Contrasting roles of MERS-CoV and SARS-CoV-2 internal proteins in pathogenesis in mice.
Contrasting roles of MERS-CoV and SARS-CoV-2 internal proteins in pathogenesis in mice.
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作者：
贝塔冠状病毒通过核衣壳基因中的另一个读框编码内部(I)基因，中东呼吸综合征冠状病毒(MERS-CoV)称为ORF8b，严重急性呼吸综合征冠状病毒(SARS-CoV)和SARS-CoV-2称为ORF9b。以往的报道表明，蛋白质8b和9b参与了多种先天免疫信号通路的逃避。然而，它们在感染动物体内的致病机制中的作用尚未确定。在本研究中，我们取消了MERS-CoV中8b蛋白和SARS-CoV-2中9b蛋白的表达。用MERS-CoV和SARS-CoV-2感染小鼠模型，发现表达8b蛋白的MERS-CoV毒力更强，而表达9b蛋白的SARS-CoV-2病毒的毒力比各自的野生型病毒弱。经进一步分析，我们检测到感染MERS冠状病毒缺乏蛋白8b表达的小鼠的I型干扰素水平增加和免疫细胞对肺的渗透增强。这些数据表明，MERS-CoV的I蛋白在限制发病中起作用，而SARS-CoV-2的I蛋白增强了疾病的严重性。贝塔冠状病毒内部蛋白的功能研究相对较少。最早关于小鼠肝炎病毒内部蛋白的报道表明，该蛋白是一种结构蛋白，在病毒复制和毒力方面没有明显的功能。然而，严重急性呼吸综合征冠状病毒(SARS-CoV)、中东呼吸综合征冠状病毒和SARS-CoV-2的内部蛋白已被证明可以逃避免疫反应。尽管已经报道了这些高致病性人类冠状病毒的内部蛋白的功能，但它在实验感染动物中的致病机制中的作用还没有确定。我们的数据表明，尽管这些内部蛋白的基因组位置和表达策略相似，但它们对毒力的影响却截然不同，并且具有病毒特异性，这突显了宿主与病毒相互作用和疾病结局之间的复杂性。
Betacoronaviruses encode an internal (I) gene via an alternative reading frame within the nucleocapsid gene, called ORF8b for Middle-East respiratory syndrome coronavirus (MERS-CoV) and ORF9b for severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. Previous reports suggested that proteins 8b and 9b are involved in evading multiple innate immune signaling pathways. However, their roles in mediating pathogenesis in infected animals have not been determined. In this study, we abrogated the expression of protein 8b in MERS-CoV and protein 9b in SARS-CoV-2. Using mouse models of MERS-CoV and SARS-CoV-2 infection, we found that MERS-CoV lacking protein 8b expression was more virulent, while SARS-CoV-2 lacking protein 9b expression was attenuated compared with the respective wild-type viruses. Upon further analysis, we detected increased levels of type I interferon and enhanced infiltration of immune cells to the lungs of mice infected with MERS-CoV lacking protein 8b expression. These data suggest that the I protein of MERS-CoV plays a role in limiting pathogenesis while that of SARS-CoV-2 enhances disease severity. The function of betacoronavirus internal protein has been relatively understudied. The earliest report on the internal protein of mouse hepatitis virus suggested that the internal protein is a structural protein without significant functions in virus replication and virulence. However, the internal proteins of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle-East respiratory syndrome coronavirus, and SARS-CoV-2 have been shown to evade immune responses. Despite the reported functions of the internal protein in these highly pathogenic human coronaviruses, its role in mediating pathogenesis in experimentally infected animals has not been characterized. Our data indicated that despite the similar genomic location and expression strategy of these internal proteins, their effects on virulence are vastly different and virus specific, highlighting the complexity between host-virus interaction and disease outcome.
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SARS-CoV-2 Orf9b 与人 TOM70 复合物的晶体结构表明病毒与宿主之间存在不寻常的相互作用
影响因子：
16.6
作者：
Gao X;Zhu K;Qin B;Olieric V;Wang M;Cui S
通讯作者：
Cui S
DOI：
10.1126/science.abe9403
发表时间：
2020-12-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gordon DE;Hiatt J;Bouhaddou M;Rezelj VV;Ulferts S;Braberg H;Jureka AS;Obernier K;Guo JZ;Batra J;Kaake RM;Weckstein AR;Owens TW;Gupta M;Pourmal S;Titus EW;Cakir M;Soucheray M;McGregor M;Cakir Z;Jang G;O'Meara MJ;Tummino TA;Zhang Z;Foussard H;Rojc A;Zhou Y;Kuchenov D;Hüttenhain R;Xu J;Eckhardt M;Swaney DL;Fabius JM;Ummadi M;Tutuncuoglu B;Rathore U;Modak M;Haas P;Haas KM;Naing ZZC;Pulido EH;Shi Y;Barrio-Hernandez I;Memon D;Petsalaki E;Dunham A;Marrero MC;Burke D;Koh C;Vallet T;Silvas JA;Azumaya CM;Billesbølle C;Brilot AF;Campbell MG;Diallo A;Dickinson MS;Diwanji D;Herrera N;Hoppe N;Kratochvil HT;Liu Y;Merz GE;Moritz M;Nguyen HC;Nowotny C;Puchades C;Rizo AN;Schulze-Gahmen U;Smith AM;Sun M;Young ID;Zhao J;Asarnow D;Biel J;Bowen A;Braxton JR;Chen J;Chio CM;Chio US;Deshpande I;Doan L;Faust B;Flores S;Jin M;Kim K;Lam VL;Li F;Li J;Li YL;Li Y;Liu X;Lo M;Lopez KE;Melo AA;Moss FR 3rd;Nguyen P;Paulino J;Pawar KI;Peters JK;Pospiech TH Jr;Safari M;Sangwan S;Schaefer K;Thomas PV;Thwin AC;Trenker R;Tse E;Tsui TKM;Wang F;Whitis N;Yu Z;Zhang K;Zhang Y;Zhou F;Saltzberg D;QCRG Structural Biology Consortium;Hodder AJ;Shun-Shion AS;Williams DM;White KM;Rosales R;Kehrer T;Miorin L;Moreno E;Patel AH;Rihn S;Khalid MM;Vallejo-Gracia A;Fozouni P;Simoneau CR;Roth TL;Wu D;Karim MA;Ghoussaini M;Dunham I;Berardi F;Weigang S;Chazal M;Park J;Logue J;McGrath M;Weston S;Haupt R;Hastie CJ;Elliott M;Brown F;Burness KA;Reid E;Dorward M;Johnson C;Wilkinson SG;Geyer A;Giesel DM;Baillie C;Raggett S;Leech H;Toth R;Goodman N;Keough KC;Lind AL;Zoonomia Consortium;Klesh RJ;Hemphill KR;Carlson-Stevermer J;Oki J;Holden K;Maures T;Pollard KS;Sali A;Agard DA;Cheng Y;Fraser JS;Frost A;Jura N;Kortemme T;Manglik A;Southworth DR;Stroud RM;Alessi DR;Davies P;Frieman MB;Ideker T;Abate C;Jouvenet N;Kochs G;Shoichet B;Ott M;Palmarini M;Shokat KM;García-Sastre A;Rassen JA;Grosse R;Rosenberg OS;Verba KA;Basler CF;Vignuzzi M;Peden AA;Beltrao P;Krogan NJ
通讯作者：
Krogan NJ
影响因子：
5.4
作者：
Li Y;Jin Y;Kuang L;Luo Z;Li F;Sun J;Zhu A;Zhuang Z;Wang Y;Wen L;Liu D;Chen C;Gan M;Zhao J;Zhao J
通讯作者：
Zhao J
影响因子：
24.8
作者：
Lee, Jeong Seok;Park, Seongwan;Shin, Eui-Cheol
通讯作者：
Shin, Eui-Cheol
影响因子：
5.4
作者：
Gutierrez-Alvarez, Javier;Wang, Li;Enjuanes, Luis
通讯作者：
Enjuanes, Luis