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Major role of iron uptake systems in the intrinsic extra-intestinal virulence of the genus Escherichia revealed by a genome-wide association study.

ABSTRACT: The genus Escherichia is composed of several species and cryptic clades, including E. coli, which behaves as a vertebrate gut commensal, but also as an opportunistic pathogen involved in both diarrheic and extra-intestinal diseases. To characterize the genetic determinants of extra-intestinal virulence within the genus, we carried out an unbiased genome-wide association study (GWAS) on 370 commensal, pathogenic and environmental strains representative of the Escherichia genus phylogenetic diversity and including E. albertii (n = 7), E. fergusonii (n = 5), Escherichia clades (n = 32) and E. coli (n = 326), tested in a mouse model of sepsis. We found that the presence of the high-pathogenicity island (HPI), a ~35 kbp gene island encoding the yersiniabactin siderophore, is highly associated with death in mice, surpassing other associated genetic factors also related to iron uptake, such as the aerobactin and the sitABCD operons. We confirmed the association in vivo by deleting key genes of the HPI in E. coli strains in two phylogenetic backgrounds. We then searched for correlations between virulence, iron capture systems and in vitro growth in a subset of E. coli strains (N = 186) previously phenotyped across growth conditions, including antibiotics and other chemical and physical stressors. We found that virulence and iron capture systems are positively correlated with growth in the presence of numerous antibiotics, probably due to co-selection of virulence and resistance. We also found negative correlations between virulence, iron uptake systems and growth in the presence of specific antibiotics (i.e. cefsulodin and tobramycin), which hints at potential "collateral sensitivities" associated with intrinsic virulence. This study points to the major role of iron capture systems in the extra-intestinal virulence of the genus Escherichia.

SUBMITTER: Galardini M

PROVIDER: S-EPMC7592755 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Major role of iron uptake systems in the intrinsic extra-intestinal virulence of the genus Escherichia revealed by a genome-wide association study.

Galardini Marco M Clermont Olivier O Baron Alexandra A Busby Bede B Dion Sara S Schubert Sören S Beltrao Pedro P Denamur Erick E

PLoS genetics 20201028 10

The genus Escherichia is composed of several species and cryptic clades, including E. coli, which behaves as a vertebrate gut commensal, but also as an opportunistic pathogen involved in both diarrheic and extra-intestinal diseases. To characterize the genetic determinants of extra-intestinal virulence within the genus, we carried out an unbiased genome-wide association study (GWAS) on 370 commensal, pathogenic and environmental strains representative of the Escherichia genus phylogenetic divers ...[more]

PMID: 33112851

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Project description:BACKGROUND:Clinical characteristics (taxonomy, virulence genes and antimicrobial resistance ) of Aeromonas in isolated from extra-intestinal and intestinal infections were investigated to describe epidemiology, associated virulence factors and optimal therapy options. METHODS:Clinical samples (n = 115) of Aeromonas were collected from a general hospital in Beijing between the period 2015 and 2017. Taxonomy was investigate by Multilocus phylogenetic analysis (MLPA), 10 putative virulence factors by use of polymerase chain reaction (PCR) and antimicrobial resistance to 15 antibiotics by use of the microbroth dilution method. RESULTS:The most common species of Aeromonas detected in samples of intestinal tract included; A. caviae (43.9%), A. veronii (35.7%), and A. dhakensis (12.2%). Prevalent species of Aeromonas collected from extra-intestinal infections included; A. hydrophila (29.4%), A. caviae (29.4%), and A. dhakensis (23.5%). A. hydrophila were detected in 1% of stool samples and 29.4% (5/17) of extra-intestinal infections. A. hydrophila strains in extra-intestinal infections were related to malignancy. The most common medical conditions among patients with Aeromonas infections included malignancy and liver-transplant related cholecystitis. Multiple drug resistance (MDR) was prevalent in extra-intestinal isolates (82.3%, 14/17) and was greater than the prevalence in intestinal isolates (30.6%, 30/98) (P < 0.05). Resistant rates of extra-intestinal isolates were 70.6, 35.3, 23.5 and 5.9% for ceftriaxone, ciprofloxacin, gentamicin and imipenem, respectively, and were higher than found in previous studies. Despite differences in the number and type of virulence genes among samples of Aeromonas, no significant correlation was found between invasion and virulent genes in intestinal or extra-intestinal infections. CONCLUSIONS:Overall results of this study support a role for Aeromonas spp. as a potential causative infectious agent of gastroenteritis, and malignancy, liver cirrhosis, post liver transplantation in immunocompromised patients. A. hydrophila was more prevalent in samples of extra-intestinal infections when compared to samples of intestinal infections, and was especially prominent in samples of patients presenting with malignancy. Aeromonas isolates from extra-intestinal samples had high rates of drug resistance but 3rd generation cephalosporins, fluoroquinolones and aminoglycosides remain as options to treat severe diarrhea. However, increasing MDR of extra-intestinal infection samples warrants monitoring.

Project description:Abnormal calcium absorption and iron overload from iron hyperabsorption can contribute to osteoporosis as found in several diseases, including hemochromatosis and thalassemia. Previous studies in thalassemic mice showed the positive effects of the iron uptake suppressor, hepcidin, on calcium transport. However, whether this effect could be replicated in other conditions is not known. Therefore, this study aimed to investigate the effects of hepcidin on iron and calcium uptake ability under physiological, iron uptake stimulation and calcium uptake suppression. To investigate the potential mechanism, effects of hepcidin on the expression of iron and calcium transporter and transport-associated protein in Caco-2 cells were also determined. Our results showed that intestinal cell iron uptake was significantly increased by ascorbic acid together with ferric ammonium citrate (FAC), but this phenomenon was suppressed by hepcidin. Interestingly, hepcidin significantly increased calcium uptake under physiological condition but not under iron uptake stimulation. While hepcidin significantly suppressed the expression of iron transporter, it had no effect on calcium transporter expression. This indicated that hepcidin-induced intestinal cell calcium uptake did not occur through the stimulation of calcium transporter expression. On the other hand, 1,25(OH)2D3 effectively induced intestinal cell calcium uptake, but it did not affect intestinal cell iron uptake or iron transporter expression. The 1,25(OH)2D3-induced intestinal cell calcium uptake was abolished by 12 mM CaCl2; however, hepcidin could not rescue intestinal cell calcium uptake suppression by CaCl2. Taken together, our results showed that hepcidin could effectively and concurrently induce intestinal cell calcium uptake while reducing intestinal cell iron uptake under physiological and iron uptake stimulation conditions, suggesting its therapeutic potential for inactive calcium absorption, particularly in thalassemic patients or patients who did not adequately respond to 1,25(OH)2D3.

Dataset Information

Major role of iron uptake systems in the intrinsic extra-intestinal virulence of the genus Escherichia revealed by a genome-wide association study.

Publications

Major role of iron uptake systems in the intrinsic extra-intestinal virulence of the genus Escherichia revealed by a genome-wide association study.

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