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1.
Nature ; 571(7766): 565-569, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31316206

RESUMO

Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo5-8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1-/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson's disease, which highlights the relevance of the gut-brain axis in the disease10.


Assuntos
Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/fisiopatologia , Intestinos/microbiologia , Doença de Parkinson/genética , Doença de Parkinson/microbiologia , Proteínas Quinases/deficiência , Proteínas Quinases/genética , Animais , Apresentação do Antígeno/imunologia , Autoantígenos/imunologia , Axônios/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Citrobacter rodentium/imunologia , Citrobacter rodentium/patogenicidade , Modelos Animais de Doenças , Neurônios Dopaminérgicos/imunologia , Neurônios Dopaminérgicos/patologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/patologia , Feminino , Intestinos/imunologia , Intestinos/patologia , Levodopa/uso terapêutico , Masculino , Camundongos , Mitocôndrias/imunologia , Mitocôndrias/patologia , Neostriado/imunologia , Neostriado/microbiologia , Neostriado/patologia , Neostriado/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Proteínas Quinases/imunologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
2.
PLoS Pathog ; 15(6): e1007898, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31251784

RESUMO

Attaching/Effacing (A/E) bacteria include human pathogens enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC), and their murine equivalent Citrobacter rodentium (CR), of which EPEC and EHEC are important causative agents of foodborne diseases worldwide. While A/E pathogen infections cause mild symptoms in the immunocompetent hosts, an increasing number of studies show that they produce more severe morbidity and mortality in immunocompromised and/or immunodeficient hosts. However, the pathogenic mechanisms and crucial host-pathogen interactions during A/E pathogen infections under immunocompromised conditions remain elusive. We performed a functional screening by infecting interleukin-22 (IL-22) knockout (Il22-/-) mice with a library of randomly mutated CR strains. Our screen reveals that interruption of the espF gene, which encodes the Type III Secretion System effector EspF (E. coli secreted protein F) conserved among A/E pathogens, completely abolishes the high mortality rates in CR-infected Il22-/- mice. Chromosomal deletion of espF in CR recapitulates the avirulent phenotype without impacting colonization and proliferation of CR, and EspF complement in ΔespF strain fully restores the virulence in mice. Moreover, the expression levels of the espF gene are elevated during CR infection and CR induces disruption of the tight junction (TJ) strands in colonic epithelium in an EspF-dependent manner. Distinct from EspF, chromosomal deletion of other known TJ-damaging effector genes espG and map failed to impede CR virulence in Il22-/- mice. Hence our findings unveil a critical pathophysiological function for EspF during CR infection in the immunocompromised host and provide new insights into the complex pathogenic mechanisms of A/E pathogens.


Assuntos
Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Hospedeiro Imunocomprometido , Mucosa Intestinal/imunologia , Junções Íntimas/imunologia , Animais , Proteínas de Bactérias/genética , Proteínas de Transporte/genética , Linhagem Celular , Citrobacter rodentium/genética , Citrobacter rodentium/patogenicidade , Colo/imunologia , Colo/microbiologia , Colo/patologia , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/patologia , Interleucinas/deficiência , Interleucinas/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Junções Íntimas/genética , Junções Íntimas/patologia
3.
Diagn Microbiol Infect Dis ; 94(3): 287-292, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31005401

RESUMO

This study aimed to assess the prognostic factors of patients with bacteremia due to extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) as well as the antimicrobial susceptibility, particularly to piperacillin/tazobactam (PTZ), among ESBL-PE strains. The medical records of 65 patients with ESBL-PE bacteremia divided into the survivor group (n = 52) and nonsurvivor group (n = 13) were retrospectively reviewed. The male-to-female ratio, age, underlying disease, leukocyte count, C-reactive protein level, and treatment did not differ between the 2 groups. Multivariate analysis showed that the independent predictors associated with hospital mortality of ESBL-PE bacteremia were sepsis (P = 0.047) and febrile neutropenia (P = 0.008); thus, early assessment of these conditions is important. Further, the minimum inhibitory concentration values of ESBL-PE isolates in nonsurvivors tended to be higher than those in survivors. PTZ should be used with caution in cases of ESBL-PE strains with low susceptibility to the drug.


Assuntos
Antibacterianos/farmacologia , Bacteriemia/mortalidade , Farmacorresistência Bacteriana , Infecções por Enterobacteriaceae/mortalidade , Enterobacteriaceae/efeitos dos fármacos , Combinação Piperacilina e Tazobactam/farmacologia , Inibidores de beta-Lactamases/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bacteriemia/microbiologia , Bacteriemia/patologia , Enterobacteriaceae/isolamento & purificação , Enterobacteriaceae/patogenicidade , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida
4.
MBio ; 10(2)2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940698

RESUMO

We used the mouse attaching and effacing (A/E) pathogen Citrobacter rodentium, which models the human A/E pathogens enteropathogenic Escherichia coli and enterohemorrhagic E. coli (EPEC and EHEC), to temporally resolve intestinal epithelial cell (IEC) responses and changes to the microbiome during in vivo infection. We found the host to be unresponsive during the first 3 days postinfection (DPI), when C. rodentium resides in the caecum. In contrast, at 4 DPI, the day of colonic colonization, despite only sporadic adhesion to the apex of the crypt, we observed robust upregulation of cell cycle and DNA repair processes, which were associated with expansion of the crypt Ki67-positive replicative zone, and downregulation of multiple metabolic processes (including the tricarboxylic acid [TCA] cycle and oxidative phosphorylation). Moreover, we observed dramatic depletion of goblet and deep crypt secretory cells and an atypical regulation of cholesterol homeostasis in IECs during early infection, with simultaneous upregulation of cholesterol biogenesis (e.g., 3-hydroxy-3-methylglutaryl-coenzyme A reductase [Hmgcr]), import (e.g., low-density lipoprotein receptor [Ldlr]), and efflux (e.g., AbcA1). We also detected interleukin 22 (IL-22) responses in IECs (e.g., Reg3γ) on the day of colonic colonization, which occurred concomitantly with a bloom of commensal Enterobacteriaceae on the mucosal surface. These results unravel a new paradigm in host-pathogen-microbiome interactions, showing for the first time that sensing a small number of pathogenic bacteria triggers swift intrinsic changes to the IEC composition and function, in tandem with significant changes to the mucosa-associated microbiome, which parallel innate immune responses.IMPORTANCE The mouse pathogen C. rodentium is a widely used model for colonic infection and has been a major tool in fundamental discoveries in the fields of bacterial pathogenesis and mucosal immunology. Despite extensive studies probing acute C. rodentium infection, our understanding of the early stages preceding the infection climax remains relatively undetailed. To this end, we apply a multiomics approach to resolve temporal changes to the host and microbiome during early infection. Unexpectedly, we found immediate and dramatic responses occurring on the day of colonic infection, both in the host intestinal epithelial cells and in the microbiome. Our study suggests changes in cholesterol and carbon metabolism in epithelial cells are instantly induced upon pathogen detection in the colon, corresponding with a shift to primarily facultative anaerobes constituting the microbiome. This study contributes to our knowledge of disease pathogenesis and mechanisms of barrier regulation, which is required for development of novel therapeutics targeting the intestinal epithelium.


Assuntos
Citrobacter rodentium/crescimento & desenvolvimento , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Microbioma Gastrointestinal , Interações Hospedeiro-Patógeno , Mucosa Intestinal/patologia , Animais , Colo/microbiologia , Colo/patologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Fatores de Tempo
5.
Microb Pathog ; 130: 38-43, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30826431

RESUMO

Erwinia persicinus (E. persicina) is a plant pathogenic bacterial species that was previously isolated from a case of human infection. This study aimed to create an experimental infection protocol for E. persicina in laboratory mice. Seventy-two adult mice were divided into four groups (18 animal/group): the control group (G1), the group infected with E. persicina (G2), the group immune-suppressed with cyclophosphamide (G3) and the group immune-suppressed with cyclophosphamide and infected with E. persicina (G4). G2 and G4 were injected with 200 µL of (1 × 1013 cfu/ml) concentration intraperitoneally. Clinical signs, such as diarrhoea, apathy and mortality were observed only in G2 and G4 animals. E. persicina was not detected in blood. Necropsies of the G2 and G4 animals showed lesions in the intestine, liver, kidney and lung tissue. These lesions were characterized by infiltration of inflammatory cells, hyperaemia and focal areas of tissue necrosis in the liver. The results of the pro-inflammatory cytokines analysis revealed a significant increase in the levels of TNF-α and IL1-ß in the liver tissue of the G4 group. E. persicina is an emerging bacterium that can cause pathological lesions into mammalian tissue, which warrants further investigation.


Assuntos
Modelos Animais de Doenças , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Erwinia/crescimento & desenvolvimento , Estruturas Animais/microbiologia , Estruturas Animais/patologia , Animais , Inflamação/patologia , Camundongos , Necrose/patologia
6.
J Exp Med ; 216(1): 84-98, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30563917

RESUMO

Klebsiella pneumoniae, Escherichia coli, and other members of the Enterobacteriaceae family are common human pathogens that have acquired broad antibiotic resistance, rendering infection by some strains virtually untreatable. Enterobacteriaceae are intestinal residents, but generally represent <1% of the adult colonic microbiota. Antibiotic-mediated destruction of the microbiota enables Enterobacteriaceae to expand to high densities in the colon, markedly increasing the risk of bloodstream invasion, sepsis, and death. Here, we demonstrate that an antibiotic-naive microbiota suppresses growth of antibiotic-resistant clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis by acidifying the proximal colon and triggering short chain fatty acid (SCFA)-mediated intracellular acidification. High concentrations of SCFAs and the acidic environment counter the competitive edge that O2 and NO3 respiration confer upon Enterobacteriaceae during expansion. Reestablishment of a microbiota that produces SCFAs enhances clearance of Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis from the intestinal lumen and represents a potential therapeutic approach to enhance clearance of antibiotic-resistant pathogens.


Assuntos
Colo/metabolismo , Farmacorresistência Bacteriana , Infecções por Enterobacteriaceae/metabolismo , Enterobacteriaceae/crescimento & desenvolvimento , Microbioma Gastrointestinal , Animais , Colo/microbiologia , Colo/patologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Ácidos Graxos/metabolismo , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos
7.
Front Immunol ; 9: 2732, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532756

RESUMO

HuR is an abundant RNA-binding protein acting as a post-transcriptional regulator of many RNAs including mRNAs encoding inflammatory mediators, cytokines, death signalers and cell cycle regulators. In the context of intestinal pathologies, elevated HuR is considered to enhance the stability and the translation of pro-tumorigenic mRNAs providing the rationale for its pharmacological targeting. However, HuR also possesses specific regulatory functions for innate immunity and cytokine mRNA control which can oppose intestinal inflammation and tumor promotion. Here, we aim to identify contexts of intestinal inflammation where the innate immune and the epithelial functions of HuR converge or diverge. To address this, we use a disease-oriented phenotypic approach using mice lacking HuR either in intestinal epithelia or myeloid-derived immune compartments. These mice were compared for their responses to (a) Chemically induced Colitis; (b) Colitis- associated Cancer (CAC); (c) T-cell mediated enterotoxicity; (d) Citrobacter rodentium-induced colitis; and (e) TNF-driven inflammatory bowel disease. Convergent functions of epithelial and myeloid HuR included their requirement for suppressing inflammation in chemically induced colitis and their redundancies in chronic TNF-driven IBD and microbiota control. In the other contexts however, their functions diversified. Epithelial HuR was required to protect the epithelial barrier from acute inflammatory or infectious degeneration but also to promote tumor growth. In contrast, myeloid HuR was required to suppress the beneficial inflammation for pathogen clearance and tumor suppression. This cellular dichotomy in HuR's functions was validated further in mice engineered to express ubiquitously higher levels of HuR which displayed diminished pathologic and beneficial inflammatory responses, resistance to epithelial damage yet a heightened susceptibility to CAC. Our study demonstrates that epithelial and myeloid HuR affect different cellular dynamics in the intestine that need to be carefully considered for its pharmacological exploitation and points toward potential windows for harnessing HuR functions in intestinal inflammation.


Assuntos
Citrobacter rodentium/imunologia , Colite/imunologia , Proteína Semelhante a ELAV 1/imunologia , Infecções por Enterobacteriaceae/imunologia , Mucosa Intestinal/imunologia , Animais , Colite/genética , Colite/microbiologia , Colite/patologia , Proteína Semelhante a ELAV 1/genética , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Imunidade Inata , Inflamação/genética , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Transgênicos
8.
Proc Natl Acad Sci U S A ; 115(36): E8469-E8478, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30127026

RESUMO

Inflammatory responses are terminated by the clearance of dead cells, a process termed efferocytosis. A consequence of efferocytosis is the synthesis of the antiinflammatory mediators TGF-ß, PGE2, and IL-10; however, the efferocytosis of infected cells favors Th17 responses by eliciting the synthesis of TGF-ß, IL-6, and IL-23. Recently, we showed that the efferocytosis of apoptotic Escherichia coli-infected macrophages by dendritic cells triggers PGE2 production in addition to pro-Th17 cytokine expression. We therefore examined the role of PGE2 during Th17 differentiation and intestinal pathology. The efferocytosis of apoptotic E. coli-infected cells by dendritic cells promoted high levels of PGE2, which impaired IL-1R expression via the EP4-PKA pathway in T cells and consequently inhibited Th17 differentiation. The outcome of murine intestinal Citrobacter rodentium infection was dependent on the EP4 receptor. Infected mice treated with EP4 antagonist showed enhanced intestinal defense against C. rodentium compared with infected mice treated with vehicle control. Those results suggest that EP4 signaling during infectious colitis could be targeted as a way to enhance Th17 immunity and host defense.


Assuntos
Citrobacter rodentium/imunologia , Colite/imunologia , Células Dendríticas/imunologia , Dinoprostona/imunologia , Infecções por Enterobacteriaceae/imunologia , Intestinos/imunologia , Macrófagos/imunologia , Animais , Colite/microbiologia , Colite/patologia , Células Dendríticas/microbiologia , Células Dendríticas/patologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Feminino , Intestinos/microbiologia , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Receptores de Prostaglandina E Subtipo EP4/imunologia
9.
Cell Host Microbe ; 23(5): 607-617.e6, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29746832

RESUMO

Bacteriophage-encoded genetic elements control bacterial biological functions. Enterohemorrhagic Escherichia coli (EHEC) strains harbor lambda-phages encoding the Shiga-toxin (Stx), which is expressed during the phage lytic cycle and associated with exacerbated disease. Phages also reside dormant within bacterial chromosomes through their lysogenic cycle, but how this impacts EHEC virulence remains unknown. We find that during lysogeny the phage transcription factor Cro activates the EHEC type III secretion system (T3SS). EHEC lambdoid phages are lysogenic under anaerobic conditions when Cro binds to and activates the promoters of T3SS genes. Interestingly, the Cro sequence varies among phages carried by different EHEC outbreak strains, and these changes affect Cro-dependent T3SS regulation. Additionally, infecting mice with the related pathogen C. rodentium harboring the bacteriophage cro from EHEC results in greater T3SS gene expression and enhanced virulence. Collectively, these findings reveal the role of phages in impacting EHEC virulence and their potential to affect outbreak strains.


Assuntos
Colífagos/metabolismo , Escherichia coli Êntero-Hemorrágica/efeitos dos fármacos , Escherichia coli Êntero-Hemorrágica/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Proteínas Repressoras/farmacologia , Proteínas Virais Reguladoras e Acessórias/farmacologia , Fatores de Virulência/genética , Animais , Cromossomos Bacterianos/efeitos dos fármacos , Citrobacter rodentium/patogenicidade , Colífagos/genética , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/metabolismo , Infecções por Enterobacteriaceae/patologia , Escherichia coli Êntero-Hemorrágica/patogenicidade , Escherichia coli Êntero-Hemorrágica/virologia , Escherichia coli/genética , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/genética , Genes Bacterianos/efeitos dos fármacos , Células HeLa , Humanos , Lipídeos , Lisogenia , Camundongos , Camundongos Endogâmicos C3H , Proteínas Repressoras/genética , Toxina Shiga/genética , Fatores de Transcrição , Sistemas de Secreção Tipo III/efeitos dos fármacos , Sistemas de Secreção Tipo III/genética , Sistemas de Secreção Tipo III/metabolismo , Ensaio de Placa Viral , Proteínas Virais Reguladoras e Acessórias/genética , Virulência/efeitos dos fármacos , Virulência/genética
10.
PLoS One ; 13(3): e0194669, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29554143

RESUMO

Edwardsiella ictaluri is a Gram-negative facultative anaerobic rod and the causative agent of enteric septicemia of channel catfish (ESC), which is one of the most prevalent diseases of catfish, causing significant economic losses in the catfish industry. E. ictaluri is resistant to complement system and macrophage killing, which results in rapid systemic septicemia. However, mechanisms of E. ictaluri stress responses under conditions of host environment are not studied well. Therefore, in this work, we report E. ictaluri stress responses during hydrogen peroxide, low pH, and catfish serum stresses as well as during catfish invasion. E. ictaluri stress responses were characterized by identifying expression of 13 universal stress protein (USP) genes (usp01-usp13) and seven USP-interacting protein genes (groEL, groES, dnaK, grpE, and clpB, grpE, relA). Data indicated that three usp genes (usp05, usp07, and usp13) were highly expressed in all stress conditions. Similarly, E. ictaluri heat shock proteins groEL, groES, dnaK, grpE, and clpB were highly expressed in oxidative stress. Also, E. ictaluri grpE and relA were highly expressed in catfish spleen and head kidney. These findings contribute to our understanding of stress response mechanisms in E. ictaluri stress response, and stress-related proteins that are essential for E. ictaluri could be potential targets for live attenuated vaccine development against ESC.


Assuntos
Edwardsiella ictaluri , Infecções por Enterobacteriaceae/genética , Doenças dos Peixes/genética , Ictaluridae/microbiologia , Estresse Fisiológico/genética , Animais , Progressão da Doença , Infecções por Enterobacteriaceae/patologia , Infecções por Enterobacteriaceae/veterinária , Doenças dos Peixes/patologia , Proteínas de Peixes/genética , Proteínas de Choque Térmico/genética , Virulência/genética
11.
BMC Infect Dis ; 18(1): 81, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29439654

RESUMO

BACKGROUND: Human fecal carriage of Enterobacteriaceae possessing mobilized colistin resistance genes (mcr-1 and mcr-2) remains obscure in Hong Kong. As part of routine surveillance on emerging antibiotic resistance, we conducted a prospective study on this topic in a regional hospital in Hong Kong. METHODS: From October 31 to November 25, 2016, all fecal specimens submitted for routine analysis were included in this surveillance study. These comprised 672 consecutive routine fecal specimens collected from 616 individuals. Fecal specimens were screened for colistin-resistant Enterobacteriaceae by culture-based method, and the presence of mcr-1 and mcr-2 genes in resistant isolates was identified by polymerase chain reaction and Sanger sequencing. Whole genome sequencing (WGS) of mcr-1-possessing Escherichia coli strains was facilitated using Illumina® MiSeq® followed by sequence analysis with appropriate bioinformatics tools. RESULTS: Fourteen mcr-1-positive E. coli strains were isolated from 14 separate individuals (2.08% of total fecal specimens), with 9 of them being asymptomatic, healthy clients coming for health assessment. No mcr-2-possessing Enterobacteriaceae was identified. Colistin minimum inhibitory concentrations of these mcr-1-positive isolates ranged from 2 to 4 µg/mL. All these isolates were susceptible to carbapenems with 2 being extended spectrum ß-lactamase producers. WGS data revealed that these isolates belonged to at least 12 different sequence types (STs) and possessed diversified plasmid replicons, virulence and acquired antibiotic resistance genes. Further study on an E. coli ST201 strain (Pasteur scheme) revealed coexistence of 47,818-bp IncP-1 and 33,309-bp IncX4 types of mcr-1 plasmids, which was a combination of stability and high transmissibility. CONCLUSIONS: To the best of our knowledge, this is the first study on human fecal carriage of Enterobacteriaceae possessing mcr-1 and mcr-2 genes in Hong Kong. Our data further revealed asymptomatic carriage of mcr-1-possessing Enterobacteriaceae by both patients and healthy individuals. This is alarming considering wide diversity and high transmissibility of mcr-1 plasmids, which potentially facilitate emergence of pan-drug-resistant bacteria in future infection. This also highlights the importance of surveillance on emerging antibiotic resistance, especially for patients under intensive care.


Assuntos
Proteínas de Bactérias/genética , Citocromo-B(5) Redutase/genética , Infecções por Enterobacteriaceae/patologia , Enterobacteriaceae/genética , Fezes/microbiologia , Adulto , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Criança , Pré-Escolar , Colistina/farmacologia , Citocromo-B(5) Redutase/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Infecções por Enterobacteriaceae/microbiologia , Escherichia coli/genética , Escherichia coli/metabolismo , Hong Kong , Hospitais , Humanos , Lactente , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Plasmídeos/metabolismo , Estudos Prospectivos , Análise de Sequência de DNA , Sequenciamento Completo do Genoma
13.
Dig Dis Sci ; 63(4): 881-889, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29327263

RESUMO

BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the most frequently prescribed medications. Side effects including an increased risk of intestinal infections have been reported. It is assumed that PPIs can increase susceptibility to enteropathogens; however, the underlying mechanisms are unknown. Here in this study, we explored whether Lansoprazole (Laz), one of the PPIs, increases the susceptibility to enteropathogens, and further investigated the mechanism of it. METHODS: Mice were administered Laz intraperitoneally once daily and orally infected with Citrobacter rodentium (C. rodentium). The establishment of intestinal infection was assessed by histology and inflammatory cytokine expression levels measured by quantitative PCR. To test whether Laz changes the intestinal environment to influence the susceptibility, intestinal pH, microbiota, metabolites and immune cell distributions were evaluated via pH measurement, 16S rRNA gene sequencing, metabolome, and flow cytometry analyses after Laz administration. RESULTS: Colitis was induced with less C. rodentium in Laz-treated mice as compared with the controls. We found that increased numbers of C. rodentium could reach the cecum following Laz administration. Laz increased pH in the stomach but not in the intestines. It induced dysbiosis and changed the metabolite content of the small intestine. However, these changes did not lead to alterations of immune cell distribution. CONCLUSIONS: Laz raised susceptibility to C. rodentium as increased numbers of the pathogen reach the site of infection. Our results suggest that it was due to increased stomach pH which allowed more peroral enteropathogens to pass the stomach, but not because of changes of intestinal environment.


Assuntos
Citrobacter rodentium , Colite/microbiologia , Colite/patologia , Infecções por Enterobacteriaceae/etiologia , Lansoprazol/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Animais , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/patologia , Lansoprazol/administração & dosagem , Masculino , Camundongos , Inibidores da Bomba de Prótons/administração & dosagem
14.
Sci Rep ; 8(1): 847, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29339782

RESUMO

Citrobacter rodentium is an intestinal mouse pathogen widely used as a model to study the mucosal response to infection. Inbred mouse strains suffer one of two fates following infection: self-limiting colitis or fatal diarrheal disease. We previously reported that Rspo2 is a major genetic determinant of the outcome of C. rodentium infection; Rspo2 induction during infection of susceptible mice leads to loss of intestinal function and mortality. Rspo2 induction does not impact bacterial colonization, but rather, impedes the ability of the host to tolerate C. rodentium infection. Here, we performed deep RNA sequencing and systematically analyzed the global gene expression profiles of C. rodentium-infected colon tissues from susceptible and resistant congenic mice strains to determine the common responses to infection and the Rspo2-mediated dysfunction pathway signatures associated with loss of disease tolerance. Our results highlight changes in metabolism, tissue remodeling, and host defence as common responses to infection. Conversely, increased Wnt and stem cell signatures, loss of epithelial differentiation, and exaggerated CD4+ T cell activation through increased antigen processing and presentation were specifically associated with the response to infection in susceptible mice. These data provide insights into the molecular mechanisms underlying intestinal dysfunction and disease tolerance during C. rodentium infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citrobacter rodentium/patogenicidade , Mucosa Intestinal/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular , Citrobacter rodentium/isolamento & purificação , Colo/metabolismo , Resistência à Doença , Infecções por Enterobacteriaceae/metabolismo , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Interleucina-17/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Análise de Componente Principal , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo , Trombospondinas/genética , Trombospondinas/metabolismo , Transcriptoma , Fator de Necrose Tumoral alfa/metabolismo
15.
Cell Microbiol ; 20(1)2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29024267

RESUMO

Bacterium usually utilises type III secretion systems (T3SS) to deliver effectors directly into host cells with the aids of chaperones. Hence, it is very important to identify bacterial T3SS effectors and chaperones for better understanding of host-pathogen interactions. Edwardsiella piscicida is an invasive enteric bacterium, which infects a wide range of hosts from fish to human. Given E. piscicida encodes a functional T3SS to promote infection, very few T3SS effectors and chaperones have been identified in this bacterium so far. Here, we reported that EseK is a new T3SS effector protein translocated by E. piscicida. Bioinformatic analysis indicated that escH and escS encode two putative class I T3SS chaperones. Further investigation indicated that EscH and EscS can enhance the secretion and translocation of EseK. EscH directly binds EseK through undetermined binding domains, whereas EscS binds EseK via its N-terminal α-helix. We also found that EseK has an N-terminal chaperone-binding domain, which binds EscH and EscS to form a ternary complex. Zebrafish infection experiments showed that EseK and its chaperones EscH and EscS are necessary for bacterial colonisation in zebrafish. This work identified a new T3SS effector, EseK, and its two T3SS chaperones, EscH and EscS, in E. piscicida, which enriches our knowledge of bacterial T3SS effector-chaperone interaction and contributes to our understanding of bacterial pathogenesis.


Assuntos
Proteínas de Bactérias/metabolismo , Edwardsiella/patogenicidade , Sistemas de Secreção Tipo III/metabolismo , Fatores de Virulência/metabolismo , Animais , Linhagem Celular Tumoral , Edwardsiella/metabolismo , Edwardsiella tarda/classificação , Infecções por Enterobacteriaceae/patologia , Doenças dos Peixes/microbiologia , Células HeLa , Interações Hospedeiro-Patógeno , Humanos , Chaperonas Moleculares/metabolismo , Ligação Proteica , Fatores de Virulência/genética , Peixe-Zebra
16.
Microb Drug Resist ; 24(3): 307-313, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28876168

RESUMO

A plasmid pCY-CTX carrying a phage-like backbone from an extensively drug-resistant Enterobacter cloacae strain Guangzhou-ECL001 (previously known as CY01) was identified in this study. By Illumina MiSeq 2 × 250-bp paired-end sequencing, de novo assembly, and PCR, full sequence of pCY-CTX was obtained. Plasmid pCY-CTX was a circular plasmid with a length of 116,700 bp, harboring 136 putative open reading frames with the average G + C content of 50.8%. The backbone of pCY-CTX showed high identity to previously reported phage-like plasmid pHCM2 and phage SSU5. In addition, pCY-CTX contained a distinctive ISEcp1-mediated Tn2 region with two resistance genes blaTEM-1 and blaCTX-M-3. Transposition unit "ISEcp1- blaCTX-M-3- orf477" was inserted into the Tn2 structure, dividing Tn2 into two parts. This represents the first identification of a plasmid carrying a phage-like backbone and a distinctive ISEcp1-mediated Tn2 region within blaTEM-1 and blaCTX-M-3 in clinical E. cloacae. The finding of phage-like regions located in plasmids provides a new perspective in gene transfer associated with antimicrobial resistance.


Assuntos
Elementos de DNA Transponíveis , Farmacorresistência Bacteriana Múltipla/genética , Enterobacter cloacae/genética , Genoma Bacteriano , Plasmídeos/química , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Bacteriófagos/genética , Conjugação Genética , Enterobacter cloacae/classificação , Enterobacter cloacae/efeitos dos fármacos , Enterobacter cloacae/isolamento & purificação , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Feminino , Humanos , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/patologia , Testes de Sensibilidade Microbiana , Mapeamento de Nucleotídeos , Plasmídeos/metabolismo , Doenças Renais Policísticas/microbiologia , Doenças Renais Policísticas/patologia , Análise de Sequência de DNA , Sequenciamento Completo do Genoma
17.
J Infect Public Health ; 11(1): 130-132, 2018 Jan - Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28433493
18.
Dis Aquat Organ ; 127(1): 41-47, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29256426

RESUMO

A 5 yr old, 184 kg, and 262 cm total length female bottlenose dolphin Tursiops truncatus was found dead in a display after bloody discharge from the blowhole was observed 3 h prior to death. Pathological examination revealed fibrinous bronchopneumonia with prominent areas of necrosis (sequestra) and numerous Gram-negative bacilli within alveoli and in blood vessels of the lungs and liver and between muscle fibers. The cause of death was attributed to septicemia. Often, cases of fibrinous bronchopneumonia are characterized by bacteremia in the latter stages of infection, resulting in the death of the animal. Septicemia likely accounts for the ecchymoses and petechiae noted on the spleen, pancreas, forestomach, lungs, visceral peritoneum, and small intestine. Additional lesions included hemothorax, stable red frothy fluid in the trachea, and lymphoid depletion in the spleen and lymph nodes. Pure growth of Morganella morganii was isolated from the lungs, blood, liver, and blowhole mucosa. Sequencing of 16s rRNA of the isolated bacteria showed more than 99.6% identity with M. morganii strain FDAARGOS_172. To our knowledge, this is the first report of fatal fibrinonecrotizing bronchopneumonia associated with M. morganii infection in a cetacean.


Assuntos
Golfinho Nariz-de-Garrafa , Broncopneumonia/veterinária , Infecções por Enterobacteriaceae/veterinária , Morganella morganii/isolamento & purificação , Animais , Broncopneumonia/microbiologia , Broncopneumonia/patologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Evolução Fatal , Feminino
19.
Vet Res Commun ; 41(4): 289-297, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29119302

RESUMO

This study demonstrates the feasibility of using goldfish as an infection model to investigate the pathogenesis of Edwardsiella piscicida. Goldfish were found to be susceptible to acute E. piscicida-induced disease and died in a dose-dependent manner. E. piscicida was further shown to replicate rapidly in the head kidneys and livers of infected goldfish from 1 d post-injection, and bacteria numbers were significantly decreased 5 d post-injection. Immune responses were successfully induced in goldfish injected with E. piscicida strains and 60% of goldfish inoculated with an attenuated E. piscicida strain were found to survive subsequent injection with a pathogenic strain. The results of differential leukocyte count experiments suggested that leukocytes were immediately recruited as an innate immune response against the infection. Thus, this well-characterized goldfish species is a suitable infection model for studying E. piscicida pathogenesis, and might be applicable to research on other fish diseases.


Assuntos
Infecções por Enterobacteriaceae/veterinária , Doenças dos Peixes/imunologia , Doenças dos Peixes/patologia , Carpa Dourada , Imunidade Inata/imunologia , Animais , Vacinas Bacterianas/imunologia , Modelos Animais de Doenças , Edwardsiella/imunologia , Edwardsiella/fisiologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/patologia , Contagem de Leucócitos , Vacinas Atenuadas/imunologia
20.
Nat Commun ; 8(1): 24, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28634323

RESUMO

Neuroinflammation caused by local deposits of Aß42 in the brain is key for the pathogenesis and progression of Alzheimer's disease. However, inflammation in the brain is not always a response to local primary insults. Gut microbiota dysbiosis, which is recently emerging as a risk factor for psychiatric disorders, can also initiate a brain inflammatory response. It still remains unclear however, whether enteric dysbiosis also contributes to Alzheimer's disease. Here we show that in a Drosophila Alzheimer's disease model, enterobacteria infection exacerbated progression of Alzheimer's disease by promoting immune hemocyte recruitment to the brain, thereby provoking TNF-JNK mediated neurodegeneration. Genetic depletion of hemocytes attenuates neuroinflammation and alleviated neurodegeneration. We further found that enteric infection increases the motility of the hemocytes, making them more readily attracted to the brain with an elevated oxidative stress status. This work highlights the importance of gut-brain crosstalk as a fundamental regulatory system in modulating Alzheimer's disease neurodegeneration.Emerging evidence suggests that gut microbiota influences immune function in the brain and may play a role in neurological diseases. Here, the authors offer in vivo evidence from a Drosophila model that supports a role for gut microbiota in modulating the progression of Alzheimer's disease.


Assuntos
Doença de Alzheimer/microbiologia , Encéfalo/microbiologia , Drosophila melanogaster/microbiologia , Disbiose/microbiologia , Infecções por Enterobacteriaceae/microbiologia , Trato Gastrointestinal/microbiologia , Doença de Alzheimer/complicações , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Movimento Celular/imunologia , Modelos Animais de Doenças , Progressão da Doença , Proteínas de Drosophila/genética , Proteínas de Drosophila/imunologia , Drosophila melanogaster/imunologia , Disbiose/complicações , Disbiose/imunologia , Disbiose/patologia , Enterobacteriaceae/crescimento & desenvolvimento , Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/complicações , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/patologia , Trato Gastrointestinal/imunologia , Regulação da Expressão Gênica , Hemócitos/imunologia , Hemócitos/microbiologia , Hemócitos/patologia , Humanos , Procedimentos de Redução de Leucócitos , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/imunologia , Microbiota/imunologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
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