A woman got a UTI. Two years later, the bacteria had evolved, invaded her brain.
A woman got a UTI. Two years later, the bacteria had evolved, invaded her brain.
一名女性患上尿路感染，两年后，细菌发生变异并侵入大脑。
A 63-year-old woman arrived at a hospital in pain. She had abruptly lost vision in her right eye. As doctors got to work, the series of findings that followed revealed not just bad news for her, but an alarming revelation of how infections can evolve within a patient. The woman’s remarkable case was reported this week in the New England Journal of Medicine.
一名 63 岁的女性因剧烈疼痛来到医院就诊。她的右眼突然失明。随着医生展开检查，随后的一系列发现不仅对她来说是个坏消息，更揭示了一个令人担忧的事实：感染如何在患者体内演变。这起非同寻常的病例于本周发表在《新英格兰医学杂志》上。
According to her doctors, initial magnetic resonance imaging scans of her brain quickly identified the key problem. The imaging indicated inflammation in her right eye, but also picked up lesions in her brain. Specifically, the imaging suggested problems in her parietal lobe, which is a hub for processing sensory information. The doctors suspected she had a brain abscess. Laboratory results of her blood and urine samples suggested an infection as well as kidney problems.
据其主治医生称，最初的脑部核磁共振成像（MRI）扫描很快锁定了关键问题。影像显示她的右眼存在炎症，同时大脑中也出现了病变。具体而言，影像提示她的顶叶（处理感觉信息的中枢）存在问题。医生怀疑她患有脑脓肿。血液和尿液样本的实验室检查结果也提示存在感染及肾脏问题。
Doctors decided to open up her skull for a brain biopsy. Inside, the surgical team was met with pus. Meanwhile, doctors worked to identify the bacteria found in two urine samples. In all, the two urine samples and the brain sample all grew the same bacteria: Klebsiella pneumoniae. This is a bacterium well known to doctors. It often dwells in the gastrointestinal tract, but can lurk in healthcare settings and spark infections, particularly pneumonia and urinary tract infections.
医生决定进行开颅手术进行脑部活检。手术团队在内部发现了脓液。与此同时，医生们致力于鉴定在两份尿液样本中发现的细菌。最终，两份尿液样本和脑部样本均培养出了同一种细菌：肺炎克雷伯菌（Klebsiella pneumoniae）。这是医生们非常熟悉的一种细菌。它常栖息于胃肠道中，但也可能潜伏在医疗环境中并引发感染，尤其是肺炎和尿路感染。
It’s also known for having a variant that can go metastatic, traveling via the bloodstream to invade other organs, particularly the liver, but also the lungs, eyes, and brain. In a standard case report, this might be the end of the story. Doctors would diagnose a disseminated K. pneumoniae infection and treat with antibiotics. But there was more.
该菌还以一种能够发生转移的变体而闻名，它可以通过血液循环侵入其他器官，尤其是肝脏，但也可能侵入肺部、眼睛和大脑。在标准的病例报告中，这可能就是故事的结局了。医生会诊断为肺炎克雷伯菌播散性感染并使用抗生素治疗。但事实远不止于此。
Doctors and researchers brought in to help with the case noticed that although the three samples all grew K. pneumoniae, the bacteria were different. Bacteria in the first urine sample looked like normal K. pneumoniae. But the bacteria from the second urine sample and the brain were gloopy and sticky. Under an electron microscope, the doctors could see that the K. pneumoniae in these two samples had thick capsules—they were seemingly encased in goop.
参与此病例的医生和研究人员注意到，尽管三个样本都培养出了肺炎克雷伯菌，但这些细菌并不相同。第一份尿液样本中的细菌看起来像正常的肺炎克雷伯菌，但来自第二份尿液样本和大脑中的细菌却呈现出粘稠状。在电子显微镜下，医生可以看到这两个样本中的肺炎克雷伯菌拥有厚厚的荚膜——它们似乎被包裹在粘液中。
Further tests showed that the thick sticky coating made these bacteria more virulent than the normal-looking bacteria from the first urine sample. With the coating, protective immune cells called macrophages couldn’t gobble up the bacteria as they could with the normal K. pneumoniae. In mice, the snotty bacteria were lethal, while the normal one wasn’t. In all, the two sticky samples met the definition of hypervirulent K. pneumoniae—the kind known for going metastatic.
进一步的测试表明，这种厚厚的粘性外壳使得这些细菌比第一份尿液样本中看起来正常的细菌毒性更强。有了这层外壳，被称为巨噬细胞的保护性免疫细胞无法像吞噬正常肺炎克雷伯菌那样吞噬它们。在小鼠实验中，这种粘液状细菌具有致命性，而正常细菌则不然。总而言之，这两个粘性样本符合高毒力肺炎克雷伯菌的定义——即那种以发生转移而闻名的类型。
But being hypervirulent wasn’t all fun and brain-eating games for these bacteria; it had drawbacks, too, the researchers found. The hypervirulent bacteria couldn’t grow nearly as quickly. They also couldn’t infect cells in the bladder as well. Genome sequencing of the three bacterial samples showed that they were all highly related. And, interestingly, they all lacked the hallmark genes associated with hypervirulence in K. pneumoniae.
但研究人员发现，对于这些细菌来说，高毒力并非全是“好事”；它也有缺点。高毒力细菌的生长速度远不如正常细菌，且感染膀胱细胞的能力也较弱。对三个细菌样本的基因组测序显示，它们之间亲缘关系极高。有趣的是，它们都缺乏与肺炎克雷伯菌高毒力相关的标志性基因。
The bacteria in the two urine samples differed by 66 small mutations, while the two hypervirulent bacterial samples differed by just four small mutations. These two hypervirulent bacterial samples had key mutations in genes that produce the bacterium’s capsule, explaining their gloopiness. (The researchers confirmed this by genetically engineering normal K. pneumoniae to contain these specific mutations, which reproduced the goopiness.)
两份尿液样本中的细菌存在 66 个微小突变差异，而两个高毒力细菌样本之间仅有 4 个微小突变差异。这两个高毒力细菌样本在产生细菌荚膜的基因中存在关键突变，这解释了它们的粘稠性。（研究人员通过基因工程改造正常的肺炎克雷伯菌，使其包含这些特定突变，从而成功复现了这种粘稠性，证实了这一点。）
With the genome sequencing, the researchers estimated that the bacteria in the two urine samples diverged from a common ancestor one to two years before the woman’s current state. Then, more recently, the hypervirulent urine bacteria disseminated, spreading to the woman’s brain. The woman’s doctors noted that two years before her brain abscess, she was hospitalized with a urinary tract infection.
通过基因组测序，研究人员估计两份尿液样本中的细菌在患者当前状况发生前的一到两年内，从共同祖先分化出来。随后，在更近的时间里，这些高毒力的尿液细菌发生了播散，扩散到了患者的大脑。患者的主治医生指出，在脑脓肿发生前两年，她曾因尿路感染住院。
Bacterial evolution within a single patient is not particularly new. Infecting bacteria often adapt to have a fitness advantage in their victim. But in most cases, the variant with the biggest edge overtakes the population. In less common cases, the population splits. This has been seen when bacteria are trying to survive antibiotic treatments. In this case, some variants become more resistant to the treatment, but the resistance comes at a cost—slower growth or less virulence, for example. This keeps them from dominating. Instead, they remain as a subpopulation. This scenario is called ‘heteroresistance,’ which is linked to treatment failure.
在单一患者体内发生细菌演变并不算新鲜事。致病细菌通常会为了在宿主体内获得生存优势而进行适应。但在大多数情况下，具有最大优势的变体最终会占据主导地位。在较少见的情况下，种群会发生分化。当细菌试图在抗生素治疗中存活时，就会出现这种情况。在这种情况下，一些变体变得对抗生素更具耐药性，但这种耐药性是有代价的——例如生长变慢或毒力降低。这使得它们无法占据主导地位，而是作为亚群存在。这种情况被称为“异质耐药性”（heteroresistance），它与治疗失败有关。
In the woman’s case, all three isolates were susceptible to antibiotics—some good news. She was able to be treated with antibiotics to clear the infection. Further, most patients with K. pneumoniae brain abscesses recover, though there were no follow-up details of how her neurologic or vision recovery went. While her infection didn’t have heteroresistance, it had something new: heterovirulence.
在这一病例中，所有三个分离株对抗生素均敏感——这算是个好消息。她能够通过抗生素治疗清除感染。此外，大多数患有肺炎克雷伯菌脑脓肿的患者都能康复，尽管目前没有关于她神经系统或视力恢复情况的后续细节。虽然她的感染没有表现出异质耐药性，但它表现出了一种新现象：异质毒力（heterovirulence）。
The hypervirulent subpopulation had a fitness disadvantage in the urinary tract—the origin of the infection. But it had an advantage for dissemination and virulence, spreading to the brain and eye. Overall, the researchers and doctors report that “this case shows the ability of K. pneumoniae to disseminate within a patient from a clinical (urinary) reservoir to distant body sites and highlights the potential for the emergence.”
高毒力亚群在尿路（感染源）中处于生存劣势，但在播散和毒力方面却具有优势，从而扩散到了大脑和眼睛。总的来说，研究人员和医生报告称：“该病例展示了肺炎克雷伯菌在患者体内从临床（尿路）储存库向身体远端部位播散的能力，并突显了这种演变出现的可能性。”