A tickborne virus uses cholesterol receptors to worm its way into the cell.

一種蜱傳播的病毒利用膽固醇受體，來鑽進細胞中。

Ticks are tiny creatures that can stick their pincers into humans and pass on some nasty disease-causing viruses, including the Crimean Congo virus. This pathogen causes an illness that starts out like the flu, but can ultimately lead to severe bleeding, liver damage, and death in 10 to 40 percent of cases.

蜱是能將其鉗子(鰲)刺入人體並傳播，包括克里米亞剛果病毒等，一些令人厭惡之致病病毒的小生物。這種病原體引起一種，開始類似流感，不過最終會導致嚴重出血、肝臟損傷，且在10%至40%之病例中，導致死亡的疾病。

With the onslaught of climate change, tickborne viruses are rapidly spreading around the world. The premise of the Crimean Congo virus dispersing across several countries was enough to spur Vanessa Monteil, a biologist in the group of virologist Ali Mirazimi at the Karolinska Institute, into action.

隨著氣候變遷的襲擊，蜱傳播的病毒正在世界各地迅速蔓延。克里米亞剛果病毒在諸多國家傳播的前述事項足以激勵，於瑞典卡羅林斯卡學院，病毒學家Ali Mirazimi團隊中的生物學家Vanessa Monteil，使之行動。

Previously, the mechanism by which Crimean Congo virus entered human cells was relatively unknown. In a study recently published in Nature Microbiology, Monteil and her colleagues found that the virus binds to the low density lipoprotein receptor (LDLR), which sequesters cholesterol inside the cell, to make its entry. These results could be useful for developing vaccines or other therapies against the virus. 

先前，克里米亞剛果病毒藉以，進入人體細胞的機制，相對上不詳。在最近發表於《自然•微生物學》期刊的一項研究中，Monteil及其同僚們發現，該種病毒與將膽固醇隔離於細胞內的低密度脂蛋白受體(LDLR)結合，而使其進入細胞。這些研究結果可能有助於開發，針對該種病毒的疫苗或其他療法。

Monteil and her colleagues first investigated where the virus might attach to cells. To do that, the researchers randomly mutated single amino acids in rodent haploid cells and then exposed these cells to the Crimean Congo virus.

Monteil及其同僚們首先調查研究了，該種病毒可能附著於細胞何處。為此，這些研究人員隨機地，使囓齒動物單倍體細胞中的單一氨基酸產生突變，然後將此些細胞暴露於克里米亞剛果病毒。

“Cells that survive will have some mutation in genes coding for proteins that are important for the virus to enter,” said Monteil. By picking out the surviving cells and sequencing them, the team found that all the cells contained mutations in the LDLR gene, indicating that the receptor was probably important for viral entry.

Monteil宣稱：「存活下來的細胞在為，對該種病毒進入而言重要之蛋白質，指定遺傳碼的基因中，會具有某種突變。」藉由撿出此些存活下來的細胞，並排序它們。該團隊發現，所有此些細胞，於LDLR基因中，皆具有突變體。這顯示，就病毒進入而言，該受體可能是重要的。

The scientists next used CRISPR-Cas9 to knock out LDLR in several cell lines (including a human line) and found that there was a significant reduction in viral infection in comparison to unedited controls.

接下來，此些科學家使用CRISPR-Cas9 (CRISPR：Clustered Regularly Interspaced Short Palindromic Repeat：群聚、規律性間隔開的短迴文結構複製)-( Cas9：CRISPR associated protein 9：CRISPR相關的蛋白質9)，來剔除幾種細胞系(包括人類細胞系)中的LDLR且發現，相較於未經編輯的對照組，在病毒感染上，有顯著的減少。

Likewise, when they used the same technique to knock out LDLR in human blood organoids, little collections of capillary-like structures derived from stem cells, they found a similar reduction in infection when Crimean Congo virus was added. This indicated that in human blood vessels, LDLR probably played an important role in allowing the virus to enter the vasculature. 

同樣地，當他們使用了相同的技術，來剔除人類血液類器官(源自幹細胞之毛細血管樣結構物的少量積聚物。是一種，於試管內之三維度中，模仿器官的關鍵功能、結構及生物複雜性，所產生之微型化且簡化版本的器官)中的LDLR時。當添加克里米亞剛果病毒時，在感染上，她們發現了類似的減少。這顯示，於人體血管中，在容許病毒進入脈管系統上，LDLR可能扮演了一種重要角色。

Given these results, the team tested if the virus would bind directly to the LDLR protein. By adding soluble LDLR protein to the cells—a strategy akin to using a “molecular decoy,” a distraction for the virus to bind to instead of the cell—the researchers blocked the virus from infecting the cells, with increasing concentrations of LDLR protein providing more protection. 

鑒於這些結果，該團隊測試了，該種病毒能否直接與LDLR蛋白質結合。藉由將可溶性LDLR蛋白質，添加到此些細胞中(一種類似使用“分子誘餌”的策略。也就是，對病毒結合而不是細胞的一種分散注意力之物)。此些研究人員阻擾了，該種病毒感染此些細胞，隨著增加LDLR蛋白濃度，提供了更多保護。

Next, they turned their attention to the virus and determined which viral proteins were involved in its binding to the receptor. They inserted a fluorescent reporter to the LDLR gene in human cells, then added candidate viral proteins to the cell culture. The team was particularly curious to see if two Crimean Congo virus glycoproteins (Gc and Gn) would mediate the virus-receptor interaction. 

接下來，他們將其注意力轉向該種病毒並確定了，哪些病毒蛋白質涉及了，其與上述受體的結合。她們將一種螢光性信息劑，嵌入人類細胞的 LDLR基因中，然後將候選病毒蛋白質，添加到此細胞培養中。該團隊特別想查明，克里米亞剛果病毒兩種糖蛋白(Gc及Gn)，是否會介導病毒與受體的交互作用。

They found that Gc directly bound to LDLR, but Gn did not. However, when Gc and Gn were added together, there was a synergistic effect on binding. “When we put the Gn with Gc, we increase the affinity of Gc for the receptor,” said Monteil. 

她們發現，Gc直接與LDLR結合，而Gn沒有。然而，當Gc及Gn一起被添加時，對結合有產生增效作用的效應。Monteil宣稱：「當我們將Gn與Gc放在一起時，我們提升了Gc對受體的親和力。」

The study results complement findings published earlier this year in Cell Research, which also implicated LDLR as an entry receptor for the pathogen. “Today, we can say that LDLR is really a receptor for Crimean Congo [virus],” Monteil said. She believes that their work adds some clarity into the additional proteins and mechanism by which this viral entry occurs. 

此些研究結果補充了，今年(2024年)稍早發表於《細胞研究》期刊，也暗示LDLR作為，該種病原體之進入受體的研究發現。Monteil宣稱：「現今，我們能說，實際上LDLR是克里米亞剛果[病毒]的一種受體。」她認為，她們的研究，為該種病毒藉以，發生進入的更多蛋白質及機制，增添了一些清晰度。

For Dennis Bente, a microbiologist at the University of Texas Medical Branch who was not involved in the research, the collective synchrony of these two papers is exciting for the field at large—especially because Crimean Congo virus requires extreme biocontainment measures and is difficult to study.

對美國德州大學醫學部門，未涉及這項研究的微生物學家，Dennis Bente而言，這兩篇論文的總體同步性，就整個此領域而言，是令人振奮的。特別是，因為克里米亞剛果病毒，需要極端的生物防護措施，且難以進行研究。

“It’s a key finding in the molecular virology of the virus,” he said. Bente noted, though, that LDLR is probably not the only way the virus can enter the cells, and more work is needed to better map out all the ways Crimean Congo virus can infect someone. 

他宣稱：「在這種病毒的分子病毒學上，這是一項重大的發現。」不過，Bente特別提及，LDLR可能並非該種病毒，能進入此些細胞的唯一途徑。因此，需要更多研究來更佳地詳細提出，克里米亞剛果病毒會感染某人的所有方式。

In the meantime, Monteil is excited to extend these findings toward therapeutic development. She hopes to design proteins that can bind to the virus itself, but not interfere with the body’s cholesterol-sequestering mechanism—since completely blocking LDLR would likely disturb critical metabolic functions. 

在此同時，Monteil很高興將此些研究發現，擴展到治療方法的開發。她希望設計出，能與病毒本身結合，而不會干擾人體隔離膽固醇之機制的蛋白質。因為，完全阻斷LDLR可能會擾亂，諸多關鍵的代謝功能。

“Maybe even one day this can be used as a treatment to save people, and to help them avoid reaching the level of severe disease," she said.

她宣稱：「也許有朝一日，這甚至能被使用，作為一種治療方法，來拯救及幫助人們，避免及於嚴重疾病水平。」

網址：https://www.the-scientist.com/how-the-crimean-congo-virus-sneaks-into-cells-72005

翻譯：許東榮