RESUMO
El síndrome urémico hemolítico (SUH), descripto en 1955, se caracteriza por la tríada de anemia hemolítica no inmunomediada, trombocitopenia y lesión renal aguda. En su patogenia interviene la toxina Shiga, producida con mayor frecuencia por E. coli O157:H. Puede manifestarse a cualquier edad, aunque es infrecuente en adultos, y se desarrolla en forma esporádica o en brote. Se presenta con un cuadro de dolor abdominal, diarrea, fiebre y vómitos. Puede afectar el sistema nervioso central, pulmones, páncreas y corazón. En adultos, el síndrome evoluciona tras un período de incubación de 1 semana posterior a la diarrea y tiene alta morbimortalidad, a diferencia de los casos pediátricos. Presentamos el caso de una paciente adulta, que cursó internación por síndrome urémico hemolítico. (AU)
Hemolytic uremic syndrome (HUS), described in 1955, is characterized by the triad of non-immune mediated hemolytic anemia, thrombocytopenia, and acute kidney injury. Shiga toxin, produced most frequently by E coli O157:H, is involved in its pathogenesis. Hus can manifest at any age, although it is rare in adults and develops sporadically or in outbreaks. HUS presents with a picture of abdominal pain, diarrhea, fever and vomiting. It can affect the central nervous system, lungs, pancreas, and heart.In adults, the syndrome evolves after an incubation period of 1 week after diarrhea, with high morbidity and mortality, unlike pediatric cases.We present the case of an adult patient who was hospitalized for hemolytic uremic syndrome. (AU)
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Escherichia coli O157/isolamento & purificação , Infecções por Escherichia coli/complicações , Síndrome Hemolítico-Urêmica/patologia , Síndrome Hemolítico-Urêmica/diagnóstico por imagem , Reação em Cadeia da Polimerase , Diarreia/etiologia , Síndrome Hemolítico-Urêmica/dietoterapia , Síndrome Hemolítico-Urêmica/sangue , Síndrome Hemolítico-Urêmica/terapia , Infusões Parenterais , Testes de Função RenalRESUMO
Shiga toxin-producing E. coli (STEC) produces Stx1 and/or Stx2, and Subtilase cytotoxin (SubAB). Since these toxins may be present simultaneously during STEC infections, the purpose of this work was to study the co-action of Stx2 and SubAB. Stx2 + SubAB was assayed in vitro on monocultures and cocultures of human glomerular endothelial cells (HGEC) with a human proximal tubular epithelial cell line (HK-2) and in vivo in mice after weaning. The effects in vitro of both toxins, co-incubated and individually, were similar, showing that Stx2 and SubAB contribute similarly to renal cell damage. However, in vivo, co-injection of toxins lethal doses reduced the survival time of mice by 24 h and mice also suffered a strong decrease in the body weight associated with a lowered food intake. Co-injected mice also exhibited more severe histological renal alterations and a worsening in renal function that was not as evident in mice treated with each toxin separately. Furthermore, co-treatment induced numerous erythrocyte morphological alterations and an increase of free hemoglobin. This work shows, for the first time, the in vivo effects of Stx2 and SubAB acting together and provides valuable information about their contribution to the damage caused in STEC infections.
Assuntos
Proteínas de Escherichia coli/toxicidade , Síndrome Hemolítico-Urêmica/etiologia , Toxina Shiga II/toxicidade , Subtilisinas/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Síndrome Hemolítico-Urêmica/patologia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Glomérulos Renais/citologia , Túbulos Renais Proximais/citologia , Masculino , Camundongos Endogâmicos BALB CRESUMO
Hemolytic Uremic Syndrome (HUS), a disease triggered by Shiga toxin (Stx), is characterized by hemolytic anemia, thrombocytopenia and renal failure. The inflammatory response mediated by polymorphonuclear neutrophils (PMNs) and monocytes is essential to HUS onset. Still, the role of anti-inflammatory cytokines is less clear. The deficiency of IL-10, an anti-inflammatory cytokine, leads to severe pathology in bacterial infections but also to beneficial effects in models of sterile injury. The aim of this work was to analyze the role of IL-10 during HUS. Control and IL-10 lacking mice (IL-10-/-) were intravenously injected with Stx type 2 (Stx2) and survival rate was evaluated. PMN and circulating and renal pro- and anti-inflammatory factors were analyzed by FACS and enzyme-linked immunosorbent assay (ELISA) respectively. IL-10-/- mice showed a higher survival associated with lower renal damage reflected by reduced plasma urea and creatinine levels than control mice. Circulating PMN increased at 72 h in both mouse strains accompanied by an up-regulation of CD11b in control mice. In parallel, renal PMN were significantly increased only in control mice after toxin. Plasma TNF-α, IL-6 and corticosterone levels were higher increased in IL-10-/- than control mice. Simultaneously renal TNF-α raised constantly but was accompanied by increased TGF-ß levels in IL-10-/- mice. These results demonstrate that the profile of circulating and renal cytokines after Stx2 differed between strains suggesting that balance of these factors could participate in renal protection. We conclude that IL-10 absence has a protective role in an experimental model of HUS by reducing PMN recruitment into kidney and renal damage, and increasing mice survival.
Assuntos
Síndrome Hemolítico-Urêmica/induzido quimicamente , Interleucina-10/metabolismo , Toxina Shiga II/toxicidade , Animais , Corticosterona/sangue , Síndrome Hemolítico-Urêmica/patologia , Interleucina-10/genética , Interleucina-6/sangue , Rim/química , Rim/patologia , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neutrófilos , Taxa de Sobrevida , Fator de Crescimento Transformador beta , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: The inflammatory response of the host to Shiga toxin and/or lipopolysaccharide (LPS) of Escherichia coli (E. coli) is included in (HUS). The TLR4-LPS complex is internalized and TLR4 induced inflammatory signaling is stopped by targeting the complex for degradation. Rab7b, a small guanosine triphosphatase (GTPase) expressed in monocytes, regulates the later stages of the endocytic pathway. OBJECTIVE: we studied the Rab7b participation on the TLR4 endocytic pathway and its effect on monocyte cytokine production along the acute course of pediatric Shiga toxin-associated HUS. METHODS AND RESULTS: Monocytes were identified according to their positivity in CD14 expression. Surface TLR4 expression in monocytes from 18 HUS patients significantly increased by day 1 to 6, showing the highest increase on day 4 compared to monocytes of 10 healthy children. Significant higher surface TLR4 expression was accompanied by increased proinflammatory intracellular cytokines, tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). In contrast, after these time points, surface TLR4 expression and intracellular TNF-α levels, returned to near control levels after 10â¯days. Furthermore, confocal immunofluorescence microscopy proved colocalization of increased intracellular TLR4/Rab7b determined by Pearson's coefficient in monocytes from HUS patients from day 1 on the highest colocalization of both proteins by day 4. Decreased TLR4/Rab7b colocalization was shown 10â¯days after HUS onset. CONCLUSION: The colocalization of TLR4 and Rab7b allows us to suggest Rab7b participation in the control of the TLR4 endocytic pathway in HUS patient monocytes. A consequential fall in cytokine production throughout the early follow up of HUS is demonstrated.
Assuntos
Endocitose , Síndrome Hemolítico-Urêmica/metabolismo , Síndrome Hemolítico-Urêmica/patologia , Toxina Shiga/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Doença Aguda , Criança , Pré-Escolar , Citocinas/sangue , Seguimentos , Síndrome Hemolítico-Urêmica/sangue , Humanos , Lactente , Receptores de Lipopolissacarídeos/metabolismo , Monócitos/metabolismo , proteínas de unión al GTP Rab7RESUMO
Hemolytic uremic syndrome (HUS) is defined as a triad of noninmune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The most frequent presentation is secondary to Shiga toxin (Stx)-producing Escherichia coli (STEC) infections, which is termed postdiarrheal, epidemiologic or Stx-HUS, considering that Stx is the necessary etiological factor. After ingestion, STEC colonize the intestine and produce Stx, which translocates across the intestinal epithelium. Once Stx enters the bloodstream, it interacts with renal endothelial and epithelial cells, and leukocytes. This review summarizes the current evidence about the involvement of inflammatory components as central pathogenic factors that could determine outcome of STEC infections. Intestinal inflammation may favor epithelial leakage and subsequent passage of Stx to the systemic circulation. Vascular damage triggered by Stx promotes not only release of thrombin and increased fibrin concentration but also production of cytokines and chemokines by endothelial cells. Recent evidence from animal models and patients strongly indicate that several immune cells types may participate in HUS physiopathology: neutrophils, through release of proteases and reactive oxygen species (ROS); monocytes/macrophages through secretion of cytokines and chemokines. In addition, high levels of Bb factor and soluble C5b-9 (sC5b-9) in plasma as well as complement factors adhered to platelet-leukocyte complexes, microparticles and microvesicles, suggest activation of the alternative pathway of complement. Thus, acute immune response secondary to STEC infection, the Stx stimulatory effect on different immune cells, and inflammatory stimulus secondary to endothelial damage all together converge to define a strong inflammatory status that worsens Stx toxicity and disease.
Assuntos
Infecções por Escherichia coli/imunologia , Síndrome Hemolítico-Urêmica/imunologia , Microvasos/patologia , Escherichia coli Shiga Toxigênica/imunologia , Animais , Via Alternativa do Complemento/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Infecções por Escherichia coli/sangue , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Síndrome Hemolítico-Urêmica/sangue , Síndrome Hemolítico-Urêmica/microbiologia , Síndrome Hemolítico-Urêmica/patologia , Humanos , Mucosa Intestinal/microbiologia , Rim/irrigação sanguínea , Rim/imunologia , Rim/patologia , Microvasos/citologia , Microvasos/imunologia , Escherichia coli Shiga Toxigênica/isolamento & purificaçãoRESUMO
Shiga toxin (Stx) producing Escherichia coli (STEC) is responsible to bloody diarrhea (hemorrhagic colitis) and the hemolytic uremic syndrome (HUS). STEC strains carry inducible lambda phages integrated into their genomes that encode Stx 1 and/or 2, with several allelic variants each one. O157:H7 is the serotype that was documented in the vast majority of HUS cases although non-O157 serotypes have been increasingly reported to account for HUS cases. However, the outbreak that occurred in central Europe during late spring of 2011 showed that the pathogen was E. coli O104:H4. More than 4,000 persons were infected mainly in Germany, and it produced more than 900 cases of HUS resulting in 54 deaths. E. coli O104:H4 is a hybrid organism that combines some of the virulence genes of STEC and enteroaggregative E. coli specially production of Stx2 and the adherence mechanisms to intestinal epithelium. The differences in the epidemiology and presentation of E. coli pathogen meant a challenge for public health and scientific research to increase the knowledge of HUS-pathophysiology and to improve available therapies to treat HUS.
Assuntos
Diarreia/genética , Síndrome Hemolítico-Urêmica/genética , Toxina Shiga II/genética , Escherichia coli Shiga Toxigênica/genética , Bacteriófago lambda/genética , Bacteriófago lambda/patogenicidade , Diarreia/epidemiologia , Diarreia/microbiologia , Diarreia/patologia , Surtos de Doenças , Alemanha/epidemiologia , Síndrome Hemolítico-Urêmica/epidemiologia , Síndrome Hemolítico-Urêmica/microbiologia , Síndrome Hemolítico-Urêmica/patologia , Humanos , Toxina Shiga II/metabolismo , Escherichia coli Shiga Toxigênica/patogenicidade , Virulência/genéticaRESUMO
Escherichia coli shigatoxigénica (STEC) es un patógeno endémico en Argentina, responsable de diarrea aguda sanguinolenta (DAS) y/o síndrome urémico hemolítico (SUH). La correlación entre SUH y alimentos contaminados ha sido documentada, aunque no siempre se estableció la fuente de infección. La ruta de contagio persona-persona es relevante. Dados los registros previos de prevalencia de STEC en animales de compañía y los hábitos de convivencia humano-animal en centros urbanos, es necesario evaluar la ruta mascota-persona. A su vez, los roedores podrían tener un papel epidemiológico en la endemia. OBJETIVO: Estudiar posibles reservorios animales relacionados con casos de SUH/DAS en la Ciudad Autónoma de Buenos Aires y estimar la prevalencia de STEC en roedores. MÉ-TODOS: Se intervino en 28 casos de SUH y 49 de DAS. Se realizó rastrillaje de cepas STEC por PCR a partir de hisopados rectales de los animales vinculados a cada caso. La prevalencia en roedores se estimó por PCR de sus hisopados rectales. RESULTADOS: Se aislaron cepas STEC en 1/10 caninos y 1/3 felinos con vivientes con casos de SUH, y 1/9 felinos contacto con casos de DAS. Rattus rattus fue hospedero de cepas STEC en 33% de los animales capturados en focos de SUH. En roedores, la prevalencia fue de 3,1%. CONCLUSIONES: Las cepas STEC circulan en los animales que conviven o tienen al menos un hábitat compartido con la población en riesgo, quienes podrían participar en la transmisión del agente. Es necesario reevaluar las intervenciones sanitarias en focos y en programas de control de SUH/DAS
Shigatoxigenic Escherichia coli(STEC) is an endemic pathogen in Argentina, which causes bloody diarrhea (BD) and/or hemolytic uremic syndrome (HUS).The co-relation between HUS and contaminated food has been documented, although the source of infection was not always established. Person-to-person route of infection is relevant. Taking into account previous STEC prevalence data in companion animals and the habits of human-animal coexistence in urban centers, it is necessary to evaluate pet-to-person transmission. On the other hand, rodents may also play an epidemiologic role in the endemic transmission. OBJECTIVE: To study potential animal reservoirs related to HUS and BD cases in the City of Buenos Aires and to estimate the prevalence of STEC in rodents. METHODS: An intervention was conducted in 28 cases of HUS and 49 of BD. Screening for STEC was performed by PCR from rectal swabs of linked animals to each case. The prevalence in rodents was estimated by PCR from rectal swabs. RESULTS: STEC strains were isolated in 1/10 dogs and 1/3 cats cohabiting with HUS cases, and in 1/9 cats in contact with DAS cases. Rattus rattus was host of STEC strains in 33% of the animals captured in HUS areas. In rodents, the prevalence was 3.1%. CONCLUSIONS: STEC strains circulate in animals that live withor share at least the same habitat with the population at risk, and could participate in the transmission of the agent. It is necessary to re-evaluate health interventions both in outbreaks and in control programs of HUS/BD
Assuntos
Humanos , Gatos , Animais , Cães , Ratos , Infecções por Escherichia coli/diagnóstico , Infecções por Escherichia coli/prevenção & controle , Fatores de Risco , Grupos de Risco , Reservatórios de Doenças/estatística & dados numéricos , Escherichia coli Shiga Toxigênica , Síndrome Hemolítico-Urêmica/patologia , Síndrome Hemolítico-Urêmica/prevenção & controle , Vigilância Sanitária/organização & administraçãoRESUMO
Escherichia coli shigatoxigénica (STEC) es un patógeno endémico en Argentina, responsable de diarrea aguda sanguinolenta (DAS) y/o síndrome urémico hemolítico (SUH). La correlación entre SUH y alimentos contaminados ha sido documentada, aunque no siempre se estableció la fuente de infección. La ruta de contagio persona-persona es relevante. Dados los registros previos de prevalencia de STEC en animales de compañía y los hábitos de convivencia humano-animal en centros urbanos, es necesario evaluar la ruta mascota-persona. A su vez, los roedores podrían tener un papel epidemiológico en la endemia. OBJETIVO: Estudiar posibles reservorios animales relacionados con casos de SUH/DAS en la Ciudad Autónoma de Buenos Aires y estimar la prevalencia de STEC en roedores. ME-TODOS: Se intervino en 28 casos de SUH y 49 de DAS. Se realizó rastrillaje de cepas STEC por PCR a partir de hisopados rectales de los animales vinculados a cada caso. La prevalencia en roedores se estimó por PCR de sus hisopados rectales. RESULTADOS: Se aislaron cepas STEC en 1/10 caninos y 1/3 felinos con vivientes con casos de SUH, y 1/9 felinos contacto con casos de DAS. Rattus rattus fue hospedero de cepas STEC en 33% de los animales capturados en focos de SUH. En roedores, la prevalencia fue de 3,1%. CONCLUSIONES: Las cepas STEC circulan en los animales que conviven o tienen al menos un hábitat compartido con la población en riesgo, quienes podrían participar en la transmisión del agente. Es necesario reevaluar las intervenciones sanitarias en focos y en programas de control de SUH/DAS (AU)
Shigatoxigenic Escherichia coli(STEC) is an endemic pathogen in Argentina, which causes bloody diarrhea (BD) and/or hemolytic uremic syndrome (HUS).The co-relation between HUS and contaminated food has been documented, although the source of infection was not always established. Person-to-person route of infection is relevant. Taking into account previous STEC prevalence data in companion animals and the habits of human-animal coexistence in urban centers, it is necessary to evaluate pet-to-person transmission. On the other hand, rodents may also play an epidemiologic role in the endemic transmission. OBJECTIVE: To study potential animal reservoirs related to HUS and BD cases in the City of Buenos Aires and to estimate the prevalence of STEC in rodents. METHODS: An intervention was conducted in 28 cases of HUS and 49 of BD. Screening for STEC was performed by PCR from rectal swabs of linked animals to each case. The prevalence in rodents was estimated by PCR from rectal swabs. RESULTS: STEC strains were isolated in 1/10 dogs and 1/3 cats cohabiting with HUS cases, and in 1/9 cats in contact with DAS cases. Rattus rattus was host of STEC strains in 33% of the animals captured in HUS areas. In rodents, the prevalence was 3.1%. CONCLUSIONS: STEC strains circulate in animals that live withor share at least the same habitat with the population at risk, and could participate in the transmission of the agent. It is necessary to re-evaluate health interventions both in outbreaks and in control programs of HUS/BD (AU)
Assuntos
Humanos , Gatos , Animais , Cães , Ratos , Síndrome Hemolítico-Urêmica/patologia , Síndrome Hemolítico-Urêmica/prevenção & controle , Infecções por Escherichia coli/diagnóstico , Infecções por Escherichia coli/prevenção & controle , Escherichia coli Shiga Toxigênica , Grupos de Risco , Reservatórios de Doenças/estatística & dados numéricos , Vigilância Sanitária/organização & administração , Fatores de RiscoRESUMO
Postdiarrhea hemolytic uremic syndrome is the most common cause of acute renal failure in children in Argentina. Renal damage has been strongly associated with Shiga toxin (Stx), which binds to the globotriaosylceramide (Gb3) receptor on the plasma membrane of target cells. The purpose of the study was to evaluate the in vivo effects of C-9, a potent inhibitor of glucosylceramide synthase and Gb3 synthesis, on kidney and colon in an experimental model of hemolytic uremic syndrome in rats. Rats were i.p. injected with supernatant from recombinant Escherichia coli expressing Stx2 (sStx2). A group of these rats were orally treated with C-9 during 6 d, from 2 d prior until 4 d after sStx2 injection. The injection of sStx2 caused renal damage as well as a loss of goblet cells in colonic mucosa. Oral treatment with C-9 significantly decreased rat mortality to 50% and reduced the extension of renal and intestinal injuries in the surviving rats. The C-9 also decreased Gb3 and glucosylceramide expression levels in rat kidneys. It is particularly interesting that an improvement was seen when C-9 was administered 2 d before challenge, which makes it potentially useful for prophylaxis.
Assuntos
Colo/efeitos dos fármacos , Dioxanos/farmacologia , Inibidores Enzimáticos/farmacologia , Glucosiltransferases/antagonistas & inibidores , Síndrome Hemolítico-Urêmica/prevenção & controle , Rim/efeitos dos fármacos , Pirrolidinas/farmacologia , Toxina Shiga II , Triexosilceramidas/metabolismo , Administração Oral , Animais , Biomarcadores/sangue , Colo/enzimologia , Colo/patologia , Creatinina/sangue , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Glucosiltransferases/metabolismo , Síndrome Hemolítico-Urêmica/induzido quimicamente , Síndrome Hemolítico-Urêmica/enzimologia , Síndrome Hemolítico-Urêmica/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/enzimologia , Mucosa Intestinal/patologia , Rim/enzimologia , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Ureia/sangueRESUMO
BACKGROUND/AIMS: In Argentina, hemolytic uremic syndrome (HUS) constitutes the most frequent cause of acute renal failure in children. The aim of our study was to analyze the early tubular response under the effect of Shiga toxin type 2 (Stx2) in a rat experimental model of HUS. METHODS: Adult male Sprague-Dawley rats were injected intraperitoneally with culture supernatant from recombinant Escherichia coli expressing Stx2. Functional, histological, immunohistochemical and Western blot studies were performed at 48 h postinoculation. RESULTS: Renal tubules showed the loss of the epithelial markers E-cadherin and ß-catenin, and an increase in transforming growth factor-ß1 expression. We detected the expression of α-smooth muscle actin in the interstitium and fibrosis in the periglomerular areas. CONCLUSION: Our results indicate that the early tubular response to the effects of Stx2 is related to an immunophenotype change of tubular cells and the presence of mild fibrosis in the interstitium.