Genome-wide association study of hemolytic uremic syndrome causing Shiga toxin-producing Escherichia coli from Sweden, 1994–2018

Abstract

Shiga toxin-producing Escherichia coli (STEC) infection can cause clinical manifestations ranging from diarrhea to potentially fatal hemolytic uremic syndrome (HUS). This study is aimed at identifying STEC genetic factors associated with the development of HUS in Sweden. A total of 238 STEC genomes from STEC-infected patients with and without HUS between 1994 and 2018 in Sweden were included in this study. Serotypes, Shiga toxin gene (stx) subtypes, and virulence genes were characterized in correlation to clinical symptoms (HUS and non-HUS), and pan-genome wide association study was performed. Sixty-five strains belonged to O157:H7, and 173 belonged to non-O157 serotypes. Our study revealed that strains of O157:H7 serotype especially clade 8 were most commonly found in patients with HUS in Sweden. stx2a and stx2a + stx2c subtypes were significantly associated with HUS. Other virulence factors associated with HUS mainly included intimin (eae) and its receptor (tir), adhesion factors, toxins, and secretion system proteins. Pangenome wide-association study identified numbers of accessory genes significantly overrepresented in HUS-STEC strains, including genes encoding outer membrane proteins, transcriptional regulators, phage-related proteins, and numerous genes related to hypothetical proteins. Whole-genome phylogeny and multiple correspondence analysis of pangenomes could not differentiate HUS-STEC from non-HUS-STEC strains. In O157:H7 cluster, strains from HUS patients clustered closely; however, no significant difference in virulence genes was found in O157 strains from patients with and without HUS. These results suggest that STEC strains from different phylogenetic backgrounds may independently acquire genes determining their pathogenicity and confirm that other non-bacterial factors and/or bacteria-host interaction may affect STEC pathogenesis.

Epidemiological Characteristics of Shiga Toxin-Producing Escherichia coli Responsible for Infections in the Polish Pediatric Population

“…The molecular mechanism underlying the pathogenicity of different STEC strains requires further elucidation. Stx2d has been described as a Shiga toxin whose cytotoxicity is activated 10- to 1,000-fold by elastase present in the intestinal mucus of mice or man ( Matussek et al 2023 ). Clinical STEC strains may have the following genes: stx2a, stx2b, stx2c, stx2d, stx2e, stx2f, stx2g, stx2h, stx2i, stx2j, stx2k, stx2l, stx2m ( Bai et al 2021 ).…”

“…Bacterial genetic factors identified as molecular predictors of the development of HUS included stx subtype stx2a , stx2a , and stx2c and genes encoding intimin, toxins, secretory system proteins, and transcription regulators ( Sallée et al 2013 ). Rapid diagnostic targeting of these genes directly in stool samples could lead to improved care and infection control measures, reducingthe number of patients suffering from severe STEC disease ( Matussek et al 2023 ).…”

“…No significant differences have been described between the fecal microflora of excretors and non-excretors ( Bibbal et al 2022 ). Matussek et al (2023 ) performed whole-genome multilocus sequence typing and genome-wide phylogeny analysis to assess the phylogenetic relatedness of STEC isolates from HUS and non-HUS patients and suggested genetic differences of pathogenic STEC strains in different geographic regions and populations. Human immunity and/or bacteria-host interaction may affect STEC-related disease progression.…”

“…Personalized medicine and sequencing of patient’s DNA in the STEC-HUS diagnostic process may answer the question of what genetic variability in human genes is a critical factor and why STEC diarrhea in a patient resolves spontaneously while in others it leads to HUS. Whole-genome phylogeny and multiple pangenome correspondence analysis did not separate HUS-STEC strains from non-HUS-STEC strains, suggesting that STEC strains of different genetic origins may independently acquire genes determining their pathogenicity and that other non-bacterial factors may play a key role in the pathogenicity of HUS development ( Matussek et al 2023 ). Recent data suggest the involvement of the complement system in the pathogenesis of STEC-HUS ( Mele et al 2014 ).…”

Complex effects of the exo-xis region of the Shiga toxin-converting bacteriophage Φ24B genome on the phage development and the Escherichia coli host physiology

“…While most Escherichia coli strains are harmless commensals, the Shiga toxin-producing E. coli (STEC) strains and related enterohemorrhagic E. coli (EHEC) subtypes contribute to food poisoning and kidney disorders in human populations throughout the world (Kaper et al 2004 ; Bugarel et al 2011 ). In the USA, STEC causes 100,000 illnesses, 3000 hospitalizations, and 90 deaths annually (Al Qabili et al 2022 ), with comparable effects in other countries (Auvray et al 2023 ; Matussek et al 2023 ; Rodwell et al 2023 ; Svendsen et al 2023 ).…”