Humanity has seen numerous pandemics during its course of evolution. The list includes several incidents from the past, such as measles, Ebola, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), etc. The latest edition to this is coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of August 18, 2020, COVID-19 has affected over 21 million people from 180 + countries with 0.7 million deaths across the globe. Genomic technologies have enabled us to understand the genomic constitution of pathogens, their virulence, evolution, and rate of mutation, etc. To date, more than 83,000 viral genomes have been deposited in public repositories, such as GISAID and NCBI. While we are writing this, India is the third most affected country by COVID-19, with 2.7 million cases and > 53,000 deaths. Gujarat is the 11th highest affected state with a 3.48% death rate compared to the national average of 1.91%. In this study, a total of 502 SARS-CoV-2 genomes from Gujarat were sequenced and analyzed to understand its phylogenetic distribution and variants against global and national sequences. Further variants were analyzed from diseased and recovered patients from Gujarat and the world to understand its role in pathogenesis. Among the missense mutations present in the Gujarat SARS-CoV-2 genomes, C28854T (Ser194Leu) had an allele frequency of 47.62 and 7.25% in deceased patients from the Gujarat and global datasets, respectively. In contrast, the allele frequency of 35.16 and 3.20% was observed in recovered patients from the Gujarat and global datasets, respectively. It is a deleterious mutation present in the nucleocapsid (N) gene and is significantly associated with mortality in Gujarat patients with a p-value of 0.067 and in the global dataset with a p-value of 0.000924. The other deleterious variant identified in deceased patients from Gujarat (p-value of 0.355) and the world (p-value of 2.43E-06) is G25563T, which is located in Orf3a and plays a potential role in viral pathogenesis. SARS-CoV-2 genomes from Gujarat are forming distinct clusters under the GH clade of GISAID. This study will shed light on the viral haplotype in SARS-CoV-2 samples from Gujarat, India.
Host-dependency factors have increasingly been targeted to minimize antiviral drug resistance. In this study, we have demonstrated that inhibition of p38 mitogen activated protein kinase (MAPK, a cellular protein) suppresses buffalopox virus (BPXV) protein synthesis by targeting p38-MNK1-eIF4E signaling pathway. In order to provide insights into the evolution of drug resistance, we selected resistant mutants by long-term sequential passages (P; n = 60) in the presence of p38 inhibitor (SB239063). The P60-SB239063 virus exhibited significant resistance to SB239063 as compared to the P60-Control virus. To provide mechanistic insights on the acquisition of resistance by BPXV-P60-SB239063, we generated p38-α and p38-ϒ (isoforms of p38) knockout Vero cells by CRISPR/Cas9-mediated genome editing. It was demonstrated that unlike the WT virus which is dependent on p38-α isoform, the resistant virus (BPXV-P60-SB239063) switches over to use p38-ϒ so as to efficiently replicate in the target cells. This is a rare evidence wherein a virus was shown to bypass the dependency on a critical cellular factor under selective pressure of a drug.
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which was first reported in Wuhan, China in November 2019 has developed into a pandemic since March 2020, causing substantial human casualties and economic losses. Studies on SARS-CoV-2 are being carried out at an unprecedented rate to tackle this threat. Genomics studies, in particular, are indispensable to elucidate the dynamic nature of the RNA genome of SARS-CoV-2. RNA viruses are marked by their unique ability to undergo high rates of mutation in their genome, much more frequently than their hosts, which diversifies their strengths qualifying them to elude host immune response and amplify drug resistance. In this study, we sequenced and analyzed the genomic information of the SARS-CoV-2 isolates from two infected Indian patients and explored the possible implications of point mutations in its biology. In addition to multiple point mutations, we found a remarkable similarity between relatively common mutations of 36nucleotide deletion in ORF8 of SARS-CoV-2. Our results corroborate with the earlier reported 29-nucleotide deletion in SARS, which was frequent during the early stage of human-to-human transmission. The results will be useful to understand the biology of SARS-CoV-2 and itsattenuation for vaccine development.
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