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Article: On the Origins of Omicron's Unique Spike Gene Insertion.

Venkatakrishnan, A J / Anand, Praveen / Lenehan, Patrick J / Suratekar, Rohit / Raghunathan, Bharathwaj / Niesen, Michiel J M / Soundararajan, Venky

Vaccines

2022 Volume 10, Issue 9

Abstract: The emergence of a heavily mutated SARS-CoV-2 variant (Omicron; Pango lineage B.1.1.529 and BA sublineages) and its rapid spread to over 75 countries raised a global public health alarm. Characterizing the mutational profile of Omicron is necessary to ... ...

Abstract	The emergence of a heavily mutated SARS-CoV-2 variant (Omicron; Pango lineage B.1.1.529 and BA sublineages) and its rapid spread to over 75 countries raised a global public health alarm. Characterizing the mutational profile of Omicron is necessary to interpret its clinical phenotypes which are shared with or distinctive from those of other SARS-CoV-2 variants. We compared the mutations of the initially circulating Omicron variant (now known as BA.1) with prior variants of concern (Alpha, Beta, Gamma, and Delta), variants of interest (Lambda, Mu, Eta, Iota, and Kappa), and ~1500 SARS-CoV-2 lineages constituting ~5.8 million SARS-CoV-2 genomes. Omicron's Spike protein harbors 26 amino acid mutations (23 substitutions, 2 deletions, and 1 insertion) that are distinct compared to other variants of concern. While the substitution and deletion mutations appeared in previous SARS-CoV-2 lineages, the insertion mutation (ins214EPE) was not previously observed in any other SARS-CoV-2 lineage. Here, we consider and discuss various mechanisms through which the nucleotide sequence encoding for ins214EPE could have been acquired, including local duplication, polymerase slippage, and template switching. Although we are not able to definitively determine the mechanism, we highlight the plausibility of template switching. Analysis of the homology of the inserted nucleotide sequence and flanking regions suggests that this template-switching event could have involved the genomes of SARS-CoV-2 variants (e.g., the B.1.1 strain), other human coronaviruses that infect the same host cells as SARS-CoV-2 (e.g., HCoV-OC43 or HCoV-229E), or a human transcript expressed in a host cell that was infected by the Omicron precursor.
Language	English
Publishing date	2022-09-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines10091509
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Article: Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest.

Anand, Praveen / Lenehan, Patrick J / Niesen, Michiel / Yoo, Unice / Patwardhan, Dhruti / Montorzi, Marcelo / Venkatakrishnan, A J / Soundararajan, Venky

Cell death discovery

2022 Volume 8, Issue 1, Page(s) 124

Abstract: Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in ... ...

Abstract	Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. Here we investigate if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome. Specifically, we compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9926 8-mers from all the viral proteins in the reference SARS-CoV-2 proteome. No 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome. However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome. Interestingly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to an MYH6 peptide encoded by the c.5410 C > A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%), and Latino/Admixed Americans (0.003%). Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants. Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. We suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as "viral variants of cardiac interest".
Language	English
Publishing date	2022-03-21
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-022-00914-9
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Article ; Online: High diversity in Delta variant across countries revealed by genome-wide analysis of SARS-CoV-2 beyond the Spike protein.

Suratekar, Rohit / Ghosh, Pritha / Niesen, Michiel J M / Donadio, Gregory / Anand, Praveen / Soundararajan, Venky / Venkatakrishnan, A J

Molecular systems biology

2022 Volume 18, Issue 2, Page(s) e10673

Abstract: The highly contagious Delta variant of SARS-CoV-2 has become a prevalent strain globally and poses a public health challenge around the world. While there has been extensive focus on understanding the amino acid mutations in the Delta variant's Spike ... ...

Abstract	The highly contagious Delta variant of SARS-CoV-2 has become a prevalent strain globally and poses a public health challenge around the world. While there has been extensive focus on understanding the amino acid mutations in the Delta variant's Spike protein, the mutational landscape of the rest of the SARS-CoV-2 proteome (25 proteins) remains poorly understood. To this end, we performed a systematic analysis of mutations in all the SARS-CoV-2 proteins from nearly 2 million SARS-CoV-2 genomes from 176 countries/territories. Six highly prevalent missense mutations in the viral life cycle-associated Membrane (I82T), Nucleocapsid (R203M, D377Y), NS3 (S26L), and NS7a (V82A, T120I) proteins are almost exclusive to the Delta variant compared to other variants of concern (mean prevalence across genomes: Delta = 99.74%, Alpha = 0.06%, Beta = 0.09%, and Gamma = 0.22%). Furthermore, we find that the Delta variant harbors a more diverse repertoire of mutations across countries compared to the previously dominant Alpha variant. Overall, our study underscores the high diversity of the Delta variant between countries and identifies a list of amino acid mutations in the Delta variant's proteome for probing the mechanistic basis of pathogenic features such as high viral loads, high transmissibility, and reduced susceptibility against neutralization by vaccines.
MeSH term(s)	COVID-19 ; Humans ; Mutation ; Mutation, Missense ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/genetics
Chemical Substances	Spike Glycoprotein, Coronavirus
Language	English
Publishing date	2022-01-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2193510-5
ISSN	1744-4292 ; 1744-4292
ISSN (online)	1744-4292
ISSN	1744-4292
DOI	10.15252/msb.202110673
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Article: Benchmarking evolutionary tinkering underlying human-viral molecular mimicry shows multiple host pulmonary-arterial peptides mimicked by SARS-CoV-2.

Venkatakrishnan, A J / Kayal, Nikhil / Anand, Praveen / Badley, Andrew D / Church, George M / Soundararajan, Venky

Cell death discovery

2020 Volume 6, Issue 1, Page(s) 96

Abstract: The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. Here, we report 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and the human reference proteome. We benchmark this ... ...

Abstract	The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. Here, we report 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and the human reference proteome. We benchmark this observation against other viral-human 8-mer/9-mer peptide identity, which suggests generally similar extents of molecular mimicry for SARS-CoV-2 and many other human viruses. Interestingly, 20 novel human peptides mimicked by SARS-CoV-2 have not been observed in any previous coronavirus strains (HCoV, SARS-CoV, and MERS). Furthermore, four of the human 8-mer/9-mer peptides mimicked by SARS-CoV-2 map onto HLA-B40:01, HLA-B40:02, and HLA-B35:01 binding peptides from human PAM, ANXA7, PGD, and ALOX5AP proteins. This mimicry of multiple human proteins by SARS-CoV-2 is made salient by single-cell RNA-seq (scRNA-seq) analysis that shows the targeted genes significantly expressed in human lungs and arteries; tissues implicated in COVID-19 pathogenesis. Finally, HLA-A03 restricted 8-mer peptides are found to be shared broadly by human and coronaviridae helicases in functional hotspots, with potential implications for nucleic acid unwinding upon initial infection. This study presents the first scan of human peptide mimicry by SARS-CoV-2, and via its benchmarking against human-viral mimicry more broadly, presents a computational framework for follow-up studies to assay how evolutionary tinkering may relate to zoonosis and herd immunity.
Keywords	covid19
Language	English
Publishing date	2020-10-02
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-020-00321-y
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Article ; Online: SARS-CoV-2 strategically mimics proteolytic activation of human ENaC.

Anand, Praveen / Puranik, Arjun / Aravamudan, Murali / Venkatakrishnan, A J / Soundararajan, Venky

eLife

2020 Volume 9

Abstract: Molecular mimicry is an evolutionary strategy adopted by viruses to exploit the host cellular machinery. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site, absent in any previous coronavirus sequenced, resulting in the striking mimicry ... ...

Abstract	Molecular mimicry is an evolutionary strategy adopted by viruses to exploit the host cellular machinery. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site, absent in any previous coronavirus sequenced, resulting in the striking mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic alteration of ENaC-α causes aldosterone dysregulation in patients, highlighting that the FURIN site is critical for activation of ENaC. Single cell RNA-seq from 66 studies shows significant overlap between expression of ENaC-α and the viral receptor ACE2 in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular characterization with cleavage signatures of 178 proteases highlights proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. Evolution of SARS-CoV-2 into a global pandemic may be driven in part by its targeted mimicry of ENaC-α, a protein critical for the homeostasis of airway surface liquid, whose misregulation is associated with respiratory conditions.
MeSH term(s)	Angiotensin-Converting Enzyme 2 ; Betacoronavirus/genetics ; Betacoronavirus/metabolism ; Betacoronavirus/pathogenicity ; COVID-19 ; Coronavirus Infections/virology ; Epithelial Sodium Channels/genetics ; Epithelial Sodium Channels/metabolism ; Host-Pathogen Interactions ; Humans ; Molecular Mimicry ; Pandemics ; Peptide Hydrolases/metabolism ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; Pneumonia, Viral/virology ; Proteolysis ; SARS-CoV-2 ; Substrate Specificity ; Viral Envelope Proteins/genetics ; Viral Envelope Proteins/metabolism ; Viral Proteins/genetics ; Viral Proteins/metabolism
Chemical Substances	Epithelial Sodium Channels ; S envelope protein, hepatitis B virus ; SCNN1A protein, human ; Viral Envelope Proteins ; Viral Proteins ; Peptide Hydrolases (EC 3.4.-) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23) ; Ace2 protein, mouse (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Keywords	covid19
Language	English
Publishing date	2020-05-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.58603
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Article ; Online: Paediatric safety assessment of BNT162b2 vaccination in a multistate hospital-based electronic health record system in the USA: a retrospective analysis.

Matson, Robert P / Niesen, Michiel J M / Levy, Emily R / Opp, Derek N / Lenehan, Patrick J / Donadio, Greg / O'Horo, John C / Venkatakrishnan, A J / Badley, Andrew D / Soundararajan, Venky

The Lancet. Digital health

2023 Volume 5, Issue 4, Page(s) e206–e216

Abstract: Background: The emergency use authorisation of BNT162b2 (tozinameran; Comirnaty, Pfizer-BioNTech) for children aged 5-17 years has resulted in rapid vaccination in the paediatric population. However, there are few studies of adverse events associated ... ...

Abstract	Background: The emergency use authorisation of BNT162b2 (tozinameran; Comirnaty, Pfizer-BioNTech) for children aged 5-17 years has resulted in rapid vaccination in the paediatric population. However, there are few studies of adverse events associated with vaccination in children. The aim of this study was to systematically assess the adverse events of two-dose BNT162b2 vaccination in the paediatric population. Methods: We conducted a retrospective analysis of patient electronic health records (EHRs) of children aged 5-17 years who received the primary two-dose series of the BNT162b2 vaccine between Jan 5, 2021, and Aug 5, 2022, at the Mayo Clinic Health System (MN, FL, AZ, IA, and WI), USA. Using natural language processing, we automatically curated adverse events reported by physicians in EHR clinical notes before and after vaccination. To determine significant adverse events after BNT162b2 vaccination, we calculated risk differences, which was defined as the percentage difference between the rate of children with an adverse event after a vaccine dose and the baseline rate of children with an adverse event before vaccination. 95% CIs and p values were calculated using the Miettinen and Nurminen score method. Findings: 56 436 individuals aged 5-17 years (20 227 aged 5-11 years and 36 209 aged 12-17 years) with EHRs in the Mayo Clinic Health Systems were included in the study. Overall, the reporting of adverse events remained low in passive surveillance. Serious adverse events were rare after the first and second doses of BNT162b2, with rates of anaphylaxis (six [0·01%] of 56 436), myocarditis (five [0·01%]), and pericarditis (three [0·01%]) consistent with previous studies. Among the 20 227 5-11-year-olds, there were increased risks of fatigue (58 after second dose vs 41 before first dose; risk difference [RD] Interpretation: Overall, this data suggests that vaccination with BNT162b2 in the paediatric population is generally safe and well-tolerated. Further research is warranted to investigate the basis for the increased risk of myocarditis in adolescent males. Additionally, further studies are needed to confirm whether the findings in our study population apply to the whole vaccinated paediatric population. Funding: nference.
MeSH term(s)	Adolescent ; Child ; Humans ; Male ; BNT162 Vaccine/adverse effects ; Electronic Health Records ; Hospitals ; Myocarditis ; Retrospective Studies ; United States/epidemiology ; Vaccination ; COVID-19/prevention & control
Chemical Substances	BNT162 Vaccine
Language	English
Publishing date	2023-03-24
Publishing country	England
Document type	Journal Article
ISSN	2589-7500
ISSN (online)	2589-7500
DOI	10.1016/S2589-7500(22)00253-9
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Article ; Online: Enoxaparin is associated with lower rates of mortality than unfractionated Heparin in hospitalized COVID-19 patients.

Pawlowski, Colin / Venkatakrishnan, A J / Kirkup, Christian / Berner, Gabriela / Puranik, Arjun / O'Horo, John C / Badley, Andrew D / Soundararajan, Venky

EClinicalMedicine

2021 Volume 33, Page(s) 100774

Abstract: Background: Coagulopathies are a major class among COVID-19 associated complications. Although anticoagulants such as unfractionated Heparin and Enoxaparin are both being used for therapeutic mitigation of COVID associated coagulopathy (CAC), ... ...

Abstract	Background: Coagulopathies are a major class among COVID-19 associated complications. Although anticoagulants such as unfractionated Heparin and Enoxaparin are both being used for therapeutic mitigation of COVID associated coagulopathy (CAC), differences in their clinical outcomes remain to be investigated. Methods: We analyzed records of 1,113 patients in the Mayo Clinic Electronic Health Record (EHR) database who were admitted to the hospital for COVID-19 between April 4, 2020 and August 31, 2020, including 19 different Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Among this patient population, we compared cohorts of patients who received different types of anticoagulants, including 441 patients who received unfractionated Heparin and 166 patients who received Enoxaparin. Clinical outcomes at 28 days were compared, and propensity score matching was used to control for potential confounding variables including: demographics, comorbidities, ICU status, chronic kidney disease stage, and oxygenation status. Patients with a history of acute kidney injury and patients who received multiple types of anticoagulants were excluded from the study. Findings: We find that COVID-19 patients administered unfractionated Heparin but not Enoxaparin have higher rates of 28-day mortality (risk ratio: 4.3; 95% Confidence Interval [C.I.].: [1.8, 10.2]; Interpretation: This study emphasizes the need for mechanistically investigating differential modulation of the COVID-associated coagulation cascades by Enoxaparin versus unfractionated Heparin. Funding: This work was supported by Nference, inc.
Language	English
Publishing date	2021-03-09
Publishing country	England
Document type	Journal Article
ISSN	2589-5370
ISSN (online)	2589-5370
DOI	10.1016/j.eclinm.2021.100774
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Article ; Online: GPCR Dynamics: Structures in Motion.

Latorraca, Naomi R / Venkatakrishnan, A J / Dror, Ron O

Chemical reviews

2016 Volume 117, Issue 1, Page(s) 139–155

Abstract: The function of G protein-coupled receptors (GPCRs)-which represent the largest class of both human membrane proteins and drug targets-depends critically on their ability to change shape, transitioning among distinct conformations. Determining the ... ...

Abstract	The function of G protein-coupled receptors (GPCRs)-which represent the largest class of both human membrane proteins and drug targets-depends critically on their ability to change shape, transitioning among distinct conformations. Determining the structural dynamics of GPCRs is thus essential both for understanding the physiology of these receptors and for the rational design of GPCR-targeted drugs. Here we review what is currently known about the flexibility and dynamics of GPCRs, as determined through crystallography, spectroscopy, and computer simulations. We first provide an overview of the types of motion exhibited by a GPCR and then discuss GPCR dynamics in the context of ligand binding, activation, allosteric modulation, and biased signaling. Finally, we discuss the implications of GPCR conformational plasticity for drug design.
MeSH term(s)	Protein Conformation ; Receptors, G-Protein-Coupled/chemistry
Chemical Substances	Receptors, G-Protein-Coupled
Language	English
Publishing date	2016-09-13
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	207949-5
ISSN	1520-6890 ; 0009-2665
ISSN (online)	1520-6890
ISSN	0009-2665
DOI	10.1021/acs.chemrev.6b00177
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Article ; Online: Constrained catecholamines gain β

Xu, Xinyu / Shonberg, Jeremy / Kaindl, Jonas / Clark, Mary J / Stößel, Anne / Maul, Luis / Mayer, Daniel / Hübner, Harald / Hirata, Kunio / Venkatakrishnan, A J / Dror, Ron O / Kobilka, Brian K / Sunahara, Roger K / Liu, Xiangyu / Gmeiner, Peter

Nature communications

2023 Volume 14, Issue 1, Page(s) 2138

Abstract: G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and ... ...

Abstract	G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β
MeSH term(s)	Catecholamines ; Ligands ; Receptors, Adrenergic, beta-2/metabolism ; Epinephrine/pharmacology ; Amino Acid Sequence
Chemical Substances	Catecholamines ; Ligands ; Receptors, Adrenergic, beta-2 ; Epinephrine (YKH834O4BH)
Language	English
Publishing date	2023-04-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-37808-y
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Article ; Online: Author Correction: Constrained catecholamines gain β

Nature communications

2023 Volume 14, Issue 1, Page(s) 2992

Language	English
Publishing date	2023-05-24
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38820-y
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