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1.
J Microbiol Immunol Infect ; 53(4): 652-656, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32527700

RESUMO

A 63-year-old diabetic smoker with alcoholism was the first mortality case of coronavirus disease 2019 (COVID-19) in Taiwan. As concurrently infected with Klebsiella pneumoniae and subsequently with Klebsiella aerogenes, he was exposed by a national survey of patients with critically influenza-negative pneumonia. We recommend COVID-19 screening for patients with severe flu-like syndrome and protecting health-care workers from being infected.


Assuntos
Coinfecção , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Infecções por Enterobacteriaceae/diagnóstico , Infecções por Enterobacteriaceae/terapia , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Betacoronavirus , Coinfecção/microbiologia , Coinfecção/virologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Cuidados Críticos , Estado Terminal , Infecções por Enterobacteriaceae/patologia , Infecções por Enterobacteriaceae/fisiopatologia , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Taiwan
2.
PLoS Pathog ; 16(5): e1008553, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453761

RESUMO

IRGM and its mouse orthologue Irgm1 are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing, and pathogen immunity. IRGM dysfunction is linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility to Citrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria. Irgm1-deficient mice fail to control C. rodentium outgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing of C. rodentium or exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response to C. rodentium infection and are essential for C. rodentium immunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced by C. rodentium infection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction.


Assuntos
Citrobacter rodentium/imunologia , Colo/imunologia , Infecções por Enterobacteriaceae/imunologia , Proteínas de Ligação ao GTP/deficiência , Doenças Inflamatórias Intestinais/imunologia , Monócitos/imunologia , Animais , Colo/microbiologia , Colo/patologia , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/patologia , Proteínas de Ligação ao GTP/imunologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Camundongos , Camundongos Knockout , Monócitos/microbiologia , Monócitos/patologia , Membrana Mucosa/imunologia , Membrana Mucosa/microbiologia , Membrana Mucosa/patologia
3.
Nat Immunol ; 21(6): 626-635, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424362

RESUMO

The inflammasome NLRP6 plays a crucial role in regulating inflammation and host defense against microorganisms in the intestine. However, the molecular mechanisms by which NLRP6 function is inhibited to prevent excessive inflammation remain unclear. Here, we demonstrate that the deubiquitinase Cyld prevents excessive interleukin 18 (IL-18) production in the colonic mucosa by deubiquitinating NLRP6. We show that deubiquitination inhibited the NLRP6-ASC inflammasome complex and regulated the maturation of IL-18. Cyld deficiency in mice resulted in elevated levels of active IL-18 and severe colonic inflammation following Citrobacter rodentium infection. Further, in patients with ulcerative colitis, the concentration of active IL-18 was inversely correlated with CYLD expression. Thus, we have identified a novel regulatory mechanism that inhibits the NLRP6-IL-18 pathway in intestinal inflammation.


Assuntos
Enzima Desubiquitinante CYLD/metabolismo , Enterocolite/etiologia , Enterocolite/metabolismo , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Citrobacter rodentium , Enzima Desubiquitinante CYLD/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/metabolismo , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Enterocolite/patologia , Expressão Gênica , Humanos , Interleucina-18/antagonistas & inibidores , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Ligação Proteica/imunologia , Ubiquitinação
4.
mBio ; 11(1)2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964739

RESUMO

Shigella species cause diarrheal disease globally. Shigellosis is typically characterized by bloody stools and colitis with mucosal damage and is the leading bacterial cause of diarrheal death worldwide. After the pathogen is orally ingested, it invades and replicates within the colonic epithelium through mechanisms that rely on its type III secretion system (T3SS). Currently, oral infection-based small animal models to study the pathogenesis of shigellosis are lacking. Here, we found that orogastric inoculation of infant rabbits with Shigella flexneri resulted in diarrhea and colonic pathology resembling that found in human shigellosis. Fasting animals prior to S. flexneri inoculation increased the frequency of disease. The pathogen colonized the colon, where both luminal and intraepithelial foci were observed. The intraepithelial foci likely arise through S. flexneri spreading from cell to cell. Robust S. flexneri intestinal colonization, invasion of the colonic epithelium, and epithelial sloughing all required the T3SS as well as IcsA, a factor required for bacterial spreading and adhesion in vitro Expression of the proinflammatory chemokine interleukin 8 (IL-8), detected with in situ mRNA labeling, was higher in animals infected with wild-type S. flexneri versus mutant strains deficient in icsA or T3SS, suggesting that epithelial invasion promotes expression of this chemokine. Collectively, our findings suggest that oral infection of infant rabbits offers a useful experimental model for studies of the pathogenesis of shigellosis and for testing of new therapeutics.IMPORTANCE Shigella species are the leading bacterial cause of diarrheal death globally. The pathogen causes bacillary dysentery, a bloody diarrheal disease characterized by damage to the colonic mucosa and is usually spread through the fecal-oral route. Small animal models of shigellosis that rely on the oral route of infection are lacking. Here, we found that orogastric inoculation of infant rabbits with S. flexneri led to a diarrheal disease and colonic pathology reminiscent of human shigellosis. Diarrhea, intestinal colonization, and pathology in this model were dependent on the S. flexneri type III secretion system and IcsA, canonical Shigella virulence factors. Thus, oral infection of infant rabbits offers a feasible model to study the pathogenesis of shigellosis and to develop and test new therapeutics.


Assuntos
Infecções por Enterobacteriaceae/microbiologia , Interações Hospedeiro-Patógeno , Shigella/fisiologia , Animais , Biópsia , Diarreia/microbiologia , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/patologia , Infecções por Enterobacteriaceae/transmissão , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Coelhos
5.
J Exp Med ; 217(2)2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31699824

RESUMO

Although innate lymphoid cells (ILCs) functionally analogous to T helper type 1 (Th1), Th2, and Th17 cells are well characterized, an ILC subset strictly equivalent to IL-10-secreting regulatory T cells has only recently been proposed. Here, we report the absence of an intestinal regulatory ILC population distinct from group 1 ILCs (ILC1s), ILC2s, and ILC3s in (1) mice bred in our animal facility; (2) mice from The Jackson Laboratory, Taconic Biosciences, and Charles River Laboratories; and (3) mice subjected to intestinal inflammation. Instead, a low percentage of intestinal ILC2s produced IL-10 at steady state. A screen for putative IL-10 elicitors revealed that IL-2, IL-4, IL-27, IL-10, and neuromedin U (NMU) increased IL-10 production in activated intestinal ILC2s, while TL1A suppressed IL-10 production. Secreted IL-10 further induced IL-10 production in ILC2s through a positive feedback loop. In summary, ILC2s provide an inducible source of IL-10 in the gastrointestinal tract, whereas ILCregs are not a generalizable immune cell population in mice.


Assuntos
Imunidade Inata , Interleucina-10/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/patologia , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Citrobacter rodentium , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Retroalimentação Fisiológica , Feminino , Genes Reporter , Proteínas de Fluorescência Verde/genética , Interleucina-10/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo
6.
Microb Pathog ; 135: 103620, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31310833

RESUMO

NDM-1-producing Enterobacteriaceae are multidrug-resistant bacteria, also called superbacteria, that have become important global human health threats in recent years. However, data about NDM-1-producing bacteria in animals are rare. In this study, an NDM-1-producing Escherichia coli isolate (designated E120413) was obtained from pigs in Henan province, China in 2012. The susceptibility of E. coli E120413 to antimicrobial agents was determined using Kirby-Bauer disk diffusion and micro-dilution methods. Susceptibility tests indicated that E. coli E120413 was resistant to almost all common antibiotics with high MIC values obtained for most antibiotics tested. E. coli E120413 was detected in the heart, liver, spleen, lung, kidney, brain, stomach, duodenum, mesenteric lymph nodes, and fecal samples of piglets in both cohabitation and experimental groups and the bacteria persisted for more than 2 weeks. However, no obvious clinical symptoms or serious pathological lesions were observed. This is the first investigation of NDM-1-producing E. coli isolate from pigs in China. Although no significant pathological lesions were observed, NDM-1-producing E. coli was found to be highly transmissible and to cause persistent infection in pigs.


Assuntos
Infecções por Enterobacteriaceae/microbiologia , Escherichia coli/enzimologia , Escherichia coli/isolamento & purificação , Suínos/microbiologia , beta-Lactamases/biossíntese , Animais , Antibacterianos/farmacologia , China , Modelos Animais de Doenças , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Infecções por Enterobacteriaceae/patologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Fezes/microbiologia , Testes de Sensibilidade Microbiana , Virulência , beta-Lactamases/genética
7.
Clin Microbiol Rev ; 32(4)2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31315895

RESUMO

The genus Enterobacter is a member of the ESKAPE group, which contains the major resistant bacterial pathogens. First described in 1960, this group member has proven to be more complex as a result of the exponential evolution of phenotypic and genotypic methods. Today, 22 species belong to the Enterobacter genus. These species are described in the environment and have been reported as opportunistic pathogens in plants, animals, and humans. The pathogenicity/virulence of this bacterium remains rather unclear due to the limited amount of work performed to date in this field. In contrast, its resistance against antibacterial agents has been extensively studied. In the face of antibiotic treatment, it is able to manage different mechanisms of resistance via various local and global regulator genes and the modulation of the expression of different proteins, including enzymes (ß-lactamases, etc.) or membrane transporters, such as porins and efflux pumps. During various hospital outbreaks, the Enterobacter aerogenes and E. cloacae complex exhibited a multidrug-resistant phenotype, which has stimulated questions about the role of cascade regulation in the emergence of these well-adapted clones.


Assuntos
Enterobacter/classificação , Enterobacter/efeitos dos fármacos , Infecções por Enterobacteriaceae/microbiologia , Animais , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/genética , Enterobacter/patogenicidade , Infecções por Enterobacteriaceae/patologia , Humanos
8.
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
10.
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
11.
Wilderness Environ Med ; 30(3): 291-294, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31221600

RESUMO

Although catfish are found worldwide and commonly consumed in the southern United States, fatal infections from catfish are rare. Edwardsiella tarda is a bacterium known to cause gastrointestinal distress most commonly, but extraintestinal infections are a rarely considered danger for those acquiring, preparing, and consuming aquatic animals. Susceptible to all gram-negative active antibiotics, it is easily treated except in immunocompromised hosts, such as those with malignancy, diabetes, and hepatic dysfunction.


Assuntos
Mordeduras e Picadas/terapia , Peixes-Gato/microbiologia , Edwardsiella tarda/isolamento & purificação , Infecções por Enterobacteriaceae/diagnóstico , Animais , Mordeduras e Picadas/microbiologia , Infecções por Enterobacteriaceae/complicações , Infecções por Enterobacteriaceae/patologia , Infecções por Enterobacteriaceae/fisiopatologia , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Choque Séptico/microbiologia
12.
Artigo em Inglês | MEDLINE | ID: mdl-30972302

RESUMO

There is great interest in safe and effective alternative therapies that could benefit patients with inflammatory bowel diseases (IBD). L-arginine (Arg) is a semi-essential amino acid with a variety of physiological effects. In this context, our aim was to investigate the role of dietary Arg in experimental colitis. We used two models of colitis in C57BL/6 mice, the dextran sulfate sodium (DSS) model of injury and repair, and Citrobacter rodentium infection. Animals were given diets containing (1) no Arg (Arg0), 6.4 g/kg (ArgNL), or 24.6 g/kg Arg (ArgHIGH); or (2) the amino acids downstream of Arg: 28 g/kg L-ornithine (OrnHIGH) or 72 g/kg L-proline (ProHIGH). Mice with DSS colitis receiving the ArgHIGH diet had increased levels of Arg, Orn, and Pro in the colon and improved body weight loss, colon length shortening, and histological injury compared to ArgNL and Arg0 diets. Histology was improved in the ArgNL vs. Arg0 group. OrnHIGH or ProHIGH diets did not provide protection. Reduction in colitis with ArgHIGH diet also occurred in C. rodentium-infected mice. Diversity of the intestinal microbiota was significantly enhanced in mice on the ArgHIGH diet compared to the ArgNL or Arg0 diets, with increased abundance of Bacteroidetes and decreased Verrucomicrobia. In conclusion, dietary supplementation of Arg is protective in colitis models. This may occur by restoring overall microbial diversity and Bacteroidetes prevalence. Our data provide a rationale for Arg as an adjunctive therapy in IBD.


Assuntos
Arginina/administração & dosagem , Colite/patologia , Colo/microbiologia , Dieta/métodos , Infecções por Enterobacteriaceae/patologia , Microbioma Gastrointestinal , Animais , Citrobacter rodentium/crescimento & desenvolvimento , Colite/induzido quimicamente , Colo/patologia , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Histocitoquímica , Camundongos Endogâmicos C57BL , Resultado do Tratamento
13.
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
14.
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
15.
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
17.
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
18.
Jpn J Infect Dis ; 72(2): 124-126, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30381688

RESUMO

We hypothesized that quick Sequential Organ Failure Assessment (qSOFA) would be associated with 30-day mortality in bacteremia caused by extended-spectrum ß-lactamase (ESBL)-producing bacteria and might be a selection criterion for the use of carbapenem as initial empirical therapy. A multicenter retrospective study was conducted in six hospitals. All patients who had bacteremia due to ESBL-producing bacteria were included in the study. Multivariable logistic regression analysis was performed to analyze 30-day mortality as the main outcome. A total of 203 adult patients were identified with bacteremia caused by ESBL-producing Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis. In multivariate logistic regression analysis, bacteremia caused by ESBL-producing K. pneumoniae or P. mirabilis (odds ratio [OR] 5.07, 95% confidence interval [CI] 1.64-15.56), underlying liver disease (OR 3.38, 95% CI 1.09-10.00), and underlying solid cancer (OR 3.45, 95% CI 1.27-9.69) were associated with 30-day mortality. In a subgroup analysis, empirical non-carbapenem therapy was associated with 30-day mortality in bacteremia caused by ESBL-producing K. pneumoniae or P. mirabilis. Our results suggest that the qSOFA score is not a selection criterion for the use of carbapenem in initial empirical therapy.


Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/patologia , Carbapenêmicos/uso terapêutico , Enterobacteriaceae/enzimologia , Escores de Disfunção Orgânica , beta-Lactamases/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Estudos de Casos e Controles , Enterobacteriaceae/isolamento & purificação , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/mortalidade , Infecções por Enterobacteriaceae/patologia , Feminino , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
19.
Gut ; 68(7): 1190-1199, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30279238

RESUMO

OBJECTIVE: Loss of the Crohn's disease predisposing NOD2 gene results in an intestinal microenvironment conducive for colonisation by attaching-and-effacing enteropathogens. However, it remains elusive whether it relies on the intracellular recruitment of the serine-threonine kinase RIPK2 by NOD2, a step that is required for its activation of the transcription factor NF-κB. DESIGN: Colonisation resistance was evaluated in wild type and mutant mice, as well as in ex-germ-free (ex-GF) mice which were colonised either with faeces from Ripk2-deficient mice or with bacteria with similar preferences for carbohydrates to those acquired by the pathogen. The severity of the mucosal pathology was quantified at several time points postinfection by using a previously established scoring. The community resilience in response to infection was evaluated by 16S ribosomal RNA gene sequence analysis. The control of pathogen virulence was evaluated by monitoring the secretion of Citrobacter-specific antibody response in the faeces. RESULTS: Primary infection was similarly outcompeted in ex-GF Ripk2-deficient and control mice, demonstrating that the susceptibility to infection resulting from RIPK2 deficiency cannot be solely attributed to specific microbiota community structures. In contrast, delayed clearance of Citrobacter rodentium and exacerbated histopathology were preceded by a weakened propensity of intestinal macrophages to afford innate lymphoid cell activation. This tissue protection unexpectedly required the regenerating family member 3ß by instigating interleukin (IL) 17A-mediated neutrophil recruitment to the intestine and subsequent phosphorylation of signal transducer and activator of transcription 3. CONCLUSIONS: These results unveil a previously unrecognised mechanism that efficiently protects from colonisation by diarrhoeagenic bacteria early in infection.


Assuntos
Doença de Crohn/microbiologia , Doença de Crohn/patologia , Infecções por Enterobacteriaceae/prevenção & controle , Interleucina-17/fisiologia , Infiltração de Neutrófilos/fisiologia , Proteína Adaptadora de Sinalização NOD2/fisiologia , Animais , Proteínas Adaptadoras de Sinalização CARD/fisiologia , Citrobacter rodentium , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/patologia , Mucosa Intestinal/patologia , Camundongos , Proteína Serina-Treonina Quinases de Interação com Receptores/fisiologia , Transdução de Sinais
20.
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
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