Comparative Genomic Analysis of Rapidly Evolving SARS-CoV-2 Reveals Mosaic Pattern of Phylogeographical Distribution
Comparative Genomic Analysis of Rapidly Evolving SARS-CoV-2 Reveals Mosaic Pattern of Phylogeographical Distribution
复制标题
DOI：
10.1128/msystems.00505-20
复制
发表时间：
2020-07-01
期刊：
影响因子：
6.4
通讯作者：
Lal, Rup
中科院分区：
文献类型：
--
作者：
Kumar, Roshan;Verma, Helianthous;Lal, Rup
2019年12月在武汉爆发的2019年冠状病毒病(新冠肺炎)中国，现已在全球范围内蔓延，成为一场全球大流行。由新型严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)引起的严重呼吸道肺炎迄今已夺走38万多人的生命，并影响到全球人类的生活。然而，由于新的SARS-CoV-2病毒表现出高传播率，其潜在的基因组严重程度需要完全了解。我们研究了来自全球不同地理区域的95株SARS-CoV-2毒株的全基因组，以揭示病毒的传播模式。我们发现，病毒在邻国之间没有直接的传播模式，这表明它的传播是受感染的人到不同国家旅行的结果。我们在10株来自美国的病毒分离株中发现了非结构蛋白13(NSP13)、非结构蛋白14(NSP14)、非结构蛋白15(NSP15)和非结构蛋白16(NSP16)以及S蛋白中独特的单核苷酸多态性(SNPs)。这些病毒蛋白参与RNA复制和与人类受体的结合，表明在美国人群中传播的病毒变体与在其他国家人群中传播的病毒变体不同。此外，我们还发现了一株美国分离株(GenBank登录号：nsp16)的nsp16(mRNACAP-1甲基转移酶)中有一个氨基酸加成。MT188341.1)导致氨基酸框架从2540位向上移动。通过对野生型和突变型蛋白质的比较结构分析，我们发现这种苯丙氨酸残基的添加使突变体中的蛋白质变得不稳定，这可能会影响mRNACap-1甲基转移酶的功能。我们进一步分析了SARS-CoV-2-人相互作用组，发现干扰素信号通路是orf1ab在感染过程中的靶向，它还与潜在的白细胞介素8(IL-8)调节因子-核因子-kappa B-抑制因子(NKRF)相互作用。我们认为，针对这种互动可能会随后改善新冠肺炎患者的健康状况。我们的分析还强调，SARS-CoV-2在感染过程中操纵剪接体机制，因此，靶向剪接可能会影响病毒的复制。综上所述，SARS-CoV-2的复制机制是以干扰素和缺口信号通路为靶点，以及剪接体机制来逃避宿主的挑战。研究表明，新冠肺炎大流行继续席卷全球，全球已有超过650万例病例。疾病的严重程度因地区而异，主要受人口密度和年龄因素的影响。在这项研究中，我们分析了来自11个不同国家的95株SARS-CoV-2基因组的传播模式。我们的研究还揭示了ORF1b和S-蛋白的几个非同义突变及其对结构稳定性的影响。我们的分析揭示了病毒蛋白通过SARS-CoV-2-人蛋白相互作用组对宿主系统的操纵，这对于了解病毒对人类健康的影响是有用的。
The outbreak of coronavirus disease 2019 (COVID-19) that started in Wuhan, China, in December 2019 has spread worldwide, emerging as a global pandemic. The severe respiratory pneumonia caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has so far claimed more than 0.38 million lives and has impacted human lives worldwide. However, as the novel SARS-CoV-2 virus displays high transmission rates, the underlying genomic severity is required to be fully understood. We studied the complete genomes of 95 SARS-CoV-2 strains from different geographical regions worldwide to uncover the pattern of the spread of the virus. We show that there is no direct transmission pattern of the virus among neighboring countries, suggesting that its spread is a result of travel of infected humans to different countries. We revealed unique single nucleotide polymorphisms (SNPs) in nonstructural protein 13 (nsp13), nsp14, nsp15, and nsp16 (ORF1b polyproteins) and in the S-protein within 10 viral isolates from the United States. These viral proteins are involved in RNA replication and binding with the human receptors, indicating that the viral variants that are circulating in the population of the United States are different from those circulating in the populations of other countries. In addition, we found an amino acid addition in nsp16 (mRNA cap-1 methyltransferase) of a U.S. isolate (GenBank accession no. MT188341.1) leading to a shift in the amino acid frame from position 2540 onward. Through comparative structural analysis of the wild-type and mutant proteins, we showed that this addition of a phenylalanine residue renders the protein in the mutant less stable, which might affect mRNA cap-1 methyltransferase function. We further analyzed the SARS-CoV-2- human interactome, which revealed that the interferon signaling pathway is targeted by orf1ab during infection and that it also interacts with NF-kappa B-repressing factor (NKRF), which is a potential regulator of interleukin-8 (IL-8). We propose that targeting this interaction may subsequently improve the health condition of COVID-19 patients. Our analysis also emphasized that SARS-CoV-2 manipulates spliceosome machinery during infection; hence, targeting splicing might affect viral replication. In conclusion, the replicative machinery of SARS-CoV-2 is targeting interferon and the notch signaling pathway along with spliceosome machinery to evade host challenges.IMPORTANCE The COVID-19 pandemic continues to storm the world, with over 6.5 million cases worldwide. The severity of the disease varies with the territories and is mainly influenced by population density and age factor. In this study, we analyzed the transmission pattern of 95 SARS-CoV-2 genomes isolated from 11 different countries. Our study also revealed several nonsynonymous mutations in ORF1b and S-proteins and the impact on their structural stability. Our analysis showed the manipulation of host system by viral proteins through SARS-CoV-2-human protein interactome, which can be useful to understand the impact of virus on human health.