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1.
Theranostics ; 12(10): 4779-4790, 2022.
Article in English | MEDLINE | ID: covidwho-2203050

ABSTRACT

New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are continuing to spread globally, contributing to the persistence of the COVID-19 pandemic. Increasing resources have been focused on developing vaccines and therapeutics that target the Spike glycoprotein of SARS-CoV-2. Recent advances in microfluidics have the potential to recapitulate viral infection in the organ-specific platforms, known as organ-on-a-chip (OoC), in which binding of SARS-CoV-2 Spike protein to the angiotensin-converting enzyme 2 (ACE2) of the host cells occurs. As the COVID-19 pandemic lingers, there remains an unmet need to screen emerging mutations, to predict viral transmissibility and pathogenicity, and to assess the strength of neutralizing antibodies following vaccination or reinfection. Conventional detection of SARS-CoV-2 variants relies on two-dimensional (2-D) cell culture methods, whereas simulating the micro-environment requires three-dimensional (3-D) systems. To this end, analyzing SARS-CoV-2-mediated pathogenicity via microfluidic platforms minimizes the experimental cost, duration, and optimization needed for animal studies, and obviates the ethical concerns associated with the use of primates. In this context, this review highlights the state-of-the-art strategy to engineer the nano-liposomes that can be conjugated with SARS-CoV-2 Spike mutations or genomic sequences in the microfluidic platforms; thereby, allowing for screening the rising SARS-CoV-2 variants and predicting COVID-19-associated coagulation. Furthermore, introducing viral genomics to the patient-specific blood accelerates the discovery of therapeutic targets in the face of evolving viral variants, including B1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), c.37 (Lambda), and B.1.1.529 (Omicron). Thus, engineering nano-liposomes to encapsulate SARS-CoV-2 viral genomic sequences enables rapid detection of SARS-CoV-2 variants in the long COVID-19 era.


Subject(s)
COVID-19 , Coronavirus Infections , Pneumonia, Viral , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/complications , COVID-19/diagnosis , Coronavirus Infections/prevention & control , Genomics , Humans , Liposomes , Microfluidics , Mutation , Pandemics/prevention & control , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus
3.
Int J Mol Sci ; 23(16)2022 Aug 20.
Article in English | MEDLINE | ID: covidwho-2200284

ABSTRACT

Rapid identification of SARS-CoV-2 variants is essential for epidemiological surveillance. RT-qPCR-based variant differentiation tests can be used to quickly screen large sets of samples for relevant variants of concern/interest; this study was conducted on specimens collected at 11 centers located in Poland during routine SARS-CoV-2 diagnostics between August 2020 and December 2021. A total of 1096 samples (with CT < 30) were screened for Alpha, Beta, Delta, Kappa and Omicron variants using commercial assays targeting repeat mutation sites. Variants were assigned to 434 (39.6%) specimens; the remaining 662 (60.4%) samples were not classified (no tested mutations detected). Alpha (n = 289; 66.59%), Delta (n = 115; 26.5%), Kappa (n = 30; 6.91%) and Omicron (n = 2; 0.46%) variants were identified and their distribution changed over time. The first Alpha variant appeared in October 2020, and it began to gradually increase its proportion of the virus population by June 2021. In July 2021, it was replaced by the Delta variant, which already dominated by the end of the year. The first Kappa was detected in October 2021, while Omicron was found in December 2021. The screening of samples allowed the determination of epidemiological trends over a time interval reflecting the national COVID-19 waves.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Testing , Humans , Mutation , Poland/epidemiology , Real-Time Polymerase Chain Reaction , SARS-CoV-2/genetics
4.
BMC Bioinformatics ; 23(1): 504, 2022 Nov 24.
Article in English | MEDLINE | ID: covidwho-2196034

ABSTRACT

BACKGROUND: Identifying polymorphism clades on phylogenetic trees could help detect punctual mutations that are associated with viral functions. With visualization tools coloring the tree, it is easy to visually find clades where most sequences have the same polymorphism state. However, with the fast accumulation of viral sequences, a computational tool to automate this process is urgently needed. RESULTS: Here, by implementing a branch-and-bound-like search method, we developed an R package named sitePath to identify polymorphism clades automatically. Based on the identified polymorphism clades, fixed and parallel mutations could be inferred. Furthermore, sitePath also integrated visualization tools to generate figures of the calculated results. In an example with the influenza A virus H3N2 dataset, the detected fixed mutations coincide with antigenic shift mutations. The highly specificity and sensitivity of sitePath in finding fixed mutations were achieved for a range of parameters and different phylogenetic tree inference software. CONCLUSIONS: The result suggests that sitePath can identify polymorphism clades per site. The clustering of sequences on a phylogenetic tree can be used to infer fixed and parallel mutations. High-quality figures of the calculated results could also be generated by sitePath.


Subject(s)
Influenza A Virus, H3N2 Subtype , Influenza, Human , Humans , Phylogeny , Influenza A Virus, H3N2 Subtype/genetics , Mutation , Software , Polymorphism, Genetic
5.
Chin Med J (Engl) ; 135(10): 1213-1222, 2022 May 20.
Article in English | MEDLINE | ID: covidwho-2190861

ABSTRACT

ABSTRACT: The pandemic of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to major public health challenges globally. The increasing viral lineages identified indicate that the SARS-CoV-2 genome is evolving at a rapid rate. Viral genomic mutations may cause antigenic drift or shift, which are important ways by which SARS-CoV-2 escapes the human immune system and changes its transmissibility and virulence. Herein, we summarize the functional mutations in SARS-CoV-2 genomes to characterize its adaptive evolution to inform the development of vaccination, treatment as well as control and intervention measures.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Mutation/genetics , Pandemics , SARS-CoV-2/genetics , Virulence
6.
Front Cell Infect Microbiol ; 12: 902914, 2022.
Article in English | MEDLINE | ID: covidwho-2154670

ABSTRACT

Identification of the main SARS-CoV-2 variants in real time is of interest to control the virus and to rapidly devise appropriate public health responses. The RT-qPCR is currently considered to be the reference method to screen SARS-CoV-2 mutations, but it has some limitations. The multiplexing capability is limited when the number of markers to detect increases. Moreover, the performance of this allele-specific method may be impacted in the presence of new mutations. Herein, we present a proof-of-concept study of a simple molecular assay to detect key SARS-CoV-2 mutations. The innovative features of the assay are the multiplex asymmetric one-step RT-PCR amplification covering different regions of SARS-CoV-2 S gene and the visual detection of mutations on a lateral flow DNA microarray. Three kits (Kit 1: N501Y, E484K; Kit 2: L452R, E484K/Q; Kit 3: K417N, L452R, E484K/Q/A) were developed to match recommendations for surveillance of SARS-CoV-2 variants between January and December 2021. The clinical performance was assessed using RNA extracts from 113 SARS-CoV-2-positive samples with cycle thresholds <30, and results demonstrated that our assay allows specific and sensitive detection of mutations, with a performance comparable to that of RT-qPCR. The VAR-CoV assay detected four SARS-CoV-2 targets and achieved specific and sensitive screening of spike mutations associated with the main variants of concern, with a performance comparable to that of RT-qPCR. With well-defined virus sequences, this assay can be rapidly adapted to other emerging mutations; it is a promising tool for variant surveillance.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , Humans , Mutation , SARS-CoV-2/genetics
7.
Viruses ; 14(9)2022 09 14.
Article in English | MEDLINE | ID: covidwho-2143631

ABSTRACT

In this retrospective, single-center study, we conducted an analysis of 13,699 samples from different individuals obtained from the Federal Research Center of Fundamental and Translational Medicine, from 1 April to 30 May 2020 in Novosibirsk region (population 2.8 million people). We identified 6.49% positive for SARS-CoV-2 cases out of the total number of diagnostic tests, and 42% of them were from asymptomatic people. We also detected two asymptomatic people, who had no confirmed contact with patients with COVID-19. The highest percentage of positive samples was observed in the 80+ group (16.3%), while among the children and adults it did not exceed 8%. Among all the people tested, 2423 came from a total of 80 different destinations and only 27 of them were positive for SARS-CoV-2. Out of all the positive samples, 15 were taken for SARS-CoV-2 sequencing. According to the analysis of the genome sequences, the SARS-CoV-2 variants isolated in the Novosibirsk region at the beginning of the pandemic belonged to three phylogenetic lineages according to the Pangolin classification: B.1, B.1.1, and B.1.1.129. All Novosibirsk isolates contained the D614G substitution in the Spike protein, two isolates werecharacterized by an additional M153T mutation, and one isolate wascharacterized by the L5F mutation.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , COVID-19/epidemiology , Child , Genome, Viral , Genomics , Humans , Mutation , Pandemics , Phylogeny , Retrospective Studies , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
8.
J Am Soc Nephrol ; 33(4): 732-745, 2022 04.
Article in English | MEDLINE | ID: covidwho-2141049

ABSTRACT

BACKGROUND: The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown. METHODS: Genetic techniques were used in patients with tubular proteinuria and deafness to identify the disease-causing gene. Diagnostic and functional studies were performed in patients and disease models to investigate the pathophysiology. RESULTS: We identified six individuals (5-33 years) with proteinuria and a high-frequency hearing deficit associated with the homozygous missense variant c.1192C>T (p.R398W) in EHD1. Proteinuria (0.7-2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1R398W/R398W knockin mice also showed a high-frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Interestingly, ciliogenesis appeared unaffected in patients and mouse models. In silico structural analysis predicted a destabilizing effect of the R398W variant and possible inference with nucleotide binding leading to impaired EHD1 oligomerization and membrane remodeling ability. CONCLUSIONS: A homozygous missense variant of EHD1 causes a previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and tubular proteinuria. Recessive EHD1 variants should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted.


Subject(s)
Deafness , Zebrafish , Adolescent , Adult , Animals , Child , Child, Preschool , Deafness/genetics , Endocytosis , Humans , Kidney Tubules, Proximal/metabolism , Low Density Lipoprotein Receptor-Related Protein-2/genetics , Low Density Lipoprotein Receptor-Related Protein-2/metabolism , Mice , Mutation , Proteinuria/metabolism , Vesicular Transport Proteins/genetics , Young Adult , Zebrafish/metabolism
9.
PLoS Pathog ; 18(11): e1010951, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2140720

ABSTRACT

SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning prospectively characterizes the impacts of mutations on these biochemical properties, enabling rapid assessment of new mutations seen during viral surveillance. However, the effects of mutations can change as the virus evolves, requiring updated deep mutational scans. We determined the impacts of all single amino acid mutations in the Omicron BA.1 and BA.2 RBDs on ACE2-binding affinity, RBD folding, and escape from binding by the LY-CoV1404 (bebtelovimab) monoclonal antibody. The effects of some mutations in Omicron RBDs differ from those measured in the ancestral Wuhan-Hu-1 background. These epistatic shifts largely resemble those previously seen in the Alpha variant due to the convergent epistatically modifying N501Y substitution. However, Omicron variants show additional lineage-specific shifts, including examples of the epistatic phenomenon of entrenchment that causes the Q498R and N501Y substitutions present in Omicron to be more favorable in that background than in earlier viral strains. In contrast, the Omicron substitution Q493R exhibits no sign of entrenchment, with the derived state, R493, being as unfavorable for ACE2 binding in Omicron RBDs as in Wuhan-Hu-1. Likely for this reason, the R493Q reversion has occurred in Omicron sub-variants including BA.4/BA.5 and BA.2.75, where the affinity buffer from R493Q reversion may potentiate concurrent antigenic change. Consistent with prior studies, we find that Omicron RBDs have reduced expression, and identify candidate stabilizing mutations that ameliorate this deficit. Last, our maps highlight a broadening of the sites of escape from LY-CoV1404 antibody binding in BA.1 and BA.2 compared to the ancestral Wuhan-Hu-1 background. These BA.1 and BA.2 deep mutational scanning datasets identify shifts in the RBD mutational landscape and inform ongoing efforts in viral surveillance.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Humans , Angiotensin-Converting Enzyme 2/genetics , Spike Glycoprotein, Coronavirus , SARS-CoV-2/genetics , COVID-19/genetics , Antibodies, Neutralizing/chemistry , Mutation
10.
Sci Rep ; 12(1): 20098, 2022 Nov 22.
Article in English | MEDLINE | ID: covidwho-2133574

ABSTRACT

The in-depth understanding of the dynamics of COVID-19 transmission among different age groups is of great interest for governments and health authorities so that strategies can be devised to reduce the pandemic's detrimental effects. We developed the SIRDV-Virulence (Susceptible-Infected-Recovered-Dead-Vaccinated-Virulence) epidemiological model based on a population balance equation to study the effects virus mutants, vaccination strategies, 'Anti/Non Vaxxer' proportions, and reinfection rates to provide methods to mitigate COVID-19 transmission among the United States population. Based on publicly available data, we obtain the key parameters governing the spread of the pandemic. The results show that a large fraction of infected cases comes from the adult and children populations in the presence of a highly infectious COVID-19 mutant. Given the situation at the end of July 2021, the results show that prioritizing children and adult vaccinations over that of seniors can contain the spread of the active cases, thereby preventing the healthcare system from being overwhelmed and minimizing subsequent deaths. The model suggests that the only option to curb the effects of this pandemic is to reduce the population of unvaccinated individuals. A higher fraction of 'Anti/Non-vaxxers' and a higher reinfection rate can both independently lead to the resurgence of the pandemic.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Adult , Child , United States/epidemiology , Humans , Reinfection/epidemiology , COVID-19/epidemiology , COVID-19/prevention & control , Vaccination/methods , Mutation
11.
Respir Med ; 199: 106878, 2022 08.
Article in English | MEDLINE | ID: covidwho-2132268

ABSTRACT

BACKGROUND: The availability of mutation-specific cystic fibrosis modulator therapies has the potential to improve the lives of children and adults with cystic fibrosis. The frequency of mutations causing defects in the cystic fibrosis transmembrane conductance regulator (CFTR) function varies between sub-groups in multi-ethnic populations. The profile of patients eligible for CFTR modulator ivacaftor/tezacaftor/elexacaftor (Kaftrio™) therapy based on ethnicity has not been reported in the United Kingdom CF population. METHODS: We conducted a descriptive cross-sectional analysis of patients in the UK CF Registry who had annual review data submissions in 2019. Data analysed included demographic characteristics, spirometry, chronic Pseudomonas status, nutrition, and CF related diabetes status. The genotype data was stratified by whether there was at least one copy of F508del or no copy of F508del as current eligibility for ivacaftor/tezacaftor/elexacaftor, or projected future eligibility, is defined as having at least one copy of F508del mutation. RESULTS: Data from 9887 patients were reviewed, 46.7% female, mean age 22.5 years. 8.6% (n = 852) patients had no copy of F508del making them ineligible for ivacaftor/tezacaftor/elexacaftor. Overall, 93.4% of patients were of white ethnicity, with a similar proportion of those with at least one F508del being white (95.6%). This was reduced to 70.0% of those with no F508del. The proportion of people of Asian ethnicity was much higher in the no F508del group (19.2% vs 1.2%). Compared with one F508del patients, the no F508del group were older (25.2 years vs 22.2 years, p < 0.001), had higher prevalence of pancreatic sufficiency (39.0% vs 14.9% p < 0.001), lower prevalence of chronic Pseudomonas infection (21.1% vs. 26.6%, p < 0.001), and higher best FEV1 from the previous year (proportion with greater than 70% FEV1 predicted, 66.1% vs 63.0%, p = 0.005). CONCLUSION: Patients from black, Asian and minority ethnic backgrounds are significantly less likely to be eligible for ivacaftor/tezacaftor/elexacaftor based on the current prescribing policy in the UK. At present this is the most highly effective CF modulator therapy available to treat people with CF. The CF community should urgently address the unmet need for effective targeted therapies for patients without F508del.


Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator , Cystic Fibrosis , Adult , Child , Cross-Sectional Studies , Cystic Fibrosis/drug therapy , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Female , Humans , Male , Mutation , Respiratory Function Tests , Young Adult
12.
Eur J Med Genet ; 65(12): 104659, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2130695

ABSTRACT

Pathogenic variants in CENPJ have been first identified in consanguineous Pakistani families with Hereditary Primary Microcephaly type 6 (MCPH6). In addition to primary microcephaly, the CENPJ-related phenotypic spectrum lately included also distinctive and peculiar 'bird-like' craniofacial dysmorphisms, intrauterine and/or postnatal growth retardation, and moderate to severe intellectual disability (ID). These features are also part of the clinical spectrum of Seckel syndrome (SCKL) a genetically heterogeneous neurodevelopmental condition caused by mutations in different genes involved in cell cycle progression. Among these, CENPJ is responsible for type 4 Seckel syndrome (SCKL4). The literature reports two individuals affected by SCKL4 suffering from seizures and other two individuals with other brain malformations in addition to microcephaly. However, neither epilepsy nor brain malformations are described in detail and genotype-phenotype information remains limited. We describe the first Caucasian affected with SCKL4 and harboring a novel, homozygous mutation in CENPJ. We detail the clinical and neuroradiological findings including structural focal epilepsy and a severe brain malformation (i.e., hydranencephaly) that was never associated with SCKL4 to date.


Subject(s)
Dwarfism , Hydranencephaly , Intellectual Disability , Microcephaly , Humans , Microcephaly/genetics , Microcephaly/pathology , Dwarfism/genetics , Facies , Intellectual Disability/genetics , Intellectual Disability/pathology , Mutation , Microtubule-Associated Proteins/genetics
13.
Nature ; 593(7857): 136-141, 2021 05.
Article in English | MEDLINE | ID: covidwho-2114170

ABSTRACT

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/therapy , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/immunology , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/isolation & purification , COVID-19/metabolism , COVID-19/virology , Female , HEK293 Cells , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Immunization, Passive , Male , Middle Aged , Models, Molecular , Mutation , Neutralization Tests , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vaccines, Synthetic/administration & dosage
14.
Int J Infect Dis ; 111: 347-353, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-2113590

ABSTRACT

AIMS: To explore the contagiousness and new SARS-CoV-2 mutations in pediatric COVID-19. METHODS: This cohort study enrolled all pediatric patients admitted to 8 hospitals in Zhejiang Province of China between 21 January and 29 February 2020, their family members and close-contact classmates. Epidemiological, demographic, clinical and laboratory data were collected. Bioinformatics was used to analyze the features of SARS-CoV-2. Individuals were divided into 3 groups by the first-generation case: Groups 1 (unclear), 2 (adult), and 3 (child). The secondary attack rate (SAR) and R0 were compared among the groups. RESULTS: The infection rate among 211 individuals was 64% (135/211). The SAR in Groups 2 and 3 was 71% (73/103) and 3% (1/30), respectively; the median R0 in Groups 2 and 3 was 2 (range: 1-8) and 0 (range: 0-1), respectively. Compared with adult cases, the SAR and R0 of pediatric cases were significantly lower (p<0.05). We obtained SARS-CoV-2 sequences from the same infant's throat and fecal samples at a two-month interval and found that the new spike protein A958D mutation detected in the stool improved thermostability theoretically. CONCLUSIONS: Children have lower ability to spread SARS-CoV-2. The new A958D mutation is a potential reason for its long residence in the intestine.


Subject(s)
COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Adult , COVID-19/virology , Child , China/epidemiology , Cohort Studies , Humans , Incidence , Infant , Mutation , SARS-CoV-2/genetics
15.
J Med Virol ; 94(7): 3421-3430, 2022 07.
Article in English | MEDLINE | ID: covidwho-2114172

ABSTRACT

The SARS-CoV-2 21K/BA.1, 21L/BA.2, and BA.3 Omicron variants have recently emerged worldwide. To date, the 21L/BA.2 Omicron variant has remained very minority globally but became predominant in Denmark instead of the 21K/BA.1 variant. Here, we describe the first cases diagnosed with this variant in south-eastern France. We identified 13 cases using variant-specific qPCR and next-generation sequencing between 28/11/2021 and 31/01/2022, the first two cases being diagnosed in travelers returning from Tanzania. Overall, viral genomes displayed a mean (±standard deviation) number of 65.9 ± 2.5 (range, 61-69) nucleotide substitutions and 31.0 ± 8.3 (27-50) nucleotide deletions, resulting in 49.6 ± 2.2 (45-52) amino acid substitutions (including 28 in the spike protein) and 12.4 ± 1.1 (12-15) amino acid deletions. Phylogeny showed the distribution in three different clusters of these genomes, which were most closely related to genomes from England and South Africa, from Singapore and Nepal, or from France and Denmark. Structural predictions highlighted a significant enlargement and flattening of the surface of the 21L/BA.2 N-terminal domain of the spike protein compared to that of the 21K/BA.1 Omicron variant, which may facilitate initial viral interactions with lipid rafts. Close surveillance is needed at global, country, and center scales to monitor the incidence and clinical outcome of the 21L/BA.2 Omicron variant.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , COVID-19/epidemiology , Humans , Mutation , Nucleotides , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
16.
Viruses ; 14(11)2022 Nov 09.
Article in English | MEDLINE | ID: covidwho-2110271

ABSTRACT

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) facilitates viral entry into host cells and is the key target for neutralizing antibodies. The SARS-CoV-2 lineage B.1.620 carries fifteen mutations in the S protein and is spread in Africa, the US and Europe, while lineage R.1 harbors four mutations in S and infections were observed in several countries, particularly Japan and the US. However, the impact of the mutations in B.1.620 and R.1 S proteins on antibody-mediated neutralization and host cell entry are largely unknown. Here, we report that these mutations are compatible with robust ACE2 binding and entry into cell lines, and they markedly reduce neutralization by vaccine-induced antibodies. Our results reveal evasion of neutralizing antibodies by B.1.620 and R.1, which might have contributed to the spread of these lineages.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2 , Virus Internalization , Peptidyl-Dipeptidase A/metabolism , Antibodies, Neutralizing , Antibodies, Viral , Mutation
17.
Saudi Med J ; 43(11): 1276-1279, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2119223

ABSTRACT

OBJECTIVES: To investigate the emergent mutations involved in the evolutionary stages of the virus for better management of pandemic. METHODS: This cross-sectional genomic investigation was performed on February 28, 2022, at the Biology Department, Faculty of Science, Tabuk University. Numerous mutations were searched in genomic isolates of Omicron variant prevalent in the Kingdom of Saudi Arabian. Whole-genome sequences were retrieved from genomic databases and were subjected to the Global Initiative on Sharing Avian Influenza Data (GISAID) CoVsurver for the Omicron variant detection and mutations. RESULTS: Approximately 8.755 million SARS-CoV-2 genomes were reported to GISAID on February 28, 2022, of which 1270 have been reported from the Kingdom of Saudi Arabia. Among the 1270 genomes, 30 were Omicron variants. Among the Saudi Arabian genomes, 30 were detected as Omicron variants. Twenty-four unique mutations have been detected in membrane, envelope, spike and non-structural proteins (NSP) 12, NSP3, and NSP2. Ten of these unique mutations have been detected in spike protein. CONCLUSION: The current study provides useful information for further experimental investigation of mutation's effects on virus transmission, severity, and vaccine efficacy.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Animals , SARS-CoV-2/genetics , Saudi Arabia/epidemiology , Genome, Viral , Cross-Sectional Studies , COVID-19/epidemiology , Mutation , Genomics
19.
BMJ Case Rep ; 15(11)2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2118551

ABSTRACT

Familial amyloidosis of the Finnish type (FAF) is a rare multisystemic disorder caused by mutations in the gelsolin gene. The clinical presentation is typically characterised by a triad of ophthalmic, neurological and dermatological findings. FAF has been reported in several countries, primarily in Finland and recently in Portugal. We report the first genetically confirmed cases of FAF from two unrelated families in our neuromuscular outpatient clinic. Gelsolin gene sequencing revealed the heterozygous gelsolin mutation (c.640G>A). The clinical features and the neurophysiological studies of two index patients and their relatives are presented. Obtaining an early diagnosis can be challenging, but FAF should be considered in the differential diagnosis of progressive bilateral facial neuropathy, even if there is no known Finnish ancestor.


Subject(s)
Amyloidosis, Familial , Gelsolin , Humans , Gelsolin/genetics , Finland , Amyloidosis, Familial/diagnosis , Amyloidosis, Familial/genetics , Mutation , Portugal
20.
Proc Biol Sci ; 289(1987): 20221747, 2022 Nov 30.
Article in English | MEDLINE | ID: covidwho-2115857

ABSTRACT

The raw material for viral evolution is provided by intra-host mutations occurring during replication, transcription or post-transcription. Replication and transcription of Coronaviridae proceed through the synthesis of negative-sense 'antigenomes' acting as templates for positive-sense genomic and subgenomic RNA. Hence, mutations in the genomes of SARS-CoV-2 and other coronaviruses can occur during (and after) the synthesis of either negative-sense or positive-sense RNA, with potentially distinct patterns and consequences. We explored for the first time the mutational spectrum of SARS-CoV-2 (sub)genomic and anti(sub)genomic RNA. We use a high-quality deep sequencing dataset produced using a quantitative strand-aware sequencing method, controlled for artefacts and sequencing errors, and scrutinized for accurate detection of within-host diversity. The nucleotide differences between negative- and positive-sense strand consensus vary between patients and do not show dependence on age or sex. Similarities and differences in mutational patterns between within-host minor variants on the two RNA strands suggested strand-specific mutations or editing by host deaminases and oxidative damage. We observe generally neutral and slight negative selection on the negative strand, contrasting with purifying selection in ORF1a, ORF1b and S genes of the positive strand of the genome.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , RNA, Viral/genetics , Genome, Viral , Mutation , Genomics
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