A Novel Method of Serum Resistance by Escherichia coli That Causes Urosepsis.
A Novel Method of Serum Resistance by Escherichia coli That Causes Urosepsis.
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DOI：
10.1128/mbio.00920-18
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发表时间：
2018-06-26
期刊：
影响因子：
6.4
通讯作者：
Wells TJ
中科院分区：
文献类型：
--
作者：
Coggon CF;Jiang A;Goh KGK;Henderson IR;Schembri MA;Wells TJ
尿路致病性大肠杆菌（UPEC）是尿路感染的最常见原因，在某些患者中可发展为危及生命的尿脓毒症。血清抗性是引起尿脓毒症的菌株的关键毒力性状。最近，我们发现了一种新的方法，在铜绿假单胞菌肺部感染患者的血清抵抗，其中患者拥有抗体，抑制补体介导的杀伤（而不是保护免受感染）。这些抑制性抗体为IgG 2亚型，对脂多糖（LPS）的O-抗原组分具有特异性，并包被细菌表面，防止补体引起的细菌裂解。由于这种机制可以适用于任何革兰氏阴性细菌感染，我们假设抑制性抗体可能代表了UPEC血清耐药的一种未表征的机制。为了测试这一点，对45名具有成对血培养UPEC分离株的尿脓毒症患者筛选对其同源菌株的LPS特异性的IgG 2的血清滴度。11例患者具有足够高的抗体滴度，以抑制合并的健康对照血清对UPEC分离株的血清介导的杀伤。消耗IgG或去除O-抗原恢复了分离株对同源患者血清的敏感性。重要的是，来自这11名患者的分离株对血清的杀伤作用比来自没有抑制性抗体的患者的分离株更敏感。这表明抑制性抗体的存在可能使这些菌株感染血液。具有抑制性抗体的患者的高患病率（24%）表明这种现象是UPEC血清抵抗的重要机制。目前已经鉴定出针对三种引起不同疾病的革兰氏阴性病原体的LPS特异性抑制性抗体。尽管脓毒症的早期检测和管理有所改善，但发病率和死亡率仍然很高。泌尿道感染是脓毒症最常见的来源之一，大肠杆菌是主要的病原体。血清抵抗力对于细菌感染血液至关重要。在这里，我们报告了一种新的方法，发现血清抵抗患者与UPEC介导的脓毒症。血清中的抗体通常可以防止感染，但我们发现24%的患者表达了“抑制性抗体”，能够阻止血清介导的对感染分离株的杀伤。我们的数据表明，这些抗体将允许否则血清敏感的UPEC菌株引起败血症。该队列中具有抑制性抗体的患者的高患病率表明，这是尿脓毒症患者中对补体介导的杀伤的抵抗的普遍机制，激发了应用新方法预防和治疗脓毒症的潜力。
Uropathogenic Escherichia coli (UPEC) is the most common cause of urinary tract infection, which in some patients can develop into life-threatening urosepsis. Serum resistance is a key virulence trait of strains that cause urosepsis. Recently, we identified a novel method of serum resistance in patients with Pseudomonas aeruginosa lung infections, where patients possessed antibodies that inhibited complement-mediated killing (instead of protecting against infection). These inhibitory antibodies were of the IgG2 subtype, specific to the O-antigen component of lipopolysaccharide (LPS) and coated the bacterial surface, preventing bacterial lysis by complement. As this mechanism could apply to any Gram-negative bacterial infection, we hypothesized that inhibitory antibodies may represent an uncharacterized mechanism of serum resistance in UPEC. To test this, 45 urosepsis patients with paired blood culture UPEC isolates were screened for serum titers of IgG2 specific for their cognate strain’s LPS. Eleven patients had sufficiently high titers of the antibody to inhibit serum-mediated killing of UPEC isolates by pooled healthy control sera. Depletion of IgG or removal of O-antigen restored sensitivity of the isolates to the cognate patient serum. Importantly, the isolates from these 11 patients were more sensitive to killing by serum than isolates from patients with no inhibitory antibodies. This suggests the presence of inhibitory antibodies may have allowed these strains to infect the bloodstream. The high prevalence of patients with inhibitory antibodies (24%) suggests that this phenomenon is an important mechanism of UPEC serum resistance. LPS-specific inhibitory antibodies have now been identified against three Gram-negative pathogens that cause disparate diseases. Despite improvements in the early detection and management of sepsis, morbidity and mortality are still high. Infections of the urinary tract are one of the most frequent sources of sepsis with Escherichia coli the main causative agent. Serum resistance is vital for bacteria to infect the bloodstream. Here we report a novel method of serum resistance found in patients with UPEC-mediated sepsis. Antibodies in sera usually protect against infection, but here we found that 24% of patients expressed “inhibitory antibodies” capable of preventing serum-mediated killing of their infecting isolate. Our data suggest that these antibodies would allow otherwise serum-sensitive UPEC strains to cause sepsis. The high prevalence of patients with inhibitory antibodies in this cohort suggests that this is a widespread mechanism of resistance to complement-mediated killing in urosepsis patients, invoking the potential for the application of new methods to prevent and treat sepsis.