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當(dāng)細(xì)菌越過(guò)我們的免疫細(xì)胞時(shí)，身體還有一招。非免疫細(xì)胞加入戰(zhàn)斗，釋放出一種類似肥皂的蛋白質(zhì)，對(duì)細(xì)菌入侵者的墻壁進(jìn)行撕咬。

When bacteria get past our immune cells, the body has one more trick up its sleeve. The nonimmune cells join the fight by unleashing a soap-like protein that takes a bite out of the walls of the bacterial invaders.

"耶魯大學(xué)的免疫學(xué)家John MacMicking告訴《Science News》的Jonathan Lambert說(shuō)："我們對(duì)在人類細(xì)胞內(nèi)發(fā)現(xiàn)類似洗滌劑的活動(dòng)感到有點(diǎn)驚訝。"

“We were a bit surprised to find detergent-like activity inside human cells,” John MacMicking, an Yale University immunologist, tells Jonathan Lambert of?Science News.

最近發(fā)表在《Science》雜志上的這項(xiàng)新研究，讓我們看到了人體為抵御病原體滲透而采取的復(fù)雜策略。雖然免疫細(xì)胞和抗體占據(jù)了研究界的大部分注意力，但這項(xiàng)新研究將焦點(diǎn)轉(zhuǎn)向了經(jīng)常被忽視的非免疫細(xì)胞的細(xì)胞防御。這些細(xì)胞是 "一個(gè)古老而原始的防御系統(tǒng) "的重要參與者，MacMicking告訴科學(xué)新聞。

The new study, recently published in the journal?Science, provides a glimpse of the complex strategies that the human body employs to defend itself against pathogenic infiltrators. While immune cells and antibodies hog most of the attention from the research community, the new research turns the spotlight onto the oft-overlooked cellular defenses of nonimmune cells. These cells are important players of “an ancient and primordial defense system,” MacMicking tells?Science News.

這種能殺死細(xì)菌的、類似肥皂的蛋白質(zhì)是一種叫做APOL3的載脂蛋白?！禨cientist》雜志的Abby Olena報(bào)道說(shuō)，載脂蛋白通常用于在身體周圍運(yùn)送脂質(zhì)分子，以作為能量或用于構(gòu)建細(xì)胞。像肥皂一樣，APOL3分子包含一個(gè)親水端和一個(gè)親脂肪端，因此它可以與細(xì)菌的脂質(zhì)膜結(jié)合，并將大塊的壁溶解到細(xì)胞內(nèi)液中。此外，MacMicking的團(tuán)隊(duì)在整個(gè)身體的各種組織中發(fā)現(xiàn)了APOL3，因此研究人員懷疑它可以提供廣泛的保護(hù)。

The bacteria-slaying, soap-like protein is an apolipoprotein called?APOL3. Apolipoproteins are normally used for ferrying lipids molecules around the body to be used as energy or for building cells, reports Abby Olena for?The?Scientist. Like soap, the?APOL3?molecules contains a water-loving end and a fat-loving end, so it can bind to the lipid membranes of bacteria and dissolve chunks of the wall into the intracellular fluid. Moreover, MacMicking’s team found?APOL3?in a variety of tissues throughout the body, so the researchers suspect it could offer wide protection.

為了研究這種細(xì)胞防御機(jī)制，MacMicking和他的同事用沙門(mén)氏菌感染了人類上皮細(xì)胞，沙門(mén)氏菌是造成食物中毒的病菌。根據(jù)霍華德-休斯醫(yī)學(xué)研究所的一份聲明，該細(xì)菌擁有兩層膜：外層膜用于裝甲，內(nèi)層膜則用于保護(hù)其免受抗生素等威脅。

To study this cellular defense mechanism, MacMicking and his colleagues infected human epithelial cells with?Salmonella, the germ responsible for food-poisoning. The bacterium possesses two membranes: an outer one for armor and an inner one as protection against threats such as antibiotics, according to a Howard Hughes Medical Institute?statement.

在篩選了超過(guò)19000個(gè)人類基因后，研究人員發(fā)現(xiàn)APOL3與GBP1蛋白協(xié)同工作，以擊潰沙門(mén)氏菌。在高分辨率顯微鏡的幫助下，研究人員拼湊出了這對(duì)蛋白質(zhì)是如何抵御細(xì)菌的。在收到來(lái)自免疫系統(tǒng)的紅色警報(bào)信號(hào)后，非免疫細(xì)胞會(huì)大規(guī)模地產(chǎn)生這兩種蛋白質(zhì)。GBP1對(duì)沙門(mén)氏菌的外膜進(jìn)行第一輪打擊，讓APOL3通過(guò)并打破內(nèi)膜。殺手級(jí)的APOL3蛋白隨后蜂擁而至，將細(xì)菌消滅。

After screening over 19,000 human genes, the researchers found that?APOL3?works in concert with the?GBP1?protein to wreck?Salmonella. With the aid of a high-resolution microscope, the researchers pieced together how the proteinaceous pair defend against bacteria. Upon receiving red-alert signals from the immune system, non-immune cells churn out both proteins?en masse.?GBP1?lands the first blow on?Salmonella’s outer membrane, allowing?APOL3?to pass through and break apart the inner membrane.?The killer?APOL3?protein then swarms the bacteria and destroys them.

研究人員還發(fā)現(xiàn)APOL3以細(xì)菌膜中的脂質(zhì)為目標(biāo)，而放過(guò)了自己的宿主。這種狡猾的蛋白質(zhì)通過(guò)避開(kāi)膽固醇來(lái)區(qū)分這兩種物質(zhì)，而膽固醇經(jīng)常在哺乳動(dòng)物細(xì)胞壁中發(fā)現(xiàn)。

The researchers also found APOL3?targets the lipids in bacterial membranes and spares its own host. The wily protein distinguishes the two kinds by avoiding cholesterol, which is often found in the walls of mammalian cells.

"伊利諾伊大學(xué)厄巴納-香檳分校的進(jìn)化免疫學(xué)家Jessica Brinkworth告訴《Science News》說(shuō)："關(guān)于這些發(fā)現(xiàn)的一切都是超級(jí)酷的。她稱APOL3對(duì)其細(xì)菌目標(biāo)的選擇性是 "一件美麗的事情"。

“Everything about these findings is supercool,” evolutionary immunologist Jessica Brinkworth of the University of Illinois at Urbana-Champaign who wasn’t involved in the study, tells Science News. She calls APOL3’s selectivity of its bacterial targets “a beautiful thing.”

MacMicking說(shuō)他的下一步行動(dòng)是揭開(kāi)與APOL3相關(guān)的其他脂蛋白的潛在防御策略。根據(jù)聲明，他還希望該研究的發(fā)現(xiàn)能夠指導(dǎo)未來(lái)開(kāi)發(fā)細(xì)菌感染新療法的努力。

MacMicking says his next move is to uncover the potential defense strategies of other apolipoproteins related to?APOL3. He also hopes the study’s findings can guide future efforts to develop new treatments for bacterial infections, per the statement.

"這是一個(gè)人類自己制造抗生素的案例，其形式是一種像洗滌劑一樣作用的蛋白質(zhì)，"MacMicking在聲明中說(shuō)。"我們可以從中學(xué)習(xí)。"

“This is a case where humans make their own antibiotic in the form a protein that acts like a detergent,” says MacMicking in the statement. “We can learn from that.”

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本文轉(zhuǎn)載自Smithsonian:

"Human Cells Ward Off Bacterial Invaders With a Protein That Behaves Like Soap"

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相關(guān)Science文章:

"A human apolipoprotein L with detergent-like activity kills intracellular pathogens"

我們確定ISG apolipoprotein L3（APOL3）是一種能夠殺死細(xì)胞膜侵入性細(xì)菌的強(qiáng)有力的效應(yīng)蛋白。人類APOL家族是一個(gè)由六個(gè)基因組成的集群，在模擬靈長(zhǎng)類動(dòng)物的正向選擇下迅速進(jìn)化；然而，除了創(chuàng)始成員APOL1（一種分泌的細(xì)胞外蛋白，形成人類血清的錐蟲(chóng)因子）外，細(xì)胞內(nèi)APOL家族成員的功能尚不清楚。經(jīng)遺傳工程改造為缺乏APOL3的人類細(xì)胞在IFN-γ激活后未能控制多種細(xì)胞膜侵襲性革蘭氏陰性細(xì)菌的復(fù)制。這種發(fā)現(xiàn)在初級(jí)人類腸道上皮細(xì)胞、腸道肌成纖維細(xì)胞和靜脈內(nèi)皮細(xì)胞中得到了驗(yàn)證--所有的細(xì)胞目標(biāo)通常不被視為免疫系統(tǒng)的一部分。

We identify the ISG apolipoprotein L3 (APOL3) as a potent effector protein capable of killing cytosol-invasive bacteria. The human APOL family is a cluster of six genes that have evolved rapidly under positive selection in simian primates; however, aside from the founding member APOL1, a secreted extracellular protein that forms the trypanolytic factor of human serum, the function of the intracellular APOL family members is unknown. Human cells genetically engineered to lack APOL3 failed to control the replication of multiple cytosol-invasive Gram-negative bacteria after IFN-γ activation. Such findings were validated in primary human intestinal epithelial cells, intestinal myofibroblasts, and venular endothelium—all cellular targets not typically considered part of the immune system.?

我們通過(guò)活體顯微鏡跟蹤APOL3，發(fā)現(xiàn)它迅速轉(zhuǎn)移到暴露在細(xì)胞膜上的細(xì)菌，而其他APOL家族成員則沒(méi)有。超分辨率成像、生物工程報(bào)告器和無(wú)細(xì)胞重組的組合顯示，當(dāng)APOL3瞄準(zhǔn)IFN-γ激活的細(xì)胞內(nèi)的病原體時(shí)，它對(duì)細(xì)菌內(nèi)膜（IM）造成了致命的傷害。在這里，APOL3與其他ISG編碼的蛋白協(xié)同作用，包括鳥(niǎo)苷酸結(jié)合蛋白1（GBP1），擾亂細(xì)菌O型抗原外膜（OM）的通透性屏障，使APOL3能夠進(jìn)入IM下方。

Using a panel of compositionally distinct liposome targets, we found that APOL3 membranolytic activity toward microbial rather than host endomembranes stemmed from an ability to dissolve bacterial polyanionic lipid substrates lacking cholesterol into discoidal lipoprotein complexes; single-particle cryo–electron microscopy found that these complexes resembled apolipoprotein- scaffold “nanodiscs.” Corroborating these findings in live bacteria by native mass spectrometry, we found that APOL3 transitioned from a partially disordered lipid-free state to tightly folded lipoprotein nanodiscs upon extracting lipid from the IM—a process that resulted in?rapid?death of?the bacterium.?

利用一組成分不同的脂質(zhì)體目標(biāo)，我們發(fā)現(xiàn)APOL3對(duì)微生物而非宿主內(nèi)膜的溶膜活性源于將缺乏膽固醇的細(xì)菌多離子脂質(zhì)底物溶解為盤(pán)狀脂蛋白復(fù)合物的能力；單粒子冷凍電鏡發(fā)現(xiàn)這些復(fù)合物類似于脂蛋白支架 "納米盤(pán)"。通過(guò)原生質(zhì)譜法證實(shí)了這些發(fā)現(xiàn)，我們發(fā)現(xiàn)APOL3在從IM中提取脂質(zhì)時(shí)，從部分無(wú)序的脂質(zhì)狀態(tài)過(guò)渡到緊密折疊的脂蛋白納米盤(pán)，這一過(guò)程導(dǎo)致了細(xì)菌的快速死亡。

We tracked APOL3 by live microscopy and found that it rapidly relocated to cytosol-exposed bacteria, whereas other APOL family members did not. A combination of superresolution imaging, bioengineered reporters, and cell- free reconstitution revealed that when APOL3 targets pathogens inside IFN-γ–activated cells, it inflicts a lethal insult to the bacterial inner membrane (IM). Here APOL3 synergizes with other ISG-encoded proteins, including guanylate-binding protein 1 (GBP1), that perturb the bacterial O- antigen outer membrane (OM) permeability barrier to allow APOL3 access to the IM underneath.?

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