COVID-19 May Share Infection Receptors with Hepatitis C Virus 新冠病毒可能與丙肝病毒共享感染受體
By Qian Xun | 文：Qian Xun
(Note from Jennifer: After publishing the previous post “Why Is Aspergillus Pneumonia Listed as the Direct Cause of Coronavirus infection ?爲何新冠病毒感染的直接死因是曲霉性肺炎?” , the author, Qian Xun posted a new article in Chinese under on NTDTV's program “Focus Talk" about the source of the coronavirus, or Covid-2019. I feel it is important in terms of further exploring the pathogenic mechanism of COVID-19, so I publish it here with an English translation mainly done by google, in the hope of drawing the attention of experts for them to further the study. )
（按：繼在新唐人「熱點互動」關於新冠病毒來源節目下的留言區貼出上篇文章《Why Is Aspergillus Pneumonia Listed as the Direct Cause of Coronavirus infection ?爲何新冠病毒感染的直接死因是曲霉性肺炎?》 後，Qian Xun又貼出此篇新的文章，討論新冠病毒的致病機理。我本人並不太懂醫學和病毒學，但覺得此文的觀點很有價值，因此發表出來供專家和讀者參考。）
When I checked the related papers of SARS virus, I accidentally saw that there is relevant French content for the S protein of SARS virus, which has a more detailed analysis than the English content I have seen before.
在查閱薩斯病毒的有關論文時，無意間看到有相關的法文內容對薩斯病毒的S蛋白，比先前看過的英文內容，有更為詳盡的解析。
La protéine S (spicule) est une protéine de fusion virale de classe I8. Comme les autres membres de cette classe, celle-ci comporte deux sous-unités (nommées S1 et S2) et s'auto-associe en trimères à la surface du virus. La sous-unité S1 reconnaît, comme récepteur de fusion, l'enzyme de conversion de l'angiotensine-2(ACE-2)9 mais pourrait reconnaître d'autres récepteurs tels que la lectine de type C CD209L(L-SIGN ), ce qui pourrait expliquer son tropisme pour des types cellulaires ACE-2 négatifs10. Cette association avec le récepteur cellulaire permet l'insertion du peptide de fusion présent sur S2 et mène à l'entrée du virus dans la cellule via fusion entre la membrane et l'enveloppe virale. Des interactions avec différentes voies de signalisation dans la cellule hôte, notamment l'induction de celles de l'apoptose, de la production de cytokines inflammatoires et de l'expression de la cyclo-oxygénase-2, sont aussi associées à la protéine de S. Elle semble aussi ê tre responsable de la régulation négative de la ACE-2 après l'infection virale11. Il s'agit aussi de la principale protéine inductrice d'anticorps in-vivo.
The above paragraph explains that the S protein of the SARS virus consists of two parts, namely two subunits that are bound together, and is named S1 and S2, where the S1 subunit is the protagonist that binds to the ACE2 receptor on the cell surface. However, in addition to the ACE2 receptor, S1 can also recognize and bind to other receptor proteins on the cell surface. One of them is the important content to be said today, that is, L-SIGN, which is a C-type lectin protein. It is as good as ACE2. Incorporates viral proteins to infect cells. After the SARS virus enters the cell, it will cause apoptosis and release cytokines from infected cells. A series of cell biochemical reactions are closely related to the SAS protein.
這段解釋說，薩斯病毒的S蛋白由兩部分組成，即兩個結合在一起的亞基組成，命名為S1和S2，其中S1亞基就是結合細胞表面ACE2受體的主角。但是，除去ACE2受體，S1還可以識別並結合其它一些細胞表面的受體蛋白，其中之一就是今天要說的重要內容，即L-SIGN，就是C型凝集素蛋白，它和ACE2一樣可以結合病毒蛋白，使細胞感染。而薩斯病毒進入細胞後，會引發細胞凋亡，感染細胞釋放細胞因子，等一系列細胞生化反應都與薩斯的S蛋白緊密相關。
I think this will explain why SARS has a rapid onset and severe symptoms after infecting the human body, probably because the S protein enters the cell as a whole. As a recent paper from Nankai University points out, the COVID-19 and SARS enter cells in different ways. The protein packaging mechanism of the COVID-19 is similar to HIV, that is, the S protein of the COVID-19 is cleaved on the cell surface by a protein called Furin It is two separate subunits, S1 and S2, and then S1 binds to the ACE2 receptor. S2 initiates cell membrane fusion and then releases RNA directly into the cell. While HIV enters the cell, its shell disintegrates. Therefore, it seems that several AIDS genes of the COVID-19 should not be fake. Compared with SARS, the COVID-19 is an improved infection method, which is interpreted by Nankai University's paper as the infection ability of the COVID-19 is dozens to 100 times that of SARS. Right or left, judging by the current number of infections, it seems to make sense.
我想這會不會解釋了，為什麼薩斯感染人體後，發病快，症狀嚴重，可能是因為S蛋白是整體進入細胞的。如最近南開大學有論文指出，新冠與薩斯進入細胞的方式不同，新冠的蛋白包裝機制和艾滋病毒相似，即新冠的S蛋白在細胞表面，被一種名為Furin富林酶的蛋白，切割為兩個分離的亞基，即S1和S2, 然後才由S1結合ACE2受體，S2啟動細胞膜融合，然後直接向細胞內釋放RNA，而艾滋病毒確實是在進入細胞同時，其外殼就解體了，所以說新冠的幾個艾滋基因看來應不是虛設的，而新冠相比薩斯，這樣一種改進的感染方式，被南開大學的論文解讀為新冠感染能力是薩斯的幾十至一百倍左右，從現在的感染人數來看，似乎是有道理的。
What needs to be focused here is that these two subunits S1 and S2 are always combined in the S protein of SARS, and then enter the cell as a whole through cell swallowing. At this time, the S protein is always As a whole, it directly causes various reactions in the cell, such as apoptosis and interferon release, and triggers a strong immune response in the body, which is characterized by acute onset, high fever and respiratory inflammation. However, the S protein of the COVID-19 was divided into two before entering the cell. Although the S1 subunit retains the function of binding to the ACE2 receptor, it may no longer have the ability of the S protein to start the cell's biochemical reaction. And if the COVID-19 really enters the cell in the same way as HIV, then it is possible that the two subunits S1 and S2 after the S protein is cleaved do not enter the cell at all, and the cell is not stimulated by the S protein, so it keeps running. I thought it was processing with incoming materials, and it would be more efficient for the replication of the COVID-19 virus, until exhaustive apoptosis, without releasing or only a small amount of cytokines. The immune system does not have enough signals, and of course it cannot respond correctly. Is this one of the reasons why the incubation period of COVID-19 is much longer than that of SARS, and that the symphtons are hidden?
而這裡需要重點關注的是，這兩個亞基S1和S2, 在薩斯的S蛋白裡，是始終結合在一起的，然後通過細胞吞入作用，整體進入細胞內，這時是S蛋白始終作為一個整體，直接導致細胞內的各類反應，如凋亡和乾擾素釋放，而引發身體強烈免疫反應，表現為發病急，高熱與呼吸道炎症等。但是，新冠的S蛋白在進入細胞前，就已一分為二，其中S1亞基雖保留著結合ACE2受體的功能，可是它單槍匹馬，可能不再具有S蛋白那樣，啟動細胞生化反應的能力，而且如果新冠真是以和艾滋病毒同樣的方式進入細胞，那就有可能S蛋白被切割後的兩個亞基S1和S2根本就不進入細胞內部，細胞沒有S蛋白的刺激，從而保持運轉，以為是來料加工，就更高效的為新冠病毒的複制出力，直至耗竭性凋亡，而不會或僅釋放少量細胞因子，免疫系統沒有足夠信號，當然無法正確應答，這會不會是新冠潛伏期比薩斯長很多，並且發病隱匿的原因之一？
Let ’s go back to the L-SIGN receptor mentioned at the beginning. From the above explanation, we can know that this L-SIGN receptor, like the ACE2 receptor, can bind the S protein of the SARS virus and infect the human body. However, the distribution and expression of these two receptor proteins in human tissues are different. ACE2 receptors are concentratedly expressed in the lung, heart, kidney, and vascular epithelial tissues throughout the body. Therefore, this new crown, that is, the new version of SARS, can cause pneumonia, heart and blood vessel damage, and kidney damage. It is easy to understand. However, Dr. Zhong Ming, who is on the front line in Wuhan, also mentioned liver damage.
下面再回到開頭提到的L-SIGN受體，從以上解釋可以知道，這個L-SIGN受體和ACE2受體一樣，可以結合薩斯病毒的S蛋白，使人體感染。但是這兩種受體蛋白在人體組織中的分佈表達是不一樣的，ACE2受體集中表達在肺部，心臟，腎臟，以及全身的血管上皮組織。所以這次新冠，也即新版薩斯，可以導致肺炎，心臟及血管損傷，腎臟損傷，就很容易理解了。不過，在武漢一線的鐘鳴醫生也提到了肝臟損傷。
I will follow the symptom information provided by Dr. Zhong Ming as an important clue for further analysis. From the above, we already know that SARS and COVID-19 both rely on the S protein on their shells to infect human cells. There are at least two ways of infection here. The first way is through binding to the ACE2 receptor. This result is already clear, which causes damage to the heart, lungs, blood vessels, liver and kidneys.
下面我就順著鐘鳴醫生提供的症狀信息，作為重要線索，做進一步分析。從上文，我們已經知道，薩斯和新冠都是依靠自身外殼上的S蛋白，去感染人體細胞。這里至少有兩種感染途徑，途徑一，就是通過結合ACE2受體感染，這個結果已經很清楚，即造成心肺，血管，肝腎的損傷。
The second channel, we need to focus on what kind of symptoms will the COVID-19’s S protein infect the human body through the L-SIGN receptor mentioned above? To answer this question, we must first talk about the distribution of L-SIGN receptors in human tissues.
而途徑二，需要重點關注，即新冠S蛋白如果是通過上文提到的L-SIGN受體感染人體，那會造成什麼樣的症狀呢？為了回答這個問題，首先還是要從L-SIGN受體在人體組織裡的分佈說起。
L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus Hepatitis C virus (HCV) infects nearly 3% of the population of the world and is a major cause of liver disease. However, the mechanism whereby the virus targets the liver for infection remains unknown, because none of the putative cellular receptors for HCV are both expressed specifically in the liver and capable of binding HCV envelope glycoproteins. Liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN) is a calcium-dependent lectin expressed on endothelial cells of liver and lymph nodes. Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), a homologous molecule expressed on dendritic cells, binds HIV and promotes infection. By using a virus-binding assay, we demonstrate that L-SIGN and DC-SIGN specifically bind naturally occurring HCV present in the sera of infected individuals. Further studies demonstrate that binding is mediated by the HCV envelope glycoprotein E2 and is blocked by specific inhibitors, including mannan, calcium chelators, and Abs to the lectin domain of the SIGN molecules. Thus, L-SIGN represents a liver-specific receptor for HCV, and L-SIGN and DC-SIGN may play important roles in HCV infection and immunity.
The above is a summary of an English thesis on L-SIGN receptor protein. The title points out that L-SIGN is a hepatitis C virus receptor protein that is expressed centrally in the liver.
這是一篇關於L-SIGN受體蛋白的英語論文提要。標題就點明L-SIGN是丙型肝炎病毒的受體蛋白，其在肝臟有集中表達。
It can be seen in the abstract of the paper that L-SIGN is concentratedly expressed in the vascular epithelial tissues of the liver and lymph nodes, and at the same time in dendritic cells, a type of lymphoid immune cell, which, like T helper cells, is responsible for transmitting antigen information. A sentinel that contributes to the immune response, and this dendritic cell has another receptor protein, DC-SIGN, which is one of the receptors for HIV infection. However, it was found in the serum of HCV-infected patients that in addition to binding to L-SIGN, HCV also bound to DC-SIGN. Therefore, L-SIGN and DC-SIGN are important vectors for hepatitis C virus infection in humans.
在論文摘要裡可以看到，L-SIGN在肝臟和淋巴結的血管上皮組織有集中表達，同時在樹突狀細胞，即一種淋巴免疫細胞，其和T輔助細胞一樣，負責傳達抗原信息，是促成免疫應答的前哨兵，而這個樹突狀細胞有另一種受體蛋白DC-SIGN 是艾滋病毒的感染受體之一。可是在丙肝病毒感染者的血清裡發現，丙肝病毒除了與L-SIGN結合，也有與DC-SIGN 的結合。所以L-SIGN和DC-SIGN是丙肝病毒感染人體的重要媒介。
At this point, the problem seems a bit complicated, and I try to analyze it step by step. First, since the S-proteins of COVID-19 and SARS can infect at least two receptors, namely ACE2 and L-SIGN, then it can be inferred that the diseases they cause are comprehensive and complex. If combined with ACE2 receptors, it will be cardiopulmonary kidney and systemic vascular symptoms If the L-SIGN receptor is bound at the same time, it is superimposed liver and lymph node damage, that is, some of the patients with COVID-19 infection mentioned by Dr. Zhong Ming have liver damage.
至此，問題顯得稍微有些複雜，我試著一步一步解析開來。首先，既然新冠和薩斯的S蛋白可以感染至少兩種受體，即ACE2和L-SIGN，那可以推知它們造成的病症就是綜合複雜的，如果結合ACE2受體，就是心肺腎和全身血管症狀，若同時結合L-SIGN受體，那就是疊加肝臟和淋巴結損傷，即鐘鳴醫生提到的部分新冠感染者出現肝臟損傷。
In addition, since COVID-19 has the potential to infect and damage lymph nodes through the L-SIGN receptor, that is to say that COVID-19 virus may also be targeted to directly weaken the human immune system. Zhong Nanshan also said in a recent paper that there is a phenomenon of lymphocytopenia caused by COVID-19 infection. This reminds me of a COVID-19 death in the early days of Wuhan ’s closure. The death medical certificate said that the direct cause of death was mycotic pneumonia, which was the main opportunistic infection after AIDS caused the immune deficiency of the human body. However, the direct role of COVID-19 and the immune system has yet to be confirmed by further observations. Therefore, not doing research and statistics on the causes of death is a waste of valuable opportunities to understand the specific pathogenic mechanism of COVID-19 . It is unscientific, and even irresponsible, to treat pneumonia as the only reported symptom.
此外，既然新冠存在經由L-SIGN受體，感染並損傷淋巴結的可能，那就是說新冠病毒亦可能具有直接削弱人體免疫系統的針對性。鐘南山最近在論文裡也說，存在新冠感染造成淋巴細胞減少的現象。這使我回想起武漢封城初期，有一新冠死亡病例，其死亡醫學證明說，其直接死因是黴菌性肺炎，而黴菌性肺炎是艾滋病造成人體免疫缺陷後，出現的主要機會性感染。但是新冠與免疫系統的直接作用還有待進一步觀察證實，所以不對死亡病例做死因的研究統計，就是在浪費寶貴的認識新冠病毒具體致病機制的機會。只把肺炎作為當前的唯一通報症狀是不科學的，更是不負責任的。
Finally, let's briefly talk about the potential prognosis of COVID-19. Since COVID-19 has shared receptors with HCV, it may have similar pathogenic mechanisms with HCV. I will not go into detail about this. Interested parties can check out the introduction of hepatitis C virus and pathological knowledge of hepatitis C, especially its current treatment status. I can only say that so far, there is far no good news on all aspects of the COVID-19 virus, but the deepening of its knowledge is itself good news.
最後再簡要說說新冠可能的預後前景，新冠既然和丙肝病毒有共享受體，那它和丙肝就可能會有類似的致病機制，這點我就不詳細說了，有興趣者可以看看丙肝病毒的介紹和丙肝的病理常識，特別是其治療現狀。我只能說，至今為止，關於新冠病毒的方方面面，還遠看不到好消息，不過對其不斷加深的認識，這本身就是個好消息吧。
附：【專訪】歐洲病毒學專家：新冠病毒有很強人工干預痕跡，似在實驗室產生；病毒有很強傳播力和毒性；中共必須透明，讓全球專家參與抗疫
NTDTV Interview: European virology experts: New crown virus has very strong traces of manual intervention, which seems to be generated in the laboratory; the virus has strong transmission and toxicity; the Chinese Communist Party must be transparent and allow global experts to participate in the epidemic
2/17/2020
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