The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways.
The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways.
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DOI：
10.1371/journal.ppat.1009500
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发表时间：
2021-04
期刊：
影响因子：
6.7
通讯作者：
Stevaert A
中科院分区：
文献类型：
--
作者：
Laporte M;Raeymaekers V;Van Berwaer R;Vandeput J;Marchand-Casas I;Thibaut HJ;Van Looveren D;Martens K;Hoffmann M;Maes P;Pöhlmann S;Naesens L;Stevaert A
SARS-CoV-2的高传播性与上呼吸道中的大量复制有关，这在其他高致病性冠状病毒SARS-CoV和MERS-CoV中没有观察到。我们在这里揭示了冠状病毒刺突（S）蛋白的特征，该蛋白优化了病毒对人类呼吸道的攻击。首先，S蛋白表现出固有的温度偏好，对应于上气道或下气道的温度。携带SARS-CoV-2刺突（SARS-2-S）的假病毒在33°C而不是37°C下产生时更具感染性，这与普通感冒冠状病毒HCoV-229 E的S蛋白共有。相比之下，SARS-CoV和MERS-CoV的S蛋白倾向于37°C，这与病毒对下呼吸道的偏好一致。接下来，SARS-2-S驱动的进入不仅被TMPRSS 2有效激活，而且被TMPRSS 13蛋白酶有效激活，从而拓宽了SARS-CoV-2的细胞嗜性。这两种蛋白酶证明与真实病毒复制有关。TMPRSS 13似乎是强毒冠状病毒的有效刺突激活剂，但不是低致病性HCoV-229 E病毒。这些表面蛋白酶激活SARS-2-S需要S1/S2切割环的加工，其中弗林蛋白酶识别基序和延长的环长度都被证明是关键的。相反，在富含组织蛋白酶的细胞中，环缺失突变体的进入显著增加。最后，我们证明了D 614 G突变增加了SARS-CoV-2的稳定性，特别是在37°C下，并增强了其对组织蛋白酶L途径的使用。这表明S蛋白的稳定性与病毒进入的这种替代途径的使用之间存在联系。由于这些刺突特性可能会促进病毒传播，它们可能解释了为什么刺突G614变体已经取代早期D 614变体成为全球主导。总的来说，我们的研究结果揭示了适应机制，通过这种机制，冠状病毒刺突蛋白被调整以匹配气道的温度和蛋白酶条件，以增强病毒的传播和病理。毁灭性的COVID-19大流行是由SARS-CoV-2引起的，SARS-CoV-2是一种新型病毒，尽管最近引入了人畜共患病，但已经非常适应其人类宿主。它的快速传播与上呼吸道中的大量复制有关，这在其他高致病性人类冠状病毒中没有观察到。为了了解病毒刺突蛋白在这种气道适应中的作用，我们构建了SARS-CoV-2和其他导致严重肺炎或相反导致轻微感冒的冠状病毒的假病毒。关键的发现已经用真实的病毒进行了验证。我们揭示了刺突蛋白的特征，这些刺突蛋白优化了冠状病毒对呼吸道特定部位的作用。也就是说，我们表明刺突蛋白表现出内在的温度偏好，以精确匹配上（~33°C）或下（37°C）气道。我们认识到人类呼吸道的哪些蛋白酶激活病毒进入的刺突，特别是一种可能介导冠状病毒毒力的蛋白酶。最后，观察到刺突稳定性和通过内体蛋白酶进入之间的联系。我们认为，这些机制的尖峰微调可能有助于全球转移的SARS-CoV-2流行病学，从早期的尖峰D 614到目前占主导地位的G614变异。
The high transmissibility of SARS-CoV-2 is related to abundant replication in the upper airways, which is not observed for the other highly pathogenic coronaviruses SARS-CoV and MERS-CoV. We here reveal features of the coronavirus spike (S) protein, which optimize the virus towards the human respiratory tract. First, the S proteins exhibit an intrinsic temperature preference, corresponding with the temperature of the upper or lower airways. Pseudoviruses bearing the SARS-CoV-2 spike (SARS-2-S) were more infectious when produced at 33°C instead of 37°C, a property shared with the S protein of HCoV-229E, a common cold coronavirus. In contrast, the S proteins of SARS-CoV and MERS-CoV favored 37°C, in accordance with virus preference for the lower airways. Next, SARS-2-S-driven entry was efficiently activated by not only TMPRSS2, but also the TMPRSS13 protease, thus broadening the cell tropism of SARS-CoV-2. Both proteases proved relevant in the context of authentic virus replication. TMPRSS13 appeared an effective spike activator for the virulent coronaviruses but not the low pathogenic HCoV-229E virus. Activation of SARS-2-S by these surface proteases requires processing of the S1/S2 cleavage loop, in which both the furin recognition motif and extended loop length proved critical. Conversely, entry of loop deletion mutants is significantly increased in cathepsin-rich cells. Finally, we demonstrate that the D614G mutation increases SARS-CoV-2 stability, particularly at 37°C, and, enhances its use of the cathepsin L pathway. This indicates a link between S protein stability and usage of this alternative route for virus entry. Since these spike properties may promote virus spread, they potentially explain why the spike-G614 variant has replaced the early D614 variant to become globally predominant. Collectively, our findings reveal adaptive mechanisms whereby the coronavirus spike protein is adjusted to match the temperature and protease conditions of the airways, to enhance virus transmission and pathology. The devastating COVID-19 pandemic is caused by SARS-CoV-2, a novel virus that despite recent zoonotic introduction is already very well adapted to its human host. Its rapid spread is related to abundant replication in the upper airways, which is not observed for other highly pathogenic human coronaviruses. To understand the role of the viral spike protein in this airway adaptation, we constructed pseudoviruses of SARS-CoV-2 and other coronaviruses that cause severe pneumonia or, on the contrary, a mild common cold. The key findings were verified with authentic virus. We reveal features of the spike proteins, which optimize the coronavirus towards specific parts of the respiratory tract. Namely, we show that the spike proteins exhibit intrinsic temperature preference to precisely match the upper (~33°C) or lower (37°C) airways. We recognized which proteases of human airways activate the spike for virus entry, in particular one protease that may mediate coronavirus virulence. Finally, a link was perceived between spike stability and entry via endosomal proteases. We propose that these mechanisms of spike fine-tuning may have contributed to a global shift in SARS-CoV-2 epidemiology, from the early spike-D614 to the currently predominating G614 variant.
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影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
DOI：
10.1038/nrmicro.2016.81
发表时间：
2016-08
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
de Wit E;van Doremalen N;Falzarano D;Munster VJ
通讯作者：
Munster VJ
DOI：
10.1126/science.abe8499
发表时间：
2020-12-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hou YJ;Chiba S;Halfmann P;Ehre C;Kuroda M;Dinnon KH 3rd;Leist SR;Schäfer A;Nakajima N;Takahashi K;Lee RE;Mascenik TM;Graham R;Edwards CE;Tse LV;Okuda K;Markmann AJ;Bartelt L;de Silva A;Margolis DM;Boucher RC;Randell SH;Suzuki T;Gralinski LE;Kawaoka Y;Baric RS
通讯作者：
Baric RS
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
影响因子：
5.4
作者：
Glowacka, Ilona;Bertram, Stephanie;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan