<i>In silico</i>analyses on the comparative sensing of SARS-CoV-2 mRNA by intracellular TLRs of human

Choudhury, Abhigyan; Das, Nabarun Chandra; Patra, Ritwik; Bhattacharya, Manojit; Mukherjee, Subhrajit

doi:10.1101/2020.11.11.377713

Cited by 5 publications

(3 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Development of pulmonary delivery of ivermectin through synthesis of better ivermectin formulation has been reported recently and this is expected to shorten the treatment duration and lead to better outcomes [33]. It is noteworthy to mention that many anti-SARS-CoV-2s are now being tested for their efficacy in shaping the immune response of humans, through targeting the cell surface as well as intracellular toll-like receptors [34,35]. In this context, ivermectin could be an effective option as well.…”

Section: Resultsmentioning

confidence: 99%

Exploring the Binding Efficacy of Ivermectin Against the Key Proteins of SARS-CoV-2 Pathogenesis: an in silico Approach

et al. 2021

Self Cite

View full text Add to dashboard Cite

Aim: COVID-19 is currently the biggest threat to mankind. Recently, ivermectin (a US FDA-approved antiparasitic drug) has been explored as an anti-SARS-CoV-2 agent. Herein, we have studied the possible mechanism of action of ivermectin using in silico approaches. Materials & methods: Interaction of ivermectin against the key proteins involved in SARS-CoV-2 pathogenesis were investigated through molecular docking and molecular dynamic simulation. Results: Ivermectin was found as a blocker of viral replicase, protease and human TMPRSS2, which could be the biophysical basis behind its antiviral efficiency. The antiviral action and ADMET profile of ivermectin was on par with the currently used anticorona drugs such as hydroxychloroquine and remdesivir. Conclusion: Our study enlightens the candidature of ivermectin as an effective drug for treating COVID-19.

show abstract

Section: Resultsmentioning

confidence: 99%

Exploring the Binding Efficacy of Ivermectin Against the Key Proteins of SARS-CoV-2 Pathogenesis: an in silico Approach

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…The variability in the host innate and adaptive immune responses to viral infections influence clinical manifestations and outcomes [ 34, 35 ]. Innate immune response is the first line of defense against the invading pathogen, and utilizes multiple pattern recognition receptors of which, Toll-like receptors (TLRs) have been implicated as key receptors in the recognition of ssRNA of MERS-CoV and SARS-CoV in murine models [ 36, 37 ]. Independent studies have identified rare genetic variants predicted to be loss of function (LOF) at 13 loci governing TLR3 and TLR7 pathway genes and affecting the type I interferon response [ 17, 18] .…”

Section: Discussionmentioning

confidence: 99%

Host genome analysis of structural variations by Optical Genome Mapping provides clinically valuable insights into genes implicated in critical immune, viral infection, and viral replication pathways in patients with severe COVID-19

Sahajpal

Lai

Hastie

et al. 2021

Preprint

View full text Add to dashboard Cite

BackgroundThe varied clinical manifestations and outcomes in patients with SARS-CoV-2 infections implicate a role of host-genetics in the predisposition to disease severity. This is supported by evidence that is now emerging, where initial reports identify common risk factors and rare genetic variants associated with high risk for severe/ life-threatening COVID-19. Impressive global efforts have focused on either identifying common genetic factors utilizing short-read sequencing data in Genome-Wide Association Studies (GWAS) or whole-exome and genome studies to interrogate the human genome at the level of detecting single nucleotide variants (SNVs) and short indels. However, these studies lack the sensitivity to accurately detect several classes of variants, especially large structural variants (SVs) including copy number variants (CNVs), which account for a substantial proportion of variation among individuals. Thus, we investigated the host genomes of individuals with severe/life-threatening COVID-19 at the level of large SVs (500bp-Mb level) to identify events that might provide insight into the inter-individual clinical variability in clinical course and outcomes of COVID-19 patients.MethodsOptical genome mapping using Bionano’s Saphyr® system was performed on thirty-seven severely ill COVID-19 patients admitted to intensive care units (ICU). To extract candidate SVs, three distinct analyses were undertaken. First, an unbiased whole-genome analysis of SVs was performed to identify rare/unique genic SVs in these patients that did not appear in population datasets to determine candidate loci as decisive predisposing factors associated with severe COVID-19. Second, common SVs with a population frequency filter was interrogated for possible association with severe COVID-19 based on literature surveys. Third, genome-wide SV enrichment in severely ill patients versus the general population was investigated by calculating odds ratios to identify top-ranked genes/loci. Candidate SVs were confirmed using qPCR and an independent bioinformatics tool (FaNDOM).ResultsOur patient-centric investigation identified 11 SVs involving 38 genes implicated in three key host-viral interaction pathways: (1) innate immunity and inflammatory response, (2) airway resistance to pathogens, and (3) viral replication, spread, and RNA editing. These included seven rare/unique SVs (not present in the control dataset), identified in 24.3% (9/37) of patients, impacting up to 31 genes, of which STK26 and DPP4 are the most promising candidates. A duplication partially overlapping STK26 was corroborated with data showing upregulation of this gene in severely ill patients. Further, using a population frequency filter of less than 20% in the Bionano control dataset, four SVs involving seven genes were identified in 56.7% (21/37) of patients.ConclusionThis study is the first to systematically assess and highlight SVs’ potential role in the pathogenesis of COVID-19 severity. The genes implicated here identify novel SVs, especially STK26, and extend previous reports involving innate immunity and type I interferon response in the pathogenesis of COVID-19. Our study also shows that optical genome mapping can be a powerful tool to identify large SVs impacting disease outcomes with split survival and add valuable genomic information to the existing sequencing-based technology databases to understand the inter-individual variability associated with SARS-CoV-2 infections and COVID-19 mortality.

show abstract

“…Variability in the host's innate and adaptive immune responses to viral infections clearly can influence clinical manifestations and outcomes (Akira et al, 2006;Brubaker et al, 2015;Channappanavar et al, 2019). The innate immune response is the first line of defense against the invading pathogen and utilizes multiple pattern recognition receptors of which, Toll-like receptors (TLRs) have been implicated as key receptors in the recognition of ssRNA of MERS-CoV and SARS-CoV in murine models (Channappanavar et al, 2019;Choudhury et al, 2020). Independent studies have identified rare predicted loss of function (LOF) variants at 13 loci governing TLR3 and TLR7 pathway genes and affecting the type I interferon response (Van der Made et al, 2020;Fallerini et al, 2021;Zhang et al, 2020).…”

Section: Svs Affecting Genes Implicated In Immune and Inflammatory Re...mentioning

confidence: 99%

Optical genome mapping identifies rare structural variations as predisposition factors associated with severe COVID-19

et al. 2022

View full text Add to dashboard Cite

Impressive global efforts have identified both rare and common gene variants associated with severe COVID-19 using sequencing technologies. However, these studies lack the sensitivity to accurately detect several classes of variants, especially large structural variants (SVs), which account for a substantial proportion of genetic diversity including clinically relevant variation. We performed optical genome mapping on 52 severely-ill COVID-19 patients to identify rare/unique SVs as decisive predisposition factors associated with COVID-19. We identified 7 SVs involving genes implicated in two key host-viral interaction pathways: innate immunity and inflammatory response, and viral replication and spread in 9 patients, of which SVs in STK26 and DPP4 genes are the most intriguing candidates. This study is the first to systematically assess the potential role of SVs in the pathogenesis of COVID-19 severity and highlights the need to evaluate SVs along with sequencing variants to comprehensively associate genomic information with inter-individual variability in COVID-19 phenotypes.

show abstract

In silicoanalyses on the comparative sensing of SARS-CoV-2 mRNA by intracellular TLRs of human

Cited by 5 publications

References 39 publications

Exploring the Binding Efficacy of Ivermectin Against the Key Proteins of SARS-CoV-2 Pathogenesis: an in silico Approach

Exploring the Binding Efficacy of Ivermectin Against the Key Proteins of SARS-CoV-2 Pathogenesis: an in silico Approach

Host genome analysis of structural variations by Optical Genome Mapping provides clinically valuable insights into genes implicated in critical immune, viral infection, and viral replication pathways in patients with severe COVID-19

Optical genome mapping identifies rare structural variations as predisposition factors associated with severe COVID-19

Contact Info

Product

Resources

About