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Dynamic Gene Network Analysis of Caco-2 Cell Response to Shiga Toxin-Producing Escherichia coli-Associated Hemolytic–Uremic Syndrome

ABSTRACT: A dynamic network approach was conducted to investigate the differential Caco-2 response to two STEC isolates - EH41, isolated from a HUS patient in Australia, and Ec472/01, isolated from bovine feces in Brazil - along in vitro enterocyte-bacteria interaction. The genomic analysis was based on temporal gene co-expression analysis (GCN) data in order to gain a better understanding on the molecular mechanisms underlying the capacity to cause HUS. The GCN topological analyses for Caco-2/EH41 group revealed loss of the scale-free status after one hour of interaction, persistence of this condition along the second hour and establishment of a new gene hierarchy thereafter. These events resemble the gene network mechanism of health-disease transition. The new established network represents an adaptive cell response to the pathogen and not the return to a “normal” state. Conversely, the networks for Caco-2/Ec472 group showed a slow and progressive loss of the scale-free status without its restoration at the end of the time interval here studied. These results contribute for a better understanding of the molecular mechanism involved in STEC pathogenicity associated to HUS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104488 | GEO | 2019/07/15

REPOSITORIES: GEO

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Dynamic Gene Network Analysis of Caco-2 Cell Response to Shiga Toxin-Producing Escherichia coli-Associated Hemolytic–Uremic Syndrome

Project description:A dynamic network approach was conducted to investigate the differential Caco-2 response to two STEC isolates - EH41, isolated from a HUS patient in Australia, and Ec472/01, isolated from bovine feces in Brazil - along in vitro enterocyte-bacteria interaction. The genomic analysis was based on temporal gene co-expression analysis (GCN) data in order to gain a better understanding on the molecular mechanisms underlying the capacity to cause HUS. The GCN topological analyses for Caco-2/EH41 group revealed loss of the scale-free status after one hour of interaction, persistence of this condition along the second hour and establishment of a new gene hierarchy thereafter. These events resemble the gene network mechanism of health-disease transition. The new established network represents an adaptive cell response to the pathogen and not the return to a “normal” state. Conversely, the networks for Caco-2/Ec472 group showed a slow and progressive loss of the scale-free status without its restoration at the end of the time interval here studied. These results contribute for a better understanding of the molecular mechanism involved in STEC pathogenicity associated to HUS.

2019-07-15 | GSE104489 | GEO

Comparative Transcriptome Profiling Reveals a Potential Role of Type VI Secretion System and Fimbriae in Virulence of Non-O157 Shiga Toxin-Producing Escherichia coli

Project description:We have used RNA sequencing to compare transcriptomes of 30 stx2a and eae positive STEC strains of non-O157 serogroups isolated from children < 5 years of age. The strains were from children with HUS (HUS group, n=15), and children with asymptomatic or mild disease (non-HUS group, n=15), either induced with mitomycin C or non-induced, to reveal potential differences in gene expression levels between groups. When the HUS and non-HUS group were compared for differential expression of protein-encoding gene families, 399 of 6119 gene families were differentially expressed (log2 fold change ≥ 1, FDR < 0.05) in the non-induced condition, whereas only one gene family was differentially expressed in the induced condition. Gene ontology and cluster analysis showed that several fimbrial operons, as well as a putative type VI secretion system (T6SS) were more highly expressed in the HUS group than in the non-HUS group, indicating a role of these in the virulence of STEC strains causing severe disease.

2018-07-16 | GSE112430 | GEO

A HUS-associated STEC expressing a dicA transcriptional module is related to gene network dysregulation in Caco-2

Project description:We conducted comparative gene co-expression network (GCN) analyses of two O113:H21 STEC strains: EH41, reference strain, isolated from hemolytic-uremic syndrome patient in Australia, and Ec472/01, isolated from cattle feces in Brazil. These strains were cultured in fresh or in Caco-2 cell conditioned media. GCN analyses were also accomplished for cultured Caco-2 cells exposed to EH41 or Ec472/01. Differential transcriptome profiles for EH41 and Ec472/01 were not significantly changed by exposure to fresh or Caco-2 conditioned media. Conversely, global gene expression comparison of both strains cultured in conditioned medium revealed a gene set exclusively expressed in EH41, which includes the dicA putative virulence factor regulator. Network analysis showed that this set of genes constitutes an EH41 specific transcriptional module. The GCNs of Caco-2 cells exposed to EH41 or to Ec472/01 presented a major transcriptional module containing many hubs related to inflammatory response that was not found in the GCN of control cells. Moreover, EH41 seems to cause gene network dysregulation in Caco-2. Therefore, EH41 virulence may be derived from its capacity for dysregulating enterocyte genome functioning and its enhanced enteric survival due to slow growth.

2018-01-05 | GSE45979 | GEO

Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review.

Project description:The severity of human infection by one of the many Shiga toxin-producing Escherichia coli (STEC) is determined by a number of factors: the bacterial genome, the capacity of human societies to prevent foodborne epidemics, the medical condition of infected patients (in particular their hydration status, often compromised by severe diarrhea), and by our capacity to devise new therapeutic approaches, most specifically to combat the bacterial virulence factors, as opposed to our current strategies that essentially aim to palliate organ deficiencies. The last major outbreak in 2011 in Germany, which killed more than 50 people in Europe, was evidence that an effective treatment was still lacking. Herein, we review the current knowledge of STEC virulence, how societies organize the prevention of human disease, and how physicians treat (and, hopefully, will treat) its potentially fatal complications. In particular, we focus on STEC-induced hemolytic and uremic syndrome (HUS), where the intrusion of toxins inside endothelial cells results in massive cell death, activation of the coagulation within capillaries, and eventually organ failure.

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Shiga Toxin-Associated Hemolytic Uremic Syndrome in Adults, France, 2009-2017.

Project description:We conducted a retrospective study on hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC) in 96 adults enrolled in the cohort of the National Reference Center for Thrombotic Microangiopathies network in France during 2009-2017. Most infections were caused by STEC strains not belonging to the O157 or O104 serogroups. Thirty (31.3%) patients had multiple risk factors for thrombotic microangiopathy. In total, 61 (63.5%) patients required dialysis, 50 (52.1%) had a serious neurologic complication, 34 (35.4%) required mechanical ventilation, and 19 (19.8%) died during hospitalization. We used multivariate analysis to determine that the greatest risk factors for death were underlying immunodeficiency (hazard ratio 3.54) and severe neurologic events (hazard ratio 3.40). According to multivariate analysis and propensity score-matching, eculizumab treatment was not associated with survival. We found that underlying conditions, especially immunodeficiency, are strongly associated with decreased survival in adults who have hemolytic uremic syndrome caused by STEC.

| S-EPMC8237898 | biostudies-literature

Shiga toxin-mediated hemolytic uremic syndrome: time to change the diagnostic paradigm?

Project description:BACKGROUND:Hemolytic uremic syndrome (HUS) is caused by enterohemorrhagic Escherichia coli (EHEC) which possess genes encoding Shiga toxin (stx), the major virulence factor, and adhesin intimin (eae). However, the frequency of stx-negative/eae-positive E. coli in stools of HUS patients and the clinical significance of such strains are unknown. METHODOLOGY/PRINCIPAL FINDINGS:Between 1996 and 2006, we sought stx-negative/eae-positive E. coli in stools of HUS patients using colony blot hybridization with the eae probe and compared the isolates to EHEC causing HUS. stx-negative/eae-positive E. coli were isolated as the only pathogens from stools of 43 (5.5%) of 787 HUS patients; additional 440 (55.9%) patients excreted EHEC. The majority (90.7%) of the stx-negative/eae-positive isolates belonged to serotypes O26:H11/NM (nonmotile), O103:H2/NM, O145:H28/NM, and O157:H7/NM, which were also the most frequent serotypes identified among EHEC. The stx-negative isolates shared non-stx virulence and fitness genes with EHEC of the corresponding serotypes and clustered with them into the same clonal complexes in multilocus sequence typing, demonstrating their close relatedness to EHEC. CONCLUSIONS/SIGNIFICANCE:At the time of microbiological analysis, approximately 5% of HUS patients shed no longer the causative EHEC, but do excrete stx-negative derivatives of EHEC that lost stx during infection. In such patients, the EHEC etiology of HUS is missed using current methods detecting solely stx or Shiga toxin; this can hamper epidemiological investigations and lead to inappropriate clinical management. While maintaining the paradigm that HUS is triggered by Shiga toxin, our data demonstrate the necessity of considering genetic changes of the pathogen during infection to adapt appropriately diagnostic strategies.

| S-EPMC1995754 | biostudies-literature

Dynamic Gene Network Analysis of Caco-2 Cell Response to Shiga Toxin-Producing Escherichia coli-Associated Hemolytic–Uremic Syndrome

Project description:Dynamic Gene Network Analysis of Caco-2 Cell Response to Shiga Toxin-Producing Escherichia coli-Associated Hemolytic–Uremic Syndrome

| PRJNA412855 | ENA

Dynamic gene network analysis of Caco-2 cell response to Shiga toxin-producing Escherichia coli-associated hemolytic-uremic syndrome

Project description:Dynamic gene network analysis of Caco-2 cell response to Shiga toxin-producing Escherichia coli-associated hemolytic-uremic syndrome

| PRJNA412830 | ENA

Dynamic Gene Network Analysis of Caco-2 Cell Response to Shiga Toxin-Producing Escherichia coli-Associated Hemolytic–Uremic Syndrome

Project description:Dynamic Gene Network Analysis of Caco-2 Cell Response to Shiga Toxin-Producing Escherichia coli-Associated Hemolytic–Uremic Syndrome

| PRJNA412854 | ENA

Complement Activation Contributes to the Pathophysiology of Shiga Toxin-Associated Hemolytic Uremic Syndrome.

Project description:Shiga toxin (Stx)-producing Escherichia coli (STEC) infections have become a threat to public health globally because of the severe illnesses that they can trigger, such as hemorrhagic colitis and the post-diarrheal hemolytic uremic syndrome (HUS), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. Glomerular endothelial cells are primary targets of Stx which, after binding to its specific receptor globotriaosylceramide, upregulates proinflammatory proteins involved both in the recruitment and adhesion of leukocytes and thrombus formation at the site of endothelial injury. In this review, we discuss the role of complement activation in promoting glomerular microvascular dysfunction, providing evidence from experimental models and patients with STEC-HUS. Within the glomerulus, an important target for Stx-induced complement activation is the podocyte, a cell type that is in close contact with endothelial cells and participates in maintaining the filtration barrier. Recently, podocyte injury and loss have been indicated as potential risk factors for long-term renal sequelae in patients with STEC-HUS. Therapeutic approaches targeting the complement system, that may be useful options for patients with STEC-HUS, will also be discussed.

| S-EPMC6352217 | biostudies-literature

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