150 research primates got diarrhea, flooding lab with priceless vaccine data
150 research primates got diarrhea, flooding lab with priceless vaccine data
150 只实验灵长类动物腹泻，为实验室提供了无价的疫苗数据
Having more than 150 non-human primates at a research center fall ill with diarrhea in a stomach-churning outbreak that flowed for over two years doesn’t sound much like good fortune. But for some scientists, it kind of was, providing a heaping pile of valuable data on how they might finally defeat a foul foe. 在一家研究中心，超过 150 只非人灵长类动物因一场令人作呕的腹泻疫情而病倒，这场疫情持续了两年多，听起来似乎并非什么好事。但对一些科学家来说，这反而成了一种机遇，为他们提供了大量宝贵的数据，帮助他们最终战胜这一顽敌。
In a study published in the latest issue of Science Translational Medicine, scientist sifted through the dump of immunological data from the infections, logging new ways to train immune cells to defeat the bacteria behind the outbreak, a type of Shigella. Researchers were able to pluck out specific bits of the bacteria that the immune system could most effectively attack, linking specific target molecules to specific types of germ-busting immune responses. 在最新一期《科学转化医学》（Science Translational Medicine）杂志发表的一项研究中，科学家们梳理了从感染中获取的海量免疫学数据，记录了训练免疫细胞以击败引发疫情的细菌（一种志贺氏菌）的新方法。研究人员成功筛选出了免疫系统最能有效攻击的细菌特定片段，并将特定的目标分子与特定类型的抗病原体免疫反应联系了起来。
The researchers even precisely homed in on some of the tiny notches within those craggy target molecules where the most potent antibodies attached. In all, the study “revealed unexpected features of the anti-Shigella antibody response in naturally infected [non-human primates] and represents a step toward the rational design of Shigella vaccine candidates,” the authors write. 研究人员甚至精确锁定了那些崎岖目标分子内部的一些微小凹槽，那里正是最强效抗体附着的位置。作者在文中写道，这项研究“揭示了自然感染（非人灵长类动物）体内抗志贺氏菌抗体反应的意外特征，代表了向志贺氏菌候选疫苗合理设计迈出的一步。”
Shigella is a gastrointestinal horror, striking more than 200 million people in the world each year and killing more than 200,000, mostly children. Those who survive typically develop some protective immune responses. But, given that there are various species and serotypes of Shigella, protective immune responses tend to only work against a narrow range of the bacteria’s family. And, on top of that, Shigella strains are only becoming more resistant to antibiotics. 志贺氏菌是一种胃肠道噩梦，每年在全球范围内感染超过 2 亿人，导致超过 20 万人死亡，其中大多数是儿童。幸存者通常会产生一定的保护性免疫反应。然而，鉴于志贺氏菌存在多种物种和血清型，保护性免疫反应往往只能针对该细菌家族中极小范围的菌株有效。此外，志贺氏菌菌株对抗生素的耐药性也日益增强。
The need for a Shigella vaccine—one that can combat the whole cruddy clan—is clear. As such, there are many vaccine development efforts underway. Still, scientists have been toiling without some of the detailed molecular and structural data needed to design a sophisticated vaccine. That’s where the outbreak came in. 开发一种能够对抗整个志贺氏菌家族的疫苗迫在眉睫。因此，目前有许多疫苗研发工作正在进行中。尽管如此，科学家们在设计复杂疫苗时，一直缺乏一些必要的详细分子和结构数据。而这次疫情的爆发恰好填补了这一空白。
Data deluge
数据洪流
The outbreak began in December 2022 at the Wisconsin National Primate Research Center in Madison. Non-human primates are natural hosts for Shigella, like humans, and it’s not uncommon for outbreaks to flare at such facilities now and then. But it is unusual for an outbreak to be so big and last so long. Even some of the people who worked at the facility fell ill. 疫情始于 2022 年 12 月，地点位于麦迪逊的威斯康星国家灵长类动物研究中心。与人类一样，非人灵长类动物也是志贺氏菌的天然宿主，这类设施偶尔爆发疫情并不罕见。但像这次规模如此之大且持续时间如此之长的疫情却很不寻常。甚至连在该设施工作的一些人员也感染了疾病。
In all, there were 169 microbiologically confirmed shigellosis cases among the non-human primates. Researchers collected 151 Shigella isolates for serotyping and did whole genome sequencing on 95 representative isolates. The outbreak was caused by two related clusters of Shigella flexneri, a species that commonly strikes captive non-human primates. (Human outbreaks are more often driven by Shigella sonnei, but both species can infect either type of primate.) 总共有 169 例经微生物学证实的非人灵长类动物志贺氏菌病病例。研究人员收集了 151 株志贺氏菌分离株进行血清分型，并对 95 株代表性分离株进行了全基因组测序。此次疫情由两组相关的福氏志贺氏菌（Shigella flexneri）引起，该物种常感染圈养的非人灵长类动物。（人类疫情更多是由宋内志贺氏菌引起，但这两个物种均可感染上述两种灵长类动物。）
Of the 90 isolates tested for antimicrobial resistance, more than half (63 percent) were multidrug resistant. Most of the cases caused only mild diarrheal symptoms, but there were some asymptomatic cases and some cases that led to severe symptoms. Infants were the hardest hit, similar to what’s seen in humans. 在接受抗菌药物耐药性测试的 90 株分离株中，超过半数（63%）具有多重耐药性。大多数病例仅表现出轻微的腹泻症状，但也有一些无症状病例和导致严重症状的病例。幼崽受到的影响最为严重，这与人类的情况类似。
The researchers drew serum, plasma, and specific types of immune cells from 41 infected animals across their infections, taking samples at 1, 2, and between 4 to 6 weeks after an infection was detected. Then they went to work dissecting the immune responses. 研究人员从 41 只受感染动物的整个感染过程中提取了血清、血浆和特定类型的免疫细胞，分别在检测到感染后的第 1 周、第 2 周以及第 4 至 6 周采集样本。随后，他们开始着手剖析这些免疫反应。
The researchers started by looking for antibodies that attacked a known target on Shigella, the O-antigen. This is the outermost component of a large molecule that juts out from the bacteria’s outermost membrane. The molecule is called LPS, or lipopolysaccharide. LPS is found exclusively on bacteria, specifically Gram-negative bacteria, a group that includes E. coli, Salmonella, and Shigella. 研究人员首先寻找攻击志贺氏菌已知目标——O-抗原的抗体。这是从细菌最外层膜伸出的大分子的最外层成分。该分子被称为 LPS，即脂多糖。LPS 仅存在于细菌中，特别是革兰氏阴性菌，这一类群包括大肠杆菌、沙门氏菌和志贺氏菌。
The molecule functions as a structural component of the outer membrane, among other things. But given its position on the rim of these bacterial cells, it—and specifically, the outer-most O-antigen component—is a common target of the immune system. However, in Shigella, it’s variable, so antibodies against one serotype’s O-antigen may not be helpful in fighting off other serotypes. 该分子除了其他功能外，还作为外膜的结构成分。但鉴于它位于这些细菌细胞的边缘，它——特别是最外层的 O-抗原成分——成为了免疫系统的常见攻击目标。然而，在志贺氏菌中，它是可变的，因此针对一种血清型 O-抗原的抗体可能无法帮助抵御其他血清型。
Key findings
关键发现
The researchers found various antibodies that bound to the Shigella’s O-antigen. But some seemed to have been honed from repeated exposures to the bacteria. And most interestingly, they seemed to develop the ability to attack O-antigen from many different Shigella serotypes—a feat that would be critical for the success of a vaccine. 研究人员发现了多种与志贺氏菌 O-抗原结合的抗体。但其中一些似乎是通过反复接触细菌而“磨练”出来的。最有趣的是，它们似乎具备了攻击多种不同志贺氏菌血清型 O-抗原的能力——这一特性对于疫苗的成功至关重要。
Moreover, they found that the antibodies that bound tightly to the O-antigen could trigger cascading reactions of plasma proteins that end with the bacterial cells being disintegrated—another useful feature. 此外，他们发现，与 O-抗原紧密结合的抗体可以触发血浆蛋白的级联反应，最终导致细菌细胞解体——这是另一个有用的特征。
Next, they looked at antibodies that attacked part of a type 3 secretion system, or T3SS for short. This is a common apparatus that bacteria assemble to attack their victims. When the components come together, a T3SS forms a syringe-like structure, complete with a needle that pokes out from the bacterial cell into a cell it’s trying to attack. 接下来，他们研究了攻击 III 型分泌系统（简称 T3SS）部分的抗体。这是细菌组装用来攻击受害者的一种常见装置。当各组件结合在一起时，T3SS 会形成一种类似注射器的结构，并配有一根从细菌细胞伸出、刺入其试图攻击的细胞的“针”。
The bacteria then pumps in a suite of proteins, called effectors. These can have a variety of specific functions but generally work to dampen the host cell’s defenses and promote a comfy environment for the invading bacteria. At the very tip of Shigella’s T3SS, there are two proteins, IpaB and IpaD, that antibodies from the non-human primates attacked. These, the scientists found, were generally able to spur protective responses from immune cells, including T cells. 随后，细菌会泵入一系列被称为“效应蛋白”的蛋白质。这些蛋白质具有多种特定功能，但通常旨在削弱宿主细胞的防御能力，并为入侵细菌营造一个舒适的环境。在志贺氏菌 T3SS 的最顶端，有两种蛋白质 IpaB 和 IpaD，它们受到了来自非人灵长类动物抗体的攻击。科学家发现，这些抗体通常能够激发包括 T 细胞在内的免疫细胞产生保护性反应。
Sorting through the antibodies, the scientists found some of them seemed to backfire, sparking reactions that helped Shigella burst blood cells. Others, however, prevented blood cell bursting. They found that these two types of antibodies bound to the tip proteins at different niches within the proteins. The researchers were able to identify the exact… 在对抗体进行分类时，科学家们发现其中一些似乎适得其反，引发了帮助志贺氏菌破坏血细胞的反应。然而，另一些抗体则阻止了血细胞的破裂。他们发现，这两类抗体结合在顶端蛋白质内部不同的位点上。研究人员成功识别出了确切的……