Dissecting Phenotype from Genotype with Clinical Isolates of SARS-CoV-2 First Wave Variants.
Dissecting Phenotype from Genotype with Clinical Isolates of SARS-CoV-2 First Wave Variants.
复制标题
DOI：
10.3390/v15030611
复制
发表时间：
2023-02-23
期刊：
影响因子：
--
通讯作者：
Jonsson CB
中科院分区：
文献类型：
--
作者：
Taylor MK;Williams EP;Xue Y;Jenjaroenpun P;Wongsurawat T;Smith AP;Smith AM;Parvathareddy J;Kong Y;Vogel P;Cao X;Reichard W;Spruill-Harrell B;Samarasinghe AE;Nookaew I;Fitzpatrick EA;Smith MD;Aranha M;Smith JC;Jonsson CB
密切相关的SARS-CoV-2临床分离株的出现和可获得性为识别可能影响表型的新的非同义突变提供了独特的机会。全球测序工作表明，自大流行开始以来，SARS-CoV-2变异体已经出现，然后被取代，但我们对变异体特异性宿主反应的广度信息有限。利用原代细胞培养和K18-hACE2小鼠，我们研究了在第一波大流行期间密切相关的临床变异的复制、先天免疫反应和病理学。四个临床分离株的肺部病毒复制的数学模型显示出两个B.1之间的二分法。感染细胞清除率明显较快和较慢的菌株。虽然分离株能诱导几种常见的免疫宿主对感染的反应，但有一株B.1分离株在促进嗜酸性粒细胞相关蛋白IL-5和CCL11方面是独一无二的。此外，它的死亡率要低得多。肺显微镜组织病理学显示，五个分离株之间的表型进一步分化，表现出三组不同的表型：(I)实变、肺泡出血和炎症，(Ii)间质性炎症/间隔增厚和细支气管/血管周围淋巴样细胞，(Iii)实变、肺泡受累和内皮肥大/边缘形成。总之，这些发现显示了这些临床分离株在表型结果上的差异，并揭示了NSP2和ORF8中非同义突变的潜在重要性。
The emergence and availability of closely related clinical isolates of SARS-CoV-2 offers a unique opportunity to identify novel nonsynonymous mutations that may impact phenotype. Global sequencing efforts show that SARS-CoV-2 variants have emerged and then been replaced since the beginning of the pandemic, yet we have limited information regarding the breadth of variant-specific host responses. Using primary cell cultures and the K18-hACE2 mouse, we investigated the replication, innate immune response, and pathology of closely related, clinical variants circulating during the first wave of the pandemic. Mathematical modeling of the lung viral replication of four clinical isolates showed a dichotomy between two B.1. isolates with significantly faster and slower infected cell clearance rates, respectively. While isolates induced several common immune host responses to infection, one B.1 isolate was unique in the promotion of eosinophil-associated proteins IL-5 and CCL11. Moreover, its mortality rate was significantly slower. Lung microscopic histopathology suggested further phenotypic divergence among the five isolates showing three distinct sets of phenotypes: (i) consolidation, alveolar hemorrhage, and inflammation, (ii) interstitial inflammation/septal thickening and peribronchiolar/perivascular lymphoid cells, and (iii) consolidation, alveolar involvement, and endothelial hypertrophy/margination. Together these findings show divergence in the phenotypic outcomes of these clinical isolates and reveal the potential importance of nonsynonymous mutations in nsp2 and ORF8.
登录
查看更多内容
影响因子：
64.5
作者：
Fauver, Joseph R.;Petrone, Mary E.;Grubaugh, Nathan D.
通讯作者：
Grubaugh, Nathan D.
影响因子：
--
作者：
Bianchi, Martina;Benvenuto, Domenico;Pascarella, Stefano
通讯作者：
Pascarella, Stefano
影响因子：
56.9
作者：
Deng, Xianding;Gu, Wei;Chiu, Charles Y.
通讯作者：
Chiu, Charles Y.
I-Mutant2.0：预测蛋白质序列或结构突变的稳定性变化。
影响因子：
14.9
作者：
Capriotti, E;Fariselli, P;Casadio, R
通讯作者：
Casadio, R
影响因子：
7.5
作者：
Eijmael M;Janssens N;le Cessie S;van Dooren Y;Koster T;Karim F
通讯作者：
Karim F