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The important role of FCS in SARS-CoV-2 evolution. (A), The number of FCS was varied in different coronavirus. SARS-CoV-2 had F1-3 sites, RaTG13 had F1-2 sites with 96% similarity to SARS-CoV-2, SARS had F2 site, HKU1 and OC43 had F1 site while HKU9-1 had no FCS. (B), the location and number of FCS may play an important role in coronavirus evolution. (C), The sequence of F1 shared high similarity among HKU1, OC43 and SARS-CoV-2, which may be caused by the Furin cleavage site translocation during the evolution of SARS-CoV-2 ancestor and finally resulted its human transmission. (D), F1-3 showed high conservation in different coronavirus, hinting the potential role in virus invasion and replication.
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We found, in our 788 confirmed COVID-19 patients, the decreased rate of severe/critical type, increased liver/kidney damage and prolonged period of nuclear acid positivity during virus dissemination, when compared with Wuhan. To investigate the underlining mechanism, we isolated one strain of SARS- CoV-2 (ZJ01) in mild COVID-19 patient and found th...
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... were three potential FCSs on the S protein. F1, F2 and F3 were separately located in S1/S2, S2 and the N-terminal domain (NTD) of S1 (Figure 4(A)). Further comparative alignment analysis of GZ02 (SARS viral strain), Wuhan-Hu-1 (the earliest sequenced SARS-CoV-2), RaTG13, HKU9-1 (the potential ancestor of SARS and SARS-CoV-2), HKU-1 and OC43 showed that the variation of FCS sequence had certain regularity in coronavirus evolution ( Figure 4(B)). ...
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... F2 and F3 were separately located in S1/S2, S2 and the N-terminal domain (NTD) of S1 (Figure 4(A)). Further comparative alignment analysis of GZ02 (SARS viral strain), Wuhan-Hu-1 (the earliest sequenced SARS-CoV-2), RaTG13, HKU9-1 (the potential ancestor of SARS and SARS-CoV-2), HKU-1 and OC43 showed that the variation of FCS sequence had certain regularity in coronavirus evolution ( Figure 4(B)). In detail, there was no FCS in HKU9-1, but one potential FCS in the F2 locus of GZ02 (Furin score 0.366) showed effective Furin binding capacity [28]. ...
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... OC43 and HKU-1 are much likely to genetically interact with original SARS-CoV-2. This genetic recombination may have caused the original SARS-CoV-2 to acquire an FCS at the F1 site and eventually become highly infectious and pathogenic (Figure 4(C)). We also found a similar FCS on the S protein of MERSCoV. ...
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... mutations may influence the tertiary and quaternary structures of the S protein and finally change the Furin binding capacity. The F1-3 sites were conserved in SARS-CoV-2 and SARS (Figure 4(D)), indicating the importance of mutations in these sites. ...
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... insertion may become a critical point for the animal-to-human change of the host of RaTG13. Sequence alignment revealed that this inserted sequence may arise from the translocation between human coronavirus HKU1 and OC43 (Figure 4). SARS-CoV-2 harbours three FCS (F1-3). ...
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... were 3 potential furin cleavage site (FCS) on S protein, where F1, F2 and F3 separately located in S1/S2, S2 and the N-terminal domain (NTD) of S1 ( Fig 4A). Further comparative alignment analysis on GZ02 (SARS viral strain), Wuhan-Hu-1 (the earliest sequenced SARS-CoV-2), RaTG13, HKU9-1 (the potential ancestor of SARS and SARS-CoV-2) and SARS-CoV-2 (HKU-1 and OC43) showed that FCS exhibited a clear sequence and rule in coronavirus evolution ( Fig 4B). ...
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... were 3 potential furin cleavage site (FCS) on S protein, where F1, F2 and F3 separately located in S1/S2, S2 and the N-terminal domain (NTD) of S1 ( Fig 4A). Further comparative alignment analysis on GZ02 (SARS viral strain), Wuhan-Hu-1 (the earliest sequenced SARS-CoV-2), RaTG13, HKU9-1 (the potential ancestor of SARS and SARS-CoV-2) and SARS-CoV-2 (HKU-1 and OC43) showed that FCS exhibited a clear sequence and rule in coronavirus evolution ( Fig 4B). In detail, there was no FCS in HKU9-1, but one potential FCS in F2 locus of GZ02 (Furin score 0.366) showed effective furin binding capacity 28 . ...
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... and CO43 could cause human upper respiratory tract infection but the symptom was milder than SARS and SARS-CoV-2. Therefore, we reckoned that the ancestor of SARS-CoV-2 may exchange gene with HKU1 or OC43 to obtain FCS in F1 site during evolution to human transmission (Fig 4C). ZJ01 had Glu702 to Lys702 substitution at the site 18 th amino acid behind F1 site, and deletion (Ala771 to -) at the site 37 th amino acid ahead of F2 site. ...
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... mutations may influence the tertiary and quaternary structure of S protein and finally change the Furin binding capacity. F1-3 sites were conservative in SARS-CoV-2 and SARS (Fig 4D), indicating the importance of mutation in these sites. ...
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... 1101 this inserted sequence may arise from the translocation between human coronavirus HKU1 and OC43 (Figure 4). SARS-CoV-2 had three FCS (F1-3), where F1 hydrolyzes S protein to S1 and S2 and promotes virus-cell fusion, F2 hydrolyzes S2 and participates in virus pathogenicity after cell entry, while F3 functions through NTD and promotes adhesion between virus and cell surface. ...
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The mutations in the SARS-CoV-2 virus genome during the spread of COVID-19 have been unclear. In 788 COVID-19 patients from Zhejiang province, we observed decreased rate of severe/critical cases, increased liver/kidney damage, and prolonged period of nuclear acid positivity, compared with patients in Wuhan, China. To investigate the underlying mech...
Citations
... SARS-CoV-2 spike (S) glycoprotein plays an integral role in the viral transmission and virulence [3]. The S protein contains two functional subunits, S1 and S2, cleaved by furin protease at the host cell [4]. The S1 subunit contains the receptor binding domain and facilitates the interactions with the host cell surface receptor, Angiotensin-converting enzyme 2 (ACE2) [5,6]. ...
COVID-19 is challenging healthcare preparedness, world economies, and livelihoods. The infection and death rates associated with this pandemic are strikingly variable in different countries. To elucidate this discrepancy, we analyzed 2431 early spread SARS-CoV-2 sequences from GISAID. We estimated continental-wise admixture proportions, assessed haplotype block estimation, and tested for the presence or absence of strains’ recombination. Herein, we identified 1010 unique missense mutations and seven different SARS-CoV-2 clusters. In samples from Asia, a small haplotype block was identified, whereas samples from Europe and North America harbored large and different haplotype blocks with nonsynonymous variants. Variant frequency and linkage disequilibrium varied among continents, especially in North America. Recombination between different strains was only observed in North American and European sequences. In addition, we structurally modelled the two most common mutations, Spike_D614G and Nsp12_P314L, which suggested that these linked mutations may enhance viral entry and replication, respectively. Overall, we propose that genomic recombination between different strains may contribute to SARS-CoV-2 virulence and COVID-19 severity and may present additional challenges for current treatment regimens and countermeasures. Furthermore, our study provides a possible explanation for the substantial second wave of COVID-19 presented with higher infection and death rates in many countries.
... FURIN takes on this role in coronaviruses including COVID-19 (70)(71)(72). Since Notch1 has been shown to transcriptionally induce FURIN, Notch signaling may indirectly lead to enhanced viral entry via enhanced FURIN expression (73,74). ...
COVID-19 is associated with a large number of cardiovascular sequelae, including dysrhythmias, myocardial injury, myocarditis and thrombosis. The Notch pathway is one likely culprit leading to these complications due to its direct role in viral entry, inflammation and coagulation processes, all shown to be key parts of COVID-19 pathogenesis. This review highlights links between the pathophysiology of SARS-CoV2 and the Notch signaling pathway that serve as primary drivers of the cardiovascular complications seen in COVID-19 patients.
... Minimal expression of key receptors required for SARS-CoV-2 entry, including ACE2 and TMPRSS2 in innate immune cells such as monocytes and macrophages, has been recently reported in nonhuman primates [112] and humans [30]. In addition, monocytes can express high levels of CD147 [113], a potential receptor for SARS-CoV-2 entry [114]. ...
Since the initial report of the novel Coronavirus Disease 2019 (COVID-19) emanating from Wuhan, China, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally. While the effects of SARS-CoV-2 infection are not completely understood, there appears to be a wide spectrum of disease ranging from mild symptoms to severe respiratory distress, hospitalization, and mortality. There are no Food and Drug Administration (FDA)-approved treatments for COVID-19 aside from remdesivir; early efforts to identify efficacious therapeutics for COVID-19 have mainly focused on drug repurposing screens to identify compounds with antiviral activity against SARS-CoV-2 in cellular infection systems. These screens have yielded intriguing hits, but the use of nonhuman immortalized cell lines derived from non-pulmonary or gastrointestinal origins poses any number of questions in predicting the physiological and pathological relevance of these potential interventions. While our knowledge of this novel virus continues to evolve, our current understanding of the key molecular and cellular interactions involved in SARS-CoV-2 infection is discussed in order to provide a framework for developing the most appropriate in vitro toolbox to support current and future drug discovery efforts.
... FURIN takes on this role in coronaviruses including COVID-19 (70)(71)(72). Since Notch1 has been shown to transcriptionally induce FURIN, Notch signaling may indirectly lead to enhanced viral entry via enhanced FURIN expression (73,74). ...
MicroRNAs (miRNAs) are small regulatory RNAs which govern gene expression post-transcriptionally by primarily binding to the 3'-UTR of mRNA target genes. miR-145 is a well-studied miRNA that has been implicated in controlling a range of biological processes. miR-145 is expressed in a variety of tissues and cell types and acts as a tumor-suppressor by regulating target gene signaling pathways involved in different aspects of tumor growth and progression. There is also strong evidence that highlights the important functions of miR-145 in the cardiovascular system. Here, we review the mechanisms of miR-145 in tumorigenesis and cancer progression and compare and contrast with the roles of miR-145 in cardiovascular development and disease. We discuss the important targets of miR-145 in cancer and their possible link to the cardiovascular system.
... Furin is found highly expressed in various tissues like lungs by which SARS-CoV-2 can successfully infect the respiratory system via this convertase and initiate activation of its surface glycoprotein [94]. Similarly, in some sample studies obtained from SARS-CoV-2 infected persons in China, various mutations in the furin cleavage site were observed which ultimately affect the binding ability of S-protein to surface [95]. Thus, this site is an important feature in the pathogenicity of SARS-CoV-2. ...
SARS-CoV-2 (COVID-19) epidemic has created an unprecedented medical and economic crisis all over the world. SARS-CoV-2 is found to have more contagious character as compared to MERS-CoV and is spreading in a very fast manner all around the globe. It has affected over 31 million people all over the world till date. This virus shares around 80% of genome similarity with SARS-CoV. In this perspective, we have explored three major targets namely; SARS-CoV-2 spike (S) protein, RNA dependent RNA polymerase, and 3CL or Mpro Protease for the inhibition of SARS-CoV-2. These targets have attracted attention of the medicinal chemists working on computer-aided drug design in developing new small molecules that might inhibit these targets for combating COVID-19 disease. Moreover, we have compared the similarity of these target proteins with earlier reported coronavirus (SARS-CoV). We have observed that both the coronaviruses share around 80% similarity in their amino acid sequence. The key amino acid interactions which can play a crucial role in designing new small molecule inhibitors against COVID-19 have been reported in this perspective. Authors believe that this study will help the medicinal chemists to understand the key amino acids essential for interactions at the active site of target proteins in SARS-CoV-2, based on their similarity with earlier reported viruses. In this review, we have also described the lead molecules under various clinical trials for their efficacy against COVID-19.
... Indeed, this has reflected in the COVID-19 trajectory. 19 For instance, COVID-19 was more severe in Wuhan in the early stage of the pandemic with 32% severe cases and 11% case fatality. 20,21 However, later data from Wuhan showed more mild form of SARS-CoV-2 infection compared to Zhejiang 22 and the entire China. ...
... 23 The transmissibility of SARS-CoV-2 increased from varied reproductive number (R 0 ) of 2.212-2.686 in Wuhan to R 0 of 3.7713 in the entire China. 19 In addition, this observation was similar to SARS-CoV-2 viral load of symptomatic and asymptomatic COVID-19 patient which revealed the capacity of occult SARS-CoV-2 transmission. 24 Indeed, these observations in the clinic-epidemiological features of COVID-19 ...
الملخص
أهداف البحث
تسبب مرض الحمة التاجية لعام ٢٠١٩ في حالة طوارئ صحية عالمية غير مسبوقة. فلقد أودى هذا الوباء بالفعل بحياة أكثر من ٣٥٠٠٠٠ شخصا في غضون خمسة أشهر من ظهوره، خاصة في الولايات المتحدة الأمريكية والقارة الأوروبية. حللت هذه الدراسة الآثار المترتبة على السارس-٢ الجينية، والطفرات على تنوع ضراوة الحمة التاجية لعام ٢٠١٩، وكيف يمكن لهذه العوامل أن تؤثر على التطوير والتطبيق الناجحين للعلاج الكيميائي المضاد للفيروسات، والعلاج المناعي والتشخيص المصلي والتطعيم.
طرق البحث
تمت تصفية واستعراض نقدي لمقالات النص الكامل المناسبة والمؤهلة، التي تم نشرها خلال الفترة من ٣١ ديسمبر ٢٠١٩ إلى ٣١ مايو ٢٠٢٠، واستخراجها من "PubMed" و "Scopus" و "Web of Science" و. "Hinari" استخدمنا مصطلحات رؤوس الموضوعات الطبية "الحمة التاجية لعام ٢٠١٩" و"الطفرة" و"التنوع الجيني" و" سارس -٢" و"الضراوة" و"الإمراضية" و"التطور" و"انتقال" لهذا البحث.
النتائج
أظهر بحثنا أن سارس-٢ تعرض لطفرات كبيرة باستمرار في أجزاء مختلفة من البروتينات غير الهيكلية، كان بروتين S هو المحدد الرئيس لتطور السارس-٢، وانتقاله، وضراوته وهدفه لتطوير اللقاح. بالإضافة إلى ذلك، يمثل البروتين غير الهيكلي هدفا مضادا للفيروسات في علاج الحمة التاجية لعام ٢٠١٩.
الاستنتاجات
نظرا للأهمية الحاسمة لطفرات سارس-٢على مسببات أمراض الحمة التاجية لعام ٢٠١٩، والتشخيص المستمر للمصل، والأدوية المضادة للفيروسات، وتطوير اللقاحات، توصي هذه الدراسة باستمرار جهود المراقبة الجزيئية لـ سارس-٢ حيث من المحتمل أن يؤدي هذا النهج إلى تحديد المسوخات الجديدة وتأثيرها على التدخلات الطبية الحيوية الجارية وتدابير مراقبة الحمة التاجية لعام ٢٠١٩.
... Genomic studies of SARS-CoV-2 suggest a phylogenetic relation with RaTG13, an endogenous variant reported in bats, based on the 96.2% identity between the two genomes [4]. Three different variants of SARS-CoV-2 have been reported, which are distributed on Asia, Europe, and America [5], to date accounting for 54 strains [6]. Additionally, among 103 strains of SARS-CoV-2 analyzed by Tang et al. [7], 101 exhibited a complete link between two specific Single Nucleotide Polymorphisms (SNPs): 72 strains exhibited a "CT" haplotype (defined as lineage L, because it is at the Leucine codon) and 29 strains exhibited a "TC" haplotype (defined as lineage S, because it is at the Serine codon) at these two SNPs. ...
... By using Equation (6) in Equation (5), we obtain Equation (7): ...
Due to the particularities of SARS-CoV-2, public health policies have played a crucial role in the control of the COVID-19 pandemic. Epidemiological parameters for assessing the stage of the outbreak, such as the Effective Reproduction Number (R t), are not always straightforward to calculate, raising barriers between the scientific community and non-scientific decision-making actors. The combination of estimators of R t with elaborated Machine Learning-based forecasting techniques provides a way to support decision-making when assessing governmental plans of action. In this work, we develop forecast models applying logistic growth strategies and auto-regression techniques based on Auto-Regressive Integrated Moving Average (ARIMA) models for each country that records information about the COVID-19 outbreak. Using the forecast for the main variables of the outbreak, namely the number of infected (I), recovered (R), and dead (D) individuals, we provide a real-time estimation of R t and its temporal evolution within a timeframe. With such models, we evaluate R t trends at the continental and country levels, providing a clear picture of the effect governmental actions have had on the spread. We expect this methodology of combining forecast models for raw data to calculate R t to serve as valuable input to support decision-making related to controlling the spread of SARS-CoV-2.
... Another possible explanation is the presence of mutant strains with varying pathogenicity, as evidenced from genomic studies in multiple nations. [13][14][15][16] These different strains may cause varying degrees of chemosensory impairment with regional discrepancy, although this has not been scientifically proven. Therefore, it is important to collect and examine regional data to depict a representative landscape for our population. ...
Background: To slow down the transmission of the coronavirus disease 2019 (COVID-19), it is important to identify specific symptoms for effective screening. While anosmia/hypsomia and dysgeusia/ageusia have been identified as a highly prevalent symptoms, there are wide geographic variations, necessitating the regional evaluation of the prevalence of the symptoms.
Methods: A cross-sectional study was performed to evaluate the self-reported symptoms among adults (over 18-year-old) who underwent COVID-19 tests at an ambulatory assessment centre. We identified 1,345 patients (102 positive and 1,243 negative) who visited the assessment centre between March 16 and April 15, 2020. We randomly sampled negative patients in a 1:3 ratio. The primary outcome was the prevalence of self-reported anosmia/hyposmia and dysgeusia/ageusia. Logistic regression was performed to evaluate the association between COVID-19 positivity and loss of smell and taste.
Results: Fifty-six of 102 (50%) positive patients and 72 of 306 (23.5%) negative patients completed the survey. Anosmia/hyposmia and dysgeusia/ageusia were more prevalent among COVID-19 positive patients (41.1% vs. 4.2%, p<0.001 for smell and 46.4% vs. 5.6%, p<0.001 for taste). Anosmia/hyposmia and dysgeusia/ageusia were independently highly associated with COVID-19 positivity (adjusted odds ratio 14.4 and 11.4 for smell and taste, respectively).
Interpretation: In this Canadian study, smell and taste loss may be key symptoms of COVID- 19. This evidence can be helpful in the clinical diagnosis of COVID-19, particularly settings of limited testing capacity.
... Yet unconfirmed studies (44,45) performed early this year reported isolation of various SARS-CoV-2 strains from patients with mutations in the RBD. Some of these mutations apparently have increased RBD-binding affinities. ...
... The existence of ADE in SARS-CoV-2 might aggravate the COVID-19 pandemic with higher morbidity and mortality, when convalescent patients will encounter infections in the future by possibly mutated strains (44,45). However, the evidence for distinct types or strains in the present stage of evolution of SARS-CoV-2, which could account for differences in morbidity and RBD binding affinity, is conflicting (48). ...
SARS-CoV-2 pandemic and recurrent dengue epidemics in tropical countries have turned into a global health threat. While both virus-caused infections may only reveal light symptoms, they can also cause severe diseases. Here, we review the possible antibody-dependent enhancement (ADE) occurrence, known for dengue infections, when there is a second infection with a different virus strain. Consequently, preexisting antibodies do not neutralize infection, but enhance it, possibly by triggering Fcγ receptor-mediated virus uptake. No clinical data exist indicating such mechanism for SARS-CoV-2, but previous coronavirus infections or infection of SARS-CoV-2 convalescent with different SARS-CoV-2 strains could promote ADE, as experimentally shown for antibodies against the MERS-CoV or SARS-CoV spike S protein. © 2020 International Society for Advancement of Cytometry.
... Apakah betul terjadi di suatu ekosistem di dekat kota Wuhan, di mana kelelawar mentransmisikan ini ke trenggiling dan akhirnya mentransmisikan ini ke manusia. 16 Penanganan Krisis COVID-19 dan Anthropocene ...
