reduced ability to support UPEC survival. In the absence of Rab35, UPEC are preferentially trafficked to degradative lysosomes and killed. Furthermore, in an in vivo murine model of persistent intracellular infection, Rab35 also colocalizes with intracellular UPEC. We propose a model in which UPEC subverts two different vesicular trafficking pathways (endosomal recycling and degradative lysosomal fusion) by modulating Rab35, thereby simultaneously enhancing iron acquisition and avoiding lysosomal degradation of the UCV within bladder epithelial cells. Our findings reveal a novel survival mechanism of intracellular UPEC and suggest a potential avenue for therapeutic intervention against recurrent UTI.


Assuntos
Infecções por Escherichia coli/metabolismo , Interações Hospedeiro-Parasita/fisiologia , Infecções Urinárias/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Acetilcisteína , Animais , Linhagem Celular , Escherichia coli/metabolismo , Feminino , Imunofluorescência , Humanos , Ferro/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Reação em Cadeia da Polimerase , Transporte Proteico/fisiologia , Transfecção , Bexiga Urinária/microbiologia , Infecções Urinárias/microbiologia , Escherichia coli Uropatogênica/metabolismo
3.
Infect Immun ; 82(3): 1112-22, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24366254

RESUMO

Acinetobacter baumannii is a major extensively drug-resistant lethal human nosocomial bacterium. However, the host innate immune mechanisms controlling A. baumannii are not well understood. Although viewed as an extracellular pathogen, A. baumannii can also invade and survive intracellularly. However, whether host innate immune pathways sensing intracellular bacteria contribute to immunity against A. baumannii is not known. Here, we provide evidence for the first time that intracellular antibacterial innate immune receptors Nod1 and Nod2, and their adaptor Rip2, play critical roles in the sensing and clearance of A. baumannii by human airway epithelial cells in vitro. A. baumannii infection upregulated Rip2 expression. Silencing of Nod1, Nod2, and Rip2 expression profoundly increased intracellular invasion and prolonged the multiplication and survival of A. baumannii in lung epithelial cells. Notably, the Nod1/2-Rip2 axis did not contribute to the control of A. baumannii infection of human macrophages, indicating that they play cell type-specific roles. The Nod1/2-Rip2 axis was needed for A. baumannii infection-induced activation of NF-κB but not mitogen-activated protein kinases. Moreover, the Nod1/2-Rip2 axis was critical to induce optimal cytokine and chemokine responses to A. baumannii infection. Mechanistic studies showed that the Nod1/2 pathway contributed to the innate control of A. baumannii infection through the production of ß-defensin 2 by airway epithelial cells. This study revealed new insights into the immune control of A. baumannii and may contribute to the development of effective immune therapeutics and vaccines against A. baumannii.


Assuntos
Infecções por Acinetobacter/imunologia , Acinetobacter baumannii/imunologia , Imunidade Inata/imunologia , Proteína Adaptadora de Sinalização NOD1/genética , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Infecções por Acinetobacter/genética , Infecções por Acinetobacter/microbiologia , Linhagem Celular , Quimiocinas/genética , Quimiocinas/imunologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Células HEK293 , Humanos , Imunidade Inata/genética , Pulmão/imunologia , Pulmão/microbiologia , Macrófagos/imunologia , Macrófagos/microbiologia , NF-kappa B/genética , NF-kappa B/imunologia , Proteína Adaptadora de Sinalização NOD1/imunologia , Proteína Adaptadora de Sinalização NOD2/imunologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Regulação para Cima/genética , Regulação para Cima/imunologia , beta-Defensinas/genética , beta-Defensinas/imunologia
4.
Cureus ; 16(1): e51520, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38304665

RESUMO

Tourette syndrome, characterized by phonic and motor tics, is a neurodevelopmental disorder that significantly affects the quality of life of people with the condition. With over 1500 articles published in the last decade alone, this study aims to analyze the gender trends in publications related to Tourette syndrome from 2013 to 2022, examining the number of female authors as first authors and predicting future changes in female participation. The aim of this study is to analyze the gender trends of the first author in publications related to "Tourette Syndrome" from PubMed-indexed publications from January 2013 to December 2022. A bibliometric analysis was conducted by the search engine PubMed for articles pertaining to "Tourette Syndrome". NamSor app V.2 (Namsor™ Applied Onomastics, NamSor SAS, Versailles, France), an application programming interface (API), was used to identify the gender of the first publishing author. Statistical analysis and graphic models were produced using R software (R Foundation for Statistical Computing, Vienna, Austria), ARIMA (Autoregressive Integrated Moving Average) model, and DataWrapper (Datawrapper GmbH, Berlin Prenzlauer Berg, Germany). Based on the analysis of 1052 publications on Tourette Syndrome, it was found that 54.8% (n=576) of the first authors were females. A significant association was observed between gender ratios and country of publication. Statistical forecasting models suggest that female participation in Tourette research is expected to rise to approximately 60 by the year 2027. Therefore, the study highlights the progress made in achieving gender parity in Tourette syndrome research, with female-led publications being on par with male-led publications. However, there is still a need to address the global gender gap and geographical disparities in research to work towards a more inclusive and diverse academic environment.

5.
Front Immunol ; 11: 514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32269573

RESUMO

Pathogenic Salmonella serovars are a major cause of enteric illness in humans and animals, and produce clinical manifestations ranging from localized gastroenteritis to systemic disease. T cells are a critical component of immunity against this intracellular pathogen. The mechanisms by which Salmonella modulates T-cell-mediated immune responses in order to establish systemic infection are not completely understood. We show that infection of mice with Salmonella enterica serovar Typhimurium (S. Typhimurium) suppresses IL-2 and increases IFN-γ and IL-17 production from T cells activated in vivo or ex vivo through the T cell receptor. Infection with S. Typhimurium brings about recruitment of CD11b+Gr1+ suppressor cells to the spleen. Ex vivo depletion of these cells restores the ability of activated T cells to produce IL-2 and brings secretion of IFN-γ and IL-17 from these cells back to basal levels. The reduction in IL-2 secretion is not seen in IFN-γ-/- and iNOS-/- mice infected with Salmonella. Our findings demonstrate that sustained innate activated IFN-γ production during progression of infection with Salmonella reduces IL-2-secreting capability of T cells through an iNOS-mediated signaling pathway that can adversely affect long term immunity against this pathogen.


Assuntos
Óxido Nítrico Sintase Tipo II/metabolismo , Infecções por Salmonella/imunologia , Salmonella typhimurium/fisiologia , Linfócitos T/imunologia , Animais , Antígenos Ly/metabolismo , Antígeno CD11b/metabolismo , Células Cultivadas , Tolerância Imunológica , Imunidade Inata , Interferon gama/metabolismo , Interleucina-2/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Transdução de Sinais
6.
Sci Rep ; 7(1): 17429, 2017 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-29234083

RESUMO

Acinetobacter baumannii (A. baumannii) is a significant cause of severe nosocomial pneumonia in immunocompromised individuals world-wide. With limited treatment options available, a better understanding of host immnity to A. baumannii infection is critical to devise alternative control strategies. Our previous study has identified that intracellular Nod1/Nod2 signaling pathway is required for the immune control of A. baumannii in airway epithelial cells in vitro. In the current study, using Nod2-/- mice and an in vivo sublethal model of pulmonary infection, we show that Nod2 contributes to the early lung defense against A. baumannii infection through reactive oxygen species (ROS)/reactive nitrogen species (RNS) production as Nod2-/- mice showed significantly reduced production of ROS/RNS in the lungs following A. baumannii infection. Consistent with the higher bacterial load, A. baumannii-induced neutrophil recruitment, cytokine/chemokine response and lung pathology was also exacerbated in Nod2-/- mice at early time points post-infection. Finally, we show that administration of Nod2 ligand muramyl dipeptide (MDP) prior to infection protected the wild- type mice from A. baumannii pulmonary challenge. Collectively, Nod2 is an important player in the early lung immunity against A. baumannii and modulating Nod2 pathway could be considered as a viable therapeutic strategy to control A. baumannii pulmonary infection.


Assuntos
Infecções por Acinetobacter/imunologia , Acinetobacter baumannii/imunologia , Imunidade Inata/fisiologia , Pulmão/imunologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/patologia , Animais , Anti-Infecciosos/farmacologia , Feminino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD2/genética , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
8.
Nat Commun ; 8: 15865, 2017 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-28656966

RESUMO

Optimal regulation of the innate immune receptor nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is essential for controlling bacterial infections and inflammatory disorders. Chronic NOD2 stimulation induces non-responsiveness to restimulation, termed NOD2-induced tolerance. Although the levels of the NOD2 adaptor, RIP2, are reported to regulate both acute and chronic NOD2 signalling, how RIP2 levels are modulated is unclear. Here we show that ZNRF4 induces K48-linked ubiquitination of RIP2 and promotes RIP2 degradation. A fraction of RIP2 localizes to the endoplasmic reticulum (ER), where it interacts with ZNRF4 under either 55 unstimulated and muramyl dipeptide-stimulated conditions. Znrf4 knockdown monocytes have sustained nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and Znrf4 knockdown mice have reduced NOD2-induced tolerance and more effective control of Listeria monocytogenes infection. Our results thus demonstrate E3-ubiquitin ligase ZNRF4-mediated RIP2 degradation as a negative regulatory mechanism of NOD2-induced NF-κB, cytokine and anti-bacterial responses in vitro and in vivo, and identify a ZNRF4-RIP2 axis of fine-tuning NOD2 signalling to promote protective host immunity.


Assuntos
Acetilmuramil-Alanil-Isoglutamina/farmacologia , Proteínas de Ligação a DNA/metabolismo , Tolerância Imunológica , Proteína Adaptadora de Sinalização NOD2/metabolismo , Acetilmuramil-Alanil-Isoglutamina/imunologia , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Células HEK293 , Humanos , Tolerância Imunológica/efeitos dos fármacos , Listeria monocytogenes/patogenicidade , Listeriose/imunologia , Listeriose/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Monócitos/metabolismo , NF-kappa B/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Transdução de Sinais/fisiologia , Ubiquitinação/efeitos dos fármacos
9.
Sci Rep ; 6: 36179, 2016 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-27782195

RESUMO

Type I interferon (IFN-I) mediated innate immune response controls virus infections by inducing the expression of interferon stimulated genes (ISGs). Although ubiquitination plays key roles in immune signaling regulation, a human genome-wide understanding of the role of E3 ubiquitin ligases in interferon mediated ISG induction is lacking. Here, we report a genome-wide profiling of the effect of ectopic expression of 521 E3 ubiquitin ligases and substrate recognition subunits encoded in the human genome (which constitutes 84.4% of all ubiquitination related genes encoded in the human genome, hereafter termed Human Ubiquitome) on IFNß mediated induction of interferon stimulated DNA response element (ISRE) driven reporter activity. We identified 96 and 42 genes of the human ubiquitome as novel negative and positive regulators of interferon signaling respectively. Furthermore, we characterized DCST1 as a novel E3 ubiquitin ligase negatively regulating interferon response. Ectopic expression and gene silencing of DCST1 respectively attenuated and increased ISRE reporter activity. DCST1 regulated Type I interferon signaling by interacting with and promoting ubiquitination-mediated degradation of STAT2, an essential component of antiviral gene induction. In summary, this study provided a systems level view on the role of human ubiquitination associated genes in Type I interferon response.


Assuntos
Interferon Tipo I/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Ubiquitinadas/metabolismo , Biologia Computacional , Genes Reporter , Células HEK293 , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Interferon beta/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT2/metabolismo , Transdução de Sinais , Transcrição Gênica/efeitos dos fármacos , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/genética , Proteínas Ubiquitinadas/genética
10.
Sci Rep ; 6: 25905, 2016 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-27174567

RESUMO

Dissecting the complexities of branched peptide-lipopolysaccharides (LPS) interactions provide rationale for the development of non-cytotoxic antibiotic adjuvants. Using various biophysical methods, we show that the branched peptide, B2088, binds to lipid A and disrupts the supramolecular organization of LPS. The disruption of outer membrane in an intact bacterium was demonstrated by fluorescence spectroscopy and checkerboard assays, the latter confirming strong to moderate synergism between B2088 and various classes of antibiotics. The potency of synergistic combinations of B2088 and antibiotics was further established by time-kill kinetics, mammalian cell culture infections model and in vivo model of bacterial keratitis. Importantly, B2088 did not show any cytotoxicity to corneal epithelial cells for at least 96 h continuous exposure or hemolytic activity even at 20 mg/ml. Peptide congeners containing norvaline, phenylalanine and tyrosine (instead of valine in B2088) displayed better synergism compared to other substitutions. We propose that high affinity and subsequent disruption of the supramolecular assembly of LPS by the branched peptides are vital for the development of non-cytotoxic antibiotic adjuvants that can enhance the accessibility of conventional antibiotics to the intracellular targets, decrease the antibiotic consumption and holds promise in averting antibiotic resistance.


Assuntos
Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Ceratite/tratamento farmacológico , Lipopolissacarídeos/química , Animais , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Carga Bacteriana/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Bactérias Gram-Negativas/metabolismo , Humanos , Ceratite/microbiologia , Lipopolissacarídeos/metabolismo , Camundongos , Simulação de Dinâmica Molecular , Espectrometria de Fluorescência
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