圖1. 金黃色葡萄球菌的光學顯微照片
Light micrograph of Staphylococcus aureus
There’s no organism on earth that lives free of threat—including bacteria. Predatory viruses known as phages are among their most dire foes, infiltrating their cells to replicate and take over. Bacteria have evolved an array of strategies to counter these infections, but how they first spot an invader in their midst has long been a mystery.
於地球上，沒有任何生物體活著免於威脅，包括細菌。被通稱為噬菌體的掠奪性病毒，是病毒中最可怕的有害物。它們滲透生物體的細胞，來進行複製及接管。細菌已經演化出一系列策略，來對抗此些感染。不過，它們如何首先發現，於其當中的入侵者，長久以來一直是個謎團。
Now researchers in the Laboratory of Bacteriology at The Rockefeller University have discovered that bacteria sense phages via a defensive response called CBASS that detects viral RNA—findings that one day may help counter the threat of antibiotic resistance. They published the results in Nature.
目前，美國洛克菲勒大學，細菌學實驗室的研究人員們已經發現，細菌經由一種發現病毒RNA，被稱為CBASS(Cyclic oligonucleotide-based antiphage signaling system：以環寡核苷酸為基礎的抗噬菌體發信號體系)的防禦反應，來感知噬菌體。此發現，有朝一日可能有助於對抗，抗生素抗藥性的威脅。他們於《自然》期刊，發表了此些研究結果。
“How CBASS is activated by phage infection has been a big unknown in our field for many years,” says Luciano Marraffini, head of the lab. “Until now, no one has understood what triggers the bacteria to initiate the CBASS immune response.”
該實驗室負責人，Luciano Marraffini宣稱：「多年來，噬菌體感染如何激活CBASS，在我們的領域中，一直是個大未知數。直到目前，無人曾瞭解什麼觸發細菌，來啟動CBASS免疫反應。」
Some core immune functions are shared across distantly related domains of life, from eukaryotes (organisms with a membrane-bound nucleus) like mammals, plants, and fungi to prokaryotes (those without such membranes) like bacteria and archaea. These immune responses must’ve evolved early in the existence of life.
有些核心免疫功能，在疏遠相關的生命領域中是共享的，從哺乳動物、植物及真菌等真核生物(具有膜束縛之核的生物)，到像細菌與古細菌等原核生物(那些無上述膜的生物)。於生命存在的早期，諒必已經演化出，此些免疫反應。
One conserved characteristic is a viral sensing mechanism that relies on a specialized enzyme known as a cyclase. In animals, it’s called cGAS (cyclic GMP-AMP synthase). In bacteria, cGAS-like cyclases are central components of the CBASS (cyclic oligonucleotide-based antiphage signaling system) immune response. Both were only discovered in the past decade.
一項守恆的特性是一種，仰賴一種被稱為環化酶之特化酶的病毒感知機制。在動物中，它被稱為環鳥苷酸-腺苷酸合成酶(cGAS：cyclic GMP-AMP synthase)。在細菌中，類cGAS的環化酶是，CBASS之免疫反應的核心成分。在過去十年，這兩者才被發現。
“CBASS cyclases are thought to be ancient ancestors of cGAS,” says co-first author Dalton Banh, an M.D.-Ph.D student in Marraffini’s lab.
首要合撰人，於Marraffini實驗室的醫學博士生，Dalton Banh宣稱：「CBASS環化酶，被認為是cGAS的遠古原型。」
But there are some differences. In an infected animal, cGAS senses viral DNA in the cytoplasm, the gelatinous liquid in a cell that surrounds the nucleus; in an uninfected organism, DNA is confined within the nucleus. Its presence elsewhere signals that something is amiss.
不過，有些差異。在遭感染的動物中，cGAS感知細胞質(於細胞中，圍繞細胞核的凝膠狀液體)中的病毒DNA。在未遭感染的生物體中，DNA被局限於細胞核內。它在其他地方的存在，表明有某事出了差錯。
However, because bacteria lack nuclei, they must take another approach. If CBASS reacted to the mere presence of DNA, it would result in rampant autoimmunity, or the bacterium attacking itself, Banh says.
然而，由於細菌缺乏細胞核，它們必須採取另一種方法。Banh表示，倘若 CBASS僅對DNA的存在作出反應，這會導致極端的自體免疫力。也就是，細菌攻擊自身。
“That was the conundrum,” he says. “CBASS cyclases look a lot like cGAS, so they have to be sensing something. But what, exactly?”
他宣稱：「那是難解的問題。CBASS環化酶看起來很像cGAS，因此它們諒必感知某些東西。不過，究竟是什麼？」
To find out, the researchers and their collaborating partners in Sean Brady’s Laboratory of Genetically Encoded Small Molecules focused on the CBASS system in Staphylococcus schleiferi, a bacterium commonly found in the mouths of dogs, cats, and other animals that on rare occasions has jumped to humans.
為了得知，此些研究人員及其於Sean Brady有關遺傳上經編碼小分子之實驗室的合作夥伴們著重於，在Staphylococcus schleiferi(一種在狗、貓及其他動物口中常被發現，於極少數情況下，曾躍進到人類身上的細菌)中的該種CBASS體系。
Marraffini is a pioneer of the study of bacterial defense systems, primarily CRISPR-Cas; because his lab has used a variety of Staphylococcus strains in this work over the years, the team has a lot of Staph phages on hand. Banh screened them all for their ability to be inhibited by CBASS.
Marraffini是研究細菌防禦系統(主要是CRISPR-Cas，也就是，群聚、規律性間隔開的短迴文結構複製(CRISPR：Clustered Regularly Interspaced Short Palindromic Repeat)-群聚、規律性間隔開的短迴文結構複製相關蛋白(Cas：CRISPR associated protein)的先驅；由於他的實驗室，多年來在這項研究中，使用了多種葡萄球菌菌株。因此，該團隊手頭上，有大量葡萄球菌噬菌體。因為防禦系統的能耐會遭CBASS抑制，因此Banh篩檢了所有上述噬菌體。
He homed in on a set of phages that were spotted by the defense system. “This led us to hypothesize that these sensitive phages produced something during infection that triggered activation of CBASS,” Banh says.
他將注意力集中於，被防禦體系發現的一組噬菌體。Banh宣稱：「這引領了我們假設，此些敏感的噬菌體，在感染期間，產生某種觸發了，激活CBASS之物。」
Next, co-first author Cameron Roberts, a Ph.D. student in the lab, meticulously tested a variety of molecules produced by either the bacterium or the virus, including DNA, RNA, and proteins.
接下來，首要合撰人，於該實驗室的博士生，Cameron Roberts仔細試驗了細菌或病毒產生的各種分子，包括DNA、RNA及蛋白質。
The experiment revealed that only RNA produced during phage infection was able to trigger an immune response. “It was very clearly viral RNA that was generated during infection,” says Roberts. “So instead of sensing a DNA mislocalization, like cGAS does, CBASS senses a specific RNA structure. This specificity is amazing.”
該項實驗揭露了，在噬菌體感染期間，僅被產生的RNA能觸發免疫反應。Roberts宣稱：「這很明確，那是在感染期間，被產生的病毒RNA。因此，CBASS並非如cGAS那樣，感知DNA錯誤定位，而是感知特定的RNA結構。這種特殊性是令人驚訝的。」
They coined the newly identified, hairpin-shaped molecule cabRNA, for CBASS-activating bacteriophage RNA. The molecule binds to a surface of the cyclase, triggering the production of a messenger molecule called cGAMP that activates the CBASS immune response.
他們為該種新近被確認、髮夾形的分子，創造了cabRNA這個字，來代表激活CBASS的噬菌體RNA。該分子與環化酶的表面結合，觸發激活CBASS 免疫反應，被稱為環單磷酸鳥苷-腺苷單磷酸(cGAMP：Cyclic guanosine monophosphate–adenosine monophosphate)之信使分子的產生。
“It was a very simple and elegant experiment, and it gave us the key finding,” Marraffini says.
Marraffini宣稱：「這是一種非常簡單且極佳的實驗，因此它賦予了我們，此重要的發現。」
Here, too, there are parallels to how the analogous system operates in humans. After detecting viral DNA, cGAS also triggers the production of cGAMP, which induces the immune system to produce Type I interferons. That antiviral signaling pathway is known as cGAS-STING.
在這裡，也有與類似系統，如何於人類中運作的諸多相似處。在發現病毒DNA後，cGAS也會觸發，誘導免疫系統產生第一型干擾素之cGAMP的產生。那抗病毒的發信號途徑，被通稱為cGAS-STING。也就是，環鳥苷酸-腺苷酸合成酶(cGAS)-干擾素基因刺激物(STING：stimulator of interferon genes)。
In future research, Roberts will continue to analyze cabRNA for its characteristics. “Two big questions are how and why the phage generates cabRNA—what is its role?” she says. “The details of how cabRNA interacts with the CBASS enzyme is also unclear. So solving a structure of the enzyme as it’s bound to the cabRNA would be a huge feat.”
於未來的研究中，Roberts將就cabRNA的特性，繼續進行分析。她宣稱：「兩項大問題是，噬菌體為何及如何產生cabRNA，什麼是其角色？cabRNA 如何與CBASS酶交互作用的細節，也不詳。因此，解開當該酶與cabRNA結合時的結構，會是一項極大的成就。」
The phages that don’t trigger a CBASS response might potentially be useful one day in combating antimicrobial resistant bacteria.
不觸發CBASS反應的噬菌體在對抗，對抗菌藥物具抵抗力的細菌上，潛在上可能是有用的。
“Right now, we don’t have the knowledge to predict which phages have the cabRNA and which phages don’t,” Marraffini says, “but if we could do that, we could potentially use those phages to attack bacteria, because they’ve figured out how to slip by this sensing mechanism. ”
Marraffini宣稱：「目前，我們無預言，哪些噬菌體具有，及哪些沒有cabRNA的知識。不過，倘若我們能有預言的知識，則潛在上我們能利用那些噬菌體，來攻擊細菌。因為，它們已經解決，如何被此種感知機制疏忽掉。」
網址：https://www.rockefeller.edu/news/34977-how-bacteria-defend-themselves-against-viruses/
翻譯：許東榮
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