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1.
Biochim Biophys Acta Gen Subj ; 1865(1): 129748, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32980501

RESUMO

BACKGROUND: Structural studies of a Salmonella Typhimurium flagellin protein indicated that four polar or charged C-terminal amino acid residues line the inner channel of the flagellum. The hydrophilic character of these putative channel-lining residues was predicted to be essential to facilitate the transport of unfolded flagellin monomers during flagellar assembly. The structure-function relationship of these putative channel-lining residues was investigated by site-directed mutagenesis to examine effects of side chain polarity and size on flagella assembly and function. METHODS: Channel-lining residue variants were generated using site-directed mutagenesis to substitute alanine and other residues to examine the effects of altered side-chain polarity on export and assembly. The export, in vivo motility function, and flagellar structure of variants was characterized by agar motility, video microscopy, immunofluorescence, and SDS-PAGE. RESULTS: Alanine substitution yielded decreased motility and flagellar assembly for three of the four residues. However, alanine substitution of residue Arg 494 did not alter export, although substitution with negatively charged glutamate decreased motility and flagellar filament length. Furthermore, many of the C-terminal mutations affected flagellar filament morphology and stability, often resulting in more tightly coiled and/or more brittle flagella than the wild type. CONCLUSIONS: The four channel-lining C-terminal residues may facilitate monomer protein transport but also have structural roles in determining the stability and morphology of the flagellum. GENERAL SIGNIFICANCE: These results provide further insight into the complex process of bacterial flagellin export and flagellar assembly and provide evidence of previously unknown structural functions for the four putative channel-lining residues.


Assuntos
Flagelina/metabolismo , Salmonella typhimurium/citologia , Flagelos/química , Flagelos/genética , Flagelos/metabolismo , Flagelos/ultraestrutura , Flagelina/química , Flagelina/genética , Humanos , Movimento (Física) , Mutagênese Sítio-Dirigida , Conformação Proteica , Infecções por Salmonella/microbiologia , Salmonella typhimurium/química , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo
2.
BMC Infect Dis ; 20(1): 828, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176707

RESUMO

BACKGROUND: Severe and disseminated non-tuberculous mycobacterial (NTM) infections are frequently linked to a genetic predisposition but acquired defects of the interferon gamma (IFNγ) / interleukin 12 (IL-12) pathway need to be considered in adult patients with persistent or recurrent infections. Neutralizing anti-IFNγ autoantibodies disrupting IFNγ signalling have been identified as the cause of a severe and unique acquired immunodeficiency syndrome with increased susceptibility to NTM and other intracellular pathogens. CASE PRESENTATION: An adult Asian female with a previous history of recurrent NTM infections presented with persistent diarrhea, abdominal pain, night sweats and weight loss. Severe colitis due to a simultaneous infection with cytomegalovirus (CMV) and Salmonella typhimurium was diagnosed, with both pathogens also detectable in blood samples. Imaging studies further revealed thoracic as well as abdominal lymphadenopathy and a disseminated Mycobacterium intracellulare infection was diagnosed after a lymph node biopsy. Further diagnostics revealed the presence of high-titer neutralizing anti-IFNγ autoantibodies, allowing for the diagnosis of adult-onset immunodeficiency with anti-IFNγ autoantibodies (AIIA). CONCLUSIONS: We here present a severe case of acquired immunodeficiency with anti-IFNγ autoantibodies with simultaneous, disseminated infections with both viral and microbial pathogens. The case illustrates how the diagnosis can cause considerable difficulties and is often delayed due to unusual presentations. Histological studies in our patient give further insight into the pathophysiological significance of impaired IFNγ signalling. B-cell-depleting therapy with rituximab offers a targeted treatment approach in AIIA.


Assuntos
Autoanticorpos/imunologia , Infecções por Citomegalovirus/diagnóstico , Citomegalovirus/isolamento & purificação , Síndromes de Imunodeficiência/diagnóstico , Interferon gama/imunologia , Linfadenopatia/diagnóstico , Complexo Mycobacterium avium/isolamento & purificação , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Infecções por Salmonella/diagnóstico , Salmonella typhimurium/isolamento & purificação , Adulto , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Autoanticorpos/sangue , Biópsia , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/virologia , Diagnóstico Tardio , Feminino , Seguimentos , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Interferon gama/metabolismo , Interleucina-12/metabolismo , Linfadenopatia/complicações , Linfadenopatia/tratamento farmacológico , Linfadenopatia/patologia , Infecção por Mycobacterium avium-intracellulare/complicações , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecções por Salmonella/complicações , Infecções por Salmonella/tratamento farmacológico , Infecções por Salmonella/microbiologia , Resultado do Tratamento
3.
Mem Inst Oswaldo Cruz ; 115: e200458, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33237133

RESUMO

BACKGROUND: Calotropis procera latex protein fraction (LP) was previously shown to protect animals from septic shock. Further investigations showed that LP modulate nitric oxide and cytokines levels. OBJECTIVES: To evaluate whether the protective effects of LP, against lethal bacterial infection, is observed in its subfractions (LPPII and LPPIII). METHODS: Subfractions (5 and 10 mg/kg) were tested by i.p. administration, 24 h before challenging with lethal injection (i.p.) of Salmonella Typhimurium. LPPIII (5 mg/kg) which showed higher survival rate was assayed to evaluate bacterial clearance, histopathology, leukocyte recruitment, plasma coagulation time, cytokines and NO levels. FINDINGS: LPPIII protected 70% of animals of death. The animals given LPPIII exhibited reduced bacterial load in blood and peritoneal fluid after 24 h compared to the control. LPPIII promoted macrophage infiltration in spleen and liver. LPPIII restored the coagulation time of infected animals, increased IL-10 and reduced NO in blood. MAIN CONCLUSIONS: LPPIII recruited macrophages to the target organs of bacterial infection. This addressed inflammatory stimulus seems to reduce bacterial colonisation in spleen and liver, down regulate bacterial spread and contribute to avoid septic shock.


Assuntos
Antibacterianos/uso terapêutico , Calotropis/química , Homeostase/efeitos dos fármacos , Inflamação/tratamento farmacológico , Látex/química , Extratos Vegetais/farmacologia , Proteínas de Plantas/uso terapêutico , Infecções por Salmonella/tratamento farmacológico , Animais , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Regulação para Baixo , Proteínas de Plantas/isolamento & purificação , Proteínas de Plantas/farmacologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia
4.
PLoS Negl Trop Dis ; 14(8): e0008440, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745137

RESUMO

Invasive Non-typhoidal Salmonella (iNTS) disease is a major public health challenge, especially in Sub-Saharan Africa (SSA). In Kenya, mortality rates are high (20-25%) unless prompt treatment is instituted. The most common serotypes are Salmonella enterica serotype Typhimurium (S. Typhimurium) and Salmonella enterica serotype Enteritidis (S. Enteritidis). In a 5 year case-control study in children residing in the Mukuru informal settlement in Nairobi, Kenya, a total of 4201 blood cultures from suspected iNTS cases and 6326 fecal samples from age-matched controls were studied. From the laboratory cultures we obtained a total of 133 S. Typhimurium isolates of which 83(62.4%) came from cases (53 blood and 30 fecal) and 50(37.6%) from controls (fecal). A total of 120 S. Enteritidis consisted of 70(58.3%) from cases (43 blood and 27 fecal) and 50(41.7%) from controls (fecal). The S. Typhimurium population fell into two distinct ST19 lineages constituting 36.1%, as well as ST313 lineage I (27.8%) and ST313 lineage II (36.1%) isolates. The S. Enteritidis isolates fell into the global epidemic lineage (46.6%), the Central/Eastern African lineage (30.5%), a novel Kenyan-specific lineage (12.2%) and a phylogenetically outlier lineage (10.7%). Detailed phylogenetic analysis revealed a high level of relatedness between NTS from blood and stool originating from cases and controls, indicating a common source pool. Multidrug resistance was common throughout, with 8.5% of such isolates resistant to extended spectrum beta lactams. The high rate of asymptomatic carriage in the population is a concern for transmission to vulnerable individuals and this group could be targeted for vaccination if an iNTS vaccine becomes available.


Assuntos
Infecções por Salmonella/epidemiologia , Infecções por Salmonella/microbiologia , Salmonella enteritidis/genética , Estudos de Casos e Controles , Pré-Escolar , Farmacorresistência Bacteriana Múltipla/genética , Fezes/microbiologia , Feminino , Genótipo , Humanos , Lactente , Quênia/epidemiologia , Masculino , Testes de Sensibilidade Microbiana , Filogenia , Áreas de Pobreza , Infecções por Salmonella/sangue , Salmonella enteritidis/isolamento & purificação
5.
BMC Infect Dis ; 20(1): 511, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669095

RESUMO

BACKGROUND: Salmonella enterica subsp. enterica serovar Typhimurium infections continue to be a significant public health threat worldwide. The aim of this study was to investigate antibiotic resistance among 147 S. Typhimurium isolates collected from patients in Henan, China from 2006 to 2015. METHODS: 147 S. Typhimurium isolates were collected from March 2006 to November 2015 in Henan Province, China. Antimicrobial susceptibility testing was performed, and the resistant genes of ciprofloxacin, cephalosporins (ceftriaxone and cefoxitin) and azithromycin were detected and sequenced. Clonal relationships were assessed by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). RESULTS: Of the 147 isolates, 91.1% were multidrug resistant (MDR), with 4.1% being resistant to all antibiotic classes tested. Of concern, 13 MDR isolates were co-resistant to the first-line treatments cephalosporins and ciprofloxacin, while three were also resistant to azithromycin. Seven PFGE patterns were identified among the 13 isolates. All of the isolates could be assigned to one of four main groups, with a similarity value of 89%. MLST assigned the 147 isolates into five STs, including two dominant STs (ST19 and ST34). Of the 43 ciprofloxacin-resistant isolates, 39 carried double gyrA mutations (Ser83Phe, Asp87Asn/Tyr/Gly) and a single parC (Ser80Arg) mutation, including 1 isolate with four mutations (gyrA: Ser83Phe, Asp87Gly; parC: Ser80Arg; parE: Ser458Pro). In addition, 12 isolates not only carried mutations in gyrA and parC but also had at least one plasmid-mediated quinolone resistance (PMQR) gene. Among the 32 cephalosporin-resistant isolates, the most common extended-spectrum ß-lactamase (ESBL) gene was blaOXA-1, followed by blaCTX-M, blaTEM-1, and blaCMY-2. Moreover, the mphA gene was identified in 5 of the 15 azithromycin-resistant isolates. Four MDR isolates contained ESBL and PMQR genes, and one of them also carried mphA in addition. CONCLUSION: The high level of antibiotic resistance observed in S. Typhimurium poses a great danger to public health, so continuous surveillance of changes in antibiotic resistance is necessary.


Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Cefalosporinas/uso terapêutico , Ciprofloxacino/uso terapêutico , Farmacorresistência Bacteriana Múltipla/genética , Infecções por Salmonella/tratamento farmacológico , Infecções por Salmonella/epidemiologia , Salmonella/genética , Sorogrupo , Adolescente , Adulto , Criança , Pré-Escolar , China/epidemiologia , Eletroforese em Gel de Campo Pulsado , Feminino , Humanos , Lactente , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Tipagem de Sequências Multilocus , Infecções por Salmonella/microbiologia , Adulto Jovem
6.
Nat Commun ; 11(1): 3547, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669546

RESUMO

Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidase-mediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81-/- mice mobilize reduced levels of neutrophils in response to LPS, unless rescued by VE-Cadherin disrupting antibodies. Lactate administration also induces release of the BM neutrophil mobilizers G-CSF, CXCL1 and CXCL2, indicating that this metabolite drives neutrophil mobilization via multiple pathways. Our study reveals a metabolic crosstalk between lactate-producing neutrophils and BM endothelium, which controls neutrophil mobilization under bacterial infection.


Assuntos
Células da Medula Óssea/imunologia , Ácido Láctico/metabolismo , Neutrófilos/imunologia , Receptores Acoplados a Proteínas-G/metabolismo , Infecções por Salmonella/imunologia , Animais , Medula Óssea/irrigação sanguínea , Células da Medula Óssea/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Feminino , Humanos , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Knockout , Neutrófilos/metabolismo , Receptores Acoplados a Proteínas-G/genética , Infecções por Salmonella/microbiologia , Salmonella typhimurium/imunologia , Transdução de Sinais/imunologia
7.
Science ; 369(6502): 450-455, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32703879

RESUMO

The guanosine triphosphatase (GTPase) Rab32 coordinates a cell-intrinsic host defense mechanism that restricts the replication of intravacuolar pathogens such as Salmonella Here, we show that this mechanism requires aconitate decarboxylase 1 (IRG1), which synthesizes itaconate, a metabolite with antimicrobial activity. We find that Rab32 interacts with IRG1 on Salmonella infection and facilitates the delivery of itaconate to the Salmonella-containing vacuole. Mice defective in IRG1 rescued the virulence defect of a S. enterica serovar Typhimurium mutant specifically defective in its ability to counter the Rab32 defense mechanism. These studies provide a link between a metabolite produced in the mitochondria after stimulation of innate immune receptors and a cell-autonomous defense mechanism that restricts the replication of an intracellular bacterial pathogen.


Assuntos
Hidroliases/imunologia , Infecções por Salmonella/imunologia , Salmonella enterica , Salmonella typhimurium , Proteínas rab de Ligação ao GTP/imunologia , Animais , Linhagem Celular , Interações Hospedeiro-Patógeno , Humanos , Hidroliases/metabolismo , Camundongos , Infecções por Salmonella/metabolismo , Infecções por Salmonella/microbiologia , Succinatos , Virulência , Proteínas rab de Ligação ao GTP/metabolismo
8.
Int J Food Microbiol ; 330: 108692, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-32521291

RESUMO

Salmonella 4,[5],12:i:- is a monophasic variant of Salmonella Typhimurium, which is responsible for global foodborne disease outbreaks. Here, 255 S. 4,[5],12:i:- strains isolated from humans (11.0%) or food-borne animals (89.0%) between 2010 and 2018 were examined. Tests of susceptibility to 19 antimicrobial agents using the broth micro dilution method showed that 99.2% (n = 253) of the isolates were resistant to at least one compound. Antibiotic susceptibility analysis demonstrated that 91.8% of the isolates were multidrug-resistant (MDR) strains with predominant resistance to tetracycline (90.6%), followed by resistance to ampicillin (86.3%), streptomycin (63.5%), chloramphenicol (62.7%), and trimethoprim-sulfamethoxazole (55.3%). The 5 major distinct patterns of multi-resistance were identified as R-type AST, R-type ACTSxt, R-type ACSTSxt, R-type ACGSTSxt and R-type ASTSxt. Among the PMQR genes examined in this study, oqxAB and aac (6')-Ib-cr were the most prevalent resistance genes in the multi-resistant isolates. Our findings highlight the prevalence of the resistance of S. 4,[5],12:i:- in some regions of China, and several common types of multidrug resistance phenotypes, to provide valuable information for epidemiological studies, risk management, and public health strategies.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Quinolonas/farmacologia , Salmonella/efeitos dos fármacos , Animais , China/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Prevalência , Salmonella/genética , Salmonella/isolamento & purificação , Infecções por Salmonella/epidemiologia , Infecções por Salmonella/microbiologia
9.
Nat Microbiol ; 5(9): 1119-1133, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32514074

RESUMO

The interplay between host and pathogen relies heavily on rapid protein synthesis and accurate protein targeting to ensure pathogen destruction. To gain insight into this dynamic interface, we combined Click chemistry with pulsed stable isotope labelling of amino acids in cell culture to quantify the host proteome response during macrophage infection with the intracellular bacterial pathogen Salmonella enterica Typhimurium. We monitored newly synthesized proteins across different host cell compartments and infection stages. Within this rich resource, we detected aberrant trafficking of lysosomal proteases to the extracellular space and the nucleus. We verified that active cathepsins re-traffic to the nucleus and that these are linked to cell death. Pharmacological cathepsin inhibition and nuclear targeting of a cellular cathepsin inhibitor (stefin B) suppressed S. enterica Typhimurium-induced cell death. We demonstrate that cathepsin activity is required for pyroptotic cell death via the non-canonical inflammasome, and that lipopolysaccharide transfection into the host cytoplasm is sufficient to trigger active cathepsin accumulation in the host nucleus and cathepsin-dependent cell death. Finally, cathepsin inhibition reduced gasdermin D expression, thus revealing an unexpected role for cathepsin activity in non-canonical inflammasome regulation. Overall, our study illustrates how resolution of host proteome dynamics during infection can drive the discovery of biological mechanisms at the host-microbe interface.


Assuntos
Catepsinas/metabolismo , Morte Celular/fisiologia , Macrófagos/metabolismo , Proteômica , Infecções por Salmonella/metabolismo , Salmonella typhimurium/metabolismo , Animais , Catepsinas/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Cistatina B/antagonistas & inibidores , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/metabolismo , Lisossomos/metabolismo , Macrófagos/microbiologia , Camundongos , Peptídeo Hidrolases/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Proteoma , Células RAW 264.7 , Infecções por Salmonella/microbiologia
10.
BMC Infect Dis ; 20(1): 422, 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32552753

RESUMO

BACKGROUND: In Kenya, typhoid fever and invasive non-typhoidal salmonellosis present a huge burden of disease, especially in poor-resource settings where clean water supply and sanitation conditions are inadequate. The epidemiology of both diseases is poorly understood in terms of severity and risk factors. The aim of the study was to determine the disease burden and spatial distribution of salmonellosis, as well as socioeconomic and environmental risk factors for these infections, in a large informal settlement near the city of Nairobi, from 2013 to 2017. METHODS: Initially, a house-to-house baseline census of 150,000 population in Mukuru informal settlement was carried out and relevant socioeconomic, demographic, and healthcare utilization information was collected using structured questionnaires. Salmonella bacteria were cultured from the blood and faeces of children < 16 years of age who reported at three outpatient facilities with fever alone or fever and diarrhea. Tests of association between specific Salmonella serotypes and risk factors were conducted using Pearson Chi-Square (χ2) test. RESULTS: A total of 16,236 children were recruited into the study. The prevalence of bloodstream infections by Non-Typhoidal Salmonella (NTS), consisting of Salmonella Typhimurium/ Enteriditis, was 1.3%; Salmonella Typhi was 1.4%, and this was highest among children < 16 years of age. Occurrence of Salmonella Typhimurium/ Enteriditis was not significantly associated with rearing any domestic animals. Rearing chicken was significantly associated with high prevalence of S. Typhi (2.1%; p = 0.011). The proportion of children infected with Salmonella Typhimurium/ Enteriditis was significantly higher in households that used water pots as water storage containers compared to using water directly from the tap (0.6%). Use of pit latrines and open defecation were significant risk factors for S. Typhi infection (1.6%; p = 0.048). The proportion of Salmonella Typhimurium/ Enteriditis among children eating street food 4 or more times per week was higher compared to 1 to 2 times/week on average (1.1%; p = 0.032). CONCLUSION: Typhoidal and NTS are important causes of illness in children in Mukuru informal settlement, especially among children less than 16 years of age. Improving Water, Sanitation and Hygiene (WASH) including boiling water, breastfeeding, hand washing practices, and avoiding animal contact in domestic settings could contribute to reducing the risk of transmission of Salmonella disease from contaminated environments.


Assuntos
Infecções por Salmonella/epidemiologia , Salmonella typhi/imunologia , Salmonella typhimurium/imunologia , Febre Tifoide/epidemiologia , Adolescente , Animais , Galinhas , Criança , Pré-Escolar , Características da Família , Fezes/microbiologia , Feminino , Humanos , Higiene , Lactente , Recém-Nascido , Quênia/epidemiologia , Masculino , Áreas de Pobreza , Prevalência , Fatores de Risco , Infecções por Salmonella/microbiologia , Salmonella typhi/isolamento & purificação , Salmonella typhimurium/isolamento & purificação , Saneamento , Testes Sorológicos , Febre Tifoide/microbiologia
11.
Appl Environ Microbiol ; 86(17)2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32591375

RESUMO

Clinical surveillance of enteric pathogens like Salmonella is integral to track outbreaks and endemic disease trends. However, clinic-centered disease monitoring biases toward detection of severe cases and underestimates the incidence of self-limiting gastroenteritis and asymptomatic strains. Monitoring pathogen loads and diversity in municipal wastewater (MW) can provide insight into asymptomatic or subclinical infections which are not reflected in clinical cases. Subclinical infection patterns may explain the unusual observation from a year-long sampling campaign in Hawaii: Salmonella enterica serovar Derby was the most abundant pulsotype in MW but was detected infrequently in clinics over the sampling period. Using whole-genome sequencing data of Salmonella isolates from MW and public databases, we demonstrate that the Derby serovar has lower virulence potential than other clinical serovars, particularly based on its reduced profile of genes linked with immune evasion and symptom production, suggesting its potential as a subclinical salmonellosis agent. Furthermore, MW had high abundance of a rare Derby sequence type (ST), ST-72 (rather than the more common ST-40). ST-72 isolates had higher frequencies of fimbrial adherence genes than ST-40 isolates; these are key virulence factors involved in colonization and persistence of infections. However, ST-72 isolates lack the Derby-specific Salmonella pathogenicity island 23 (SPI-23), which invokes host immune responses. In combination, ST-72's genetic features may lead to appreciable infection rates without obvious symptom production, allowing for subclinical persistence in the community. This study demonstrated wastewater's capability to provide community infectious disease information-such as background infection rates of subclinical enteric illness-which is otherwise inaccessible through clinical approaches.IMPORTANCE Wastewater-based epidemiology (WBE) has been conventionally used to analyze community health via the detection of chemicals, such as legal and illicit drugs; however, municipal wastewater contains microbiological determinants of health and disease as well, including enteric pathogens. Here, we demonstrate that WBE can be used to examine subclinical community salmonellosis patterns. Derby was the most abundant Salmonella serovar detected in Hawaii wastewater over a year-long sampling study, with few corresponding clinical cases. Comparative genomics analyses indicate that the normally rare strain of S Derby found in wastewater has a unique combination of genes which allow it to persist as a subclinical infection without producing symptoms of severe gastroenteritis. This study shows that WBE can be used to explore trends in community infectious disease patterns which may not be reflected in clinical monitoring, shedding light on overall enteric disease burden and rates of asymptomatic cases.


Assuntos
Monitoramento Epidemiológico , Infecções por Salmonella/epidemiologia , Salmonella enterica/isolamento & purificação , Águas Residuárias/microbiologia , Hawaii/epidemiologia , Humanos , Infecções por Salmonella/microbiologia , Sorogrupo
12.
Epidemiol Infect ; 148: e180, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32364094

RESUMO

Raw milk cheeses are commonly consumed in France and are also a common source of foodborne outbreaks (FBOs). Both an FBO surveillance system and a laboratory-based surveillance system aim to detect Salmonella outbreaks. In early August 2018, five familial FBOs due to Salmonella spp. were reported to a regional health authority. Investigation identified common exposure to a raw goats' milk cheese, from which Salmonella spp. were also isolated, leading to an international product recall. Three weeks later, on 22 August, a national increase in Salmonella Newport ST118 was detected through laboratory surveillance. Concomitantly isolates from the earlier familial clusters were confirmed as S. Newport ST118. Interviews with a selection of the laboratory-identified cases revealed exposure to the same cheese, including exposure to batches not included in the previous recall, leading to an expansion of the recall. The outbreak affected 153 cases, including six cases in Scotland. S. Newport was detected in the cheese and in the milk of one of the producer's goats. The difference in the two alerts generated by this outbreak highlight the timeliness of the FBO system and the precision of the laboratory-based surveillance system. It is also a reminder of the risks associated with raw milk cheeses.


Assuntos
Queijo/microbiologia , Surtos de Doenças , Microbiologia de Alimentos , Doenças Transmitidas por Alimentos/microbiologia , Infecções por Salmonella/microbiologia , Salmonella/classificação , Animais , Controle de Doenças Transmissíveis , Doenças Transmitidas por Alimentos/epidemiologia , França/epidemiologia , Cabras , Humanos , Infecções por Salmonella/epidemiologia
13.
PLoS Pathog ; 16(5): e1008503, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32365138

RESUMO

Salmonella enterica serovar Typhimurium (S.Tm) infections of cultured cell lines have given rise to the ruffle model for epithelial cell invasion. According to this model, the Type-Three-Secretion-System-1 (TTSS-1) effectors SopB, SopE and SopE2 drive an explosive actin nucleation cascade, resulting in large lamellipodia- and filopodia-containing ruffles and cooperative S.Tm uptake. However, cell line experiments poorly recapitulate many of the cell and tissue features encountered in the host's gut mucosa. Here, we employed bacterial genetics and multiple imaging modalities to compare S.Tm invasion of cultured epithelial cell lines and the gut absorptive epithelium in vivo in mice. In contrast to the prevailing ruffle-model, we find that absorptive epithelial cell entry in the mouse gut occurs through "discreet-invasion". This distinct entry mode requires the conserved TTSS-1 effector SipA, involves modest elongation of local microvilli in the absence of expansive ruffles, and does not favor cooperative invasion. Discreet-invasion preferentially targets apicolateral hot spots at cell-cell junctions and shows strong dependence on local cell neighborhood. This proof-of-principle evidence challenges the current model for how S.Tm can enter gut absorptive epithelial cells in their intact in vivo context.


Assuntos
Aderência Bacteriana , Mucosa Intestinal/microbiologia , Infecções por Salmonella , Salmonella typhimurium , Sistemas de Secreção Tipo I/metabolismo , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Cães , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Células HeLa , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Infecções por Salmonella/genética , Infecções por Salmonella/metabolismo , Infecções por Salmonella/microbiologia , Infecções por Salmonella/patologia , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidade , Sistemas de Secreção Tipo I/genética
14.
PLoS One ; 15(4): e0225873, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32352968

RESUMO

Black soldier fly (BSF; Hermetia illucens L.) larvae can convert fresh pig manure into protein and fat-rich biomass, which can then be used as aquafeed for select species. Currently, BSF is the only approved insect for such purposes in Canada, USA, and the European Union. Pig manure could serve as a feed substrate for BSF; however, it is contaminated with zoonotic pathogens (e.g., Staphylococcus aureus and Salmonella spp.). Fortunately, BSF larvae inhibit many of these zoonotic pathogens; however, the mechanisms employed are unclear. We employed RNAi, qRT-PCR, and Illumina MiSeq 16S rDNA high-throughput sequencing to examine the interaction between two immune genes (Duox in Duox-reactive oxygen species [ROS] immune system and TLR3 in the Toll signaling pathway) and select pathogens common in pig manure to decipher the mechanisms resulting in pathogen suppression. Results indicate Bsf Duox-TLR3 RNAi increased bacterial load but decreased relative abundance of Providencia and Dysgonomonas, which are thought to be commensals in the BSF larval gut. Bsf Duox-TLR3 RNAi also inactivated the NF-κB signaling pathway, downregulated the expression of antimicrobial peptides, and diminished inhibitory effects on zoonotic pathogen. The resulting dysbiosis stimulated an immune response by activating BsfDuox and promoting ROS, which regulated the composition and structure of the gut bacterial community. Thus, BsfDuox and BsfTLR3 are important factors in regulating these key gut microbes, while inhibiting target zoonotic pathogens.


Assuntos
Oxidases Duais/imunologia , Microbioma Gastrointestinal , Proteínas de Insetos/imunologia , Esterco/microbiologia , Simuliidae/imunologia , Receptor 3 Toll-Like/imunologia , Animais , Homeostase , Humanos , Larva/imunologia , Larva/microbiologia , Salmonella/imunologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Transdução de Sinais , Simuliidae/microbiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Suínos , Zoonoses/imunologia , Zoonoses/microbiologia
15.
Epidemiol Infect ; 148: e144, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32450932

RESUMO

Non-typhoidal Salmonella (NTS) serovars, sequences types and antimicrobial susceptibility profiles have specific associations with animal and human infections in Vietnam. Antimicrobial resistance may have an effect on the manifestation of human NTS infections, with isolates from asymptomatic individuals being more susceptible to antimicrobials than those associated with animals and human diarrhoea.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Infecções por Salmonella/epidemiologia , Infecções por Salmonella/microbiologia , Salmonella/efeitos dos fármacos , Animais , Criança , Fezes , Humanos , Vietnã
16.
PLoS Pathog ; 16(4): e1008360, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32330185

RESUMO

Intestinal epithelial cells (IECs) are at the forefront of host-pathogen interactions, coordinating a cascade of immune responses to protect against pathogens. Here we show that IEC-intrinsic vitamin A signaling restricts pathogen invasion early in the infection and subsequently activates immune cells to promote pathogen clearance. Mice blocked for retinoic acid receptor (RAR) signaling selectively in IECs (stopΔIEC) showed higher Salmonella burden in colonic tissues early in the infection that associated with higher luminal and systemic loads of the pathogen at later stages. Higher pathogen burden in stopΔIEC mice correlated with attenuated mucosal interferon gamma (IFNγ) production by underlying immune cells. We found that, at homeostasis, the intestinal epithelium of stopΔIEC mice produced significantly lower amounts of interleukin 18 (IL-18), a potent inducer of IFNγ. Regulation of IL-18 by vitamin A was also observed in a dietary model of vitamin A supplementation. IL-18 reconstitution in stopΔIEC mice restored resistance to Salmonella by promoting epithelial cell shedding to eliminate infected cells and limit pathogen invasion early in infection. Further, IL-18 augmented IFNγ production by underlying immune cells to restrict pathogen burden and systemic spread. Our work uncovers a critical role for vitamin A in coordinating a biphasic immune response to Salmonella infection by regulating IL-18 production by IECs.


Assuntos
Microbioma Gastrointestinal , Interleucina-18/metabolismo , Mucosa Intestinal/imunologia , Proteínas Associadas aos Microtúbulos/fisiologia , Infecções por Salmonella/prevenção & controle , Salmonella typhimurium/imunologia , Vitamina A/metabolismo , Animais , Interações Hospedeiro-Patógeno , Interferon gama/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores do Ácido Retinoico/metabolismo , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Infecções por Salmonella/patologia , Transdução de Sinais
17.
Nat Commun ; 11(1): 2013, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332720

RESUMO

The long external filament of bacterial flagella is composed of several thousand copies of a single protein, flagellin. Here, we explore the role played by lysine methylation of flagellin in Salmonella, which requires the methylase FliB. We show that both flagellins of Salmonella enterica serovar Typhimurium, FliC and FljB, are methylated at surface-exposed lysine residues by FliB. A Salmonella Typhimurium mutant deficient in flagellin methylation is outcompeted for gut colonization in a gastroenteritis mouse model, and methylation of flagellin promotes bacterial invasion of epithelial cells in vitro. Lysine methylation increases the surface hydrophobicity of flagellin, and enhances flagella-dependent adhesion of Salmonella to phosphatidylcholine vesicles and epithelial cells. Therefore, posttranslational methylation of flagellin facilitates adhesion of Salmonella Typhimurium to hydrophobic host cell surfaces, and contributes to efficient gut colonization and host infection.


Assuntos
Aderência Bacteriana , Flagelina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Infecções por Salmonella/patologia , Salmonella typhimurium/patogenicidade , Animais , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais , Flagelos/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Metilação , Camundongos , Células NIH 3T3 , Processamento de Proteína Pós-Traducional , Infecções por Salmonella/microbiologia , Salmonella typhimurium/metabolismo
18.
Nat Commun ; 11(1): 1978, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332737

RESUMO

There is the notion that infection with a virulent intestinal pathogen induces generally stronger mucosal adaptive immunity than the exposure to an avirulent strain. Whether the associated mucosal inflammation is important or redundant for effective induction of immunity is, however, still unclear. Here we use a model of auxotrophic Salmonella infection in germ-free mice to show that live bacterial virulence factor-driven immunogenicity can be uncoupled from inflammatory pathogenicity. Although live auxotrophic Salmonella no longer causes inflammation, its mucosal virulence factors remain the main drivers of protective mucosal immunity; virulence factor-deficient, like killed, bacteria show reduced efficacy. Assessing the involvement of innate pathogen sensing mechanisms, we show MYD88/TRIF, Caspase-1/Caspase-11 inflammasome, and NOD1/NOD2 nodosome signaling to be individually redundant. In colonized animals we show that microbiota metabolite cross-feeding may recover intestinal luminal colonization but not pathogenicity. Consequent immunoglobulin A immunity and microbial niche competition synergistically protect against Salmonella wild-type infection.


Assuntos
Imunidade nas Mucosas , Mucosa Intestinal/microbiologia , Infecções por Salmonella/microbiologia , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Antígenos de Bactérias , Caspase 1/metabolismo , Caspases Iniciadoras/metabolismo , Proliferação de Células , Microbioma Gastrointestinal , Imunidade Inata , Imunoglobulina A/imunologia , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Fator 88 de Diferenciação Mieloide/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Salmonella typhimurium/patogenicidade , Transdução de Sinais , Virulência , Fatores de Virulência
19.
Am J Trop Med Hyg ; 102(6): 1249-1252, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32228778

RESUMO

We investigated an outbreak of hepatitis A infection among children in an urban settlement of Vellore, South India. A total of 58 cases of jaundice were reported between April and August 2019. Sera from children who presented with jaundice were tested for hepatitis A virus (HAV) IgM. HAV IgM was positive in 18 (94.7%) of the 19 cases tested. These children also received a blood culture at the same time, as a part of the ongoing Surveillance for Enteric Fever in India (SEFI). Blood cultures from three children with confirmed hepatitis A infection grew Salmonella sp.: two with Salmonella Typhi and one with Salmonella Poona. Salmonella Poona is being reported for the first time from India. The overall hospitalization rate during the outbreak was 21%. Outbreaks of hepatitis A continue to occur with substantial morbidity in children from endemic settings, with notable emergence of other concurrent enteric infections, thereby warranting continued surveillance.


Assuntos
Hepatite A/complicações , Hepatite A/epidemiologia , Infecções por Salmonella/complicações , Infecções por Salmonella/microbiologia , Salmonella/classificação , População Urbana , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Coinfecção , Feminino , Humanos , Imunoglobulina M/sangue , Índia/epidemiologia , Masculino , Infecções por Salmonella/epidemiologia
20.
PLoS Negl Trop Dis ; 14(4): e0008121, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32240161

RESUMO

BACKGROUND: Non-typhoidal Salmonella (NTS) are a major cause of bloodstream infection (BSI) in sub-Saharan Africa. This study aimed to assess its longitudinal evolution as cause of BSI, its serotype distribution and its antibiotic resistance pattern in Kisantu, DR Congo. METHODS: As part of a national surveillance network, blood cultures were sampled in patients with suspected BSI admitted to Kisantu referral hospital from 2015-2017. Blood cultures were worked-up according to international standards. Results were compared to similar data from 2007 onwards. RESULTS: In 2015-2017, NTS (n = 896) represented the primary cause of BSI. NTS were isolated from 7.6% of 11,764 suspected and 65.4% of 1371 confirmed BSI. In children <5 years, NTS accounted for 9.6% of suspected BSI. These data were in line with data from previous surveillance periods, except for the proportion of confirmed BSI, which was lower in previous surveillance periods. Salmonella Typhimurium accounted for 63.1% of NTS BSI and Salmonella Enteritidis for 36.4%. Of all Salmonella Typhimurium, 36.9% did not express the O5-antigen (i.e. variant Copenhagen). O5-negative Salmonella Typhimurium were rare before 2013, but increased gradually from then onwards. Multidrug resistance was observed in 87.4% of 864 NTS isolates, decreased ciprofloxacin susceptibility in 7.3%, ceftriaxone resistance in 15.7% and azithromycin resistance in 14.9%. A total of 14.2% of NTS isolates, that were all Salmonella Typhimurium, were multidrug resistant and ceftriaxone and azithromycin co-resistant. These Salmonella isolates were called extensively drug resistant. Compared to previous surveillance periods, proportions of NTS isolates with resistance to ceftriaxone and azithromycin and decreased ciprofloxacin susceptibility increased. CONCLUSION: As in previous surveillance periods, NTS ranked first as the cause of BSI in children. The emergence of O5-negative Salmonella Typhimurium needs to be considered in the light of vaccine development. The high proportions of antibiotic resistance are worrisome.


Assuntos
Antibacterianos/farmacologia , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Infecções por Salmonella/epidemiologia , Infecções por Salmonella/microbiologia , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/isolamento & purificação , Adolescente , Adulto , Azitromicina , Ceftriaxona , Criança , Pré-Escolar , Ciprofloxacino , Congo/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana , Salmonella/efeitos dos fármacos , Infecções por Salmonella/diagnóstico , Salmonella enteritidis/efeitos dos fármacos , Sorogrupo , Febre Tifoide/tratamento farmacológico , Adulto Jovem
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