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.产志贺毒素大肠埃希菌（Shiga toxin-producing Escherichia coli, STEC）作为一种食源性细菌病原菌，其引发的临床结局谱广泛，从无症状携带状态直至致死性溶血性尿毒症综合征（hemolytic uremic syndrome, HUS）。本研究收集了1994年至2018年间HUS患者的临床数据与STEC菌株，通过全基因组测序对HUS相关STEC菌株进行分子特征解析，并开展统计学分析以筛选与HUS患者重症结局相关的细菌遗传因子。 在54株HUS相关STEC菌株中，O157:H7为最优势血清型（占比57%），其次为O121:H19（19%）与O26:H11（7%）。值得注意的是，部分非优势血清型如O59:H17（2%）与O109:H21（2%）同样可引发HUS。除1株例外，所有O157:H7菌株均属于进化分支8。 在中位时长为4年的随访期间，41%的患者出现了肾脏后遗症。本研究共鉴定出59个与重症肾脏后遗症显著相关的毒力基因，这些基因编码Ⅱ型与Ⅲ型分泌系统效应蛋白、分子伴侣及其他相关因子。值得关注的是，与重症临床结局相关的毒力基因在O157:H7菌株中的携带率显著更高。与之相反，与轻症症状相关的基因则在所有血清型菌株中均匀分布。 全基因组系统发育分析结果显示，HUS相关STEC菌株具有较高的基因组多样性，且未发现HUS相关菌株与非HUS STEC菌株存在明显的进化聚类。 本研究表明，尽管非O157血清型的临床重要性日益凸显，但O157:H7仍是STEC相关HUS的主要致病菌。此外，O157:H7菌株与患者随访期间出现的重症肾脏后遗症相关，这可能是HUS患者长期预后的一项风险因素。