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

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.

Whole-genome characterization of hemolytic uremic syndrome-causing Shiga toxin-producing Escherichia coli in Sweden.

Shiga toxin-producing Escherichia coli, a foodborne bacterial pathogen, has been linked to a broad spectrum of clinical outcomes ranging from asymptomatic carriage to fatal hemolytic uremic syndrome (HUS). Here, we collected clinical data and STEC strains from HUS patients from 1994 through 2018, whole-genome sequencing was performed to molecularly characterize HUS-associated STEC strains, statistical analysis was conducted to identify bacterial genetic factors associated with severe outcomes in HUS patients. O157:H7 was the most predominant serotype (57%) among 54 HUS-associated STEC strains, followed by O121:H19 (19%) and O26:H11 (7%). Notably, some non-predominant serotypes such as O59:H17 (2%) and O109:H21 (2%) also caused HUS. All O157:H7 strains with one exception belonged to clade 8. During follow-up at a median of 4 years, 41% of the patients had renal sequelae. Fifty-nine virulence genes were found to be statistically associated with severe renal sequelae, these genes encoded type II and type III secretion system effectors, chaperones, and other factors. Notably, virulence genes associated with severe clinical outcomes were significantly more prevalent in O157:H7 strains. In contrast, genes related to mild symptoms were evenly distributed across all serotypes. The whole-genome phylogeny indicated high genomic diversity among HUS-STEC strains. No distinct cluster was found between HUS and non-HUS STEC strains. The current study showed that O157:H7 remains the main cause of STEC-associated HUS, despite the rising importance of other non-O157 serotypes. Besides, O157:H7 is associated with severe renal sequelae in the follow-up, which could be a risk factor for long-term prognosis in HUS patients.