Understanding the Role of SARS-CoV-2 ORF3a in Viral Pathogenesis and COVID-19
Jiantao Zhang,Amara Ejikemeuwa,Volodymyr Gerzanich,M. Nasr,Qiyi Tang,J. Marc Simard,Richard Y. Zhao +6 more
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TLDR
This review provides an in-depth analysis of ORF3a protein’s structure, origin, evolution, and mutant variants, and how these characteristics affect its functional role in viral pathogenesis and COVID-19.Abstract:
The ongoing SARS-CoV-2 pandemic has shocked the world due to its persistence, COVID-19-related morbidity and mortality, and the high mutability of the virus. One of the major concerns is the emergence of new viral variants that may increase viral transmission and disease severity. In addition to mutations of spike protein, mutations of viral proteins that affect virulence, such as ORF3a, also must be considered. The purpose of this article is to review the current literature on ORF3a, to summarize the molecular actions of SARS-CoV-2 ORF3a, and its role in viral pathogenesis and COVID-19. ORF3a is a polymorphic, multifunctional viral protein that is specific to SARS-CoV/SARS-CoV-2. It was acquired from β-CoV lineage and likely originated from bats through viral evolution. SARS-CoV-2 ORF3a is a viroporin that interferes with ion channel activities in host plasma and endomembranes. It is likely a virion-associated protein that exerts its effect on the viral life cycle during viral entry through endocytosis, endomembrane-associated viral transcription and replication, and viral release through exocytosis. ORF3a induces cellular innate and pro-inflammatory immune responses that can trigger a cytokine storm, especially under hypoxic conditions, by activating NLRP3 inflammasomes, HMGB1, and HIF-1α to promote the production of pro-inflammatory cytokines and chemokines. ORF3a induces cell death through apoptosis, necrosis, and pyroptosis, which leads to tissue damage that affects the severity of COVID-19. ORF3a continues to evolve along with spike and other viral proteins to adapt in the human cellular environment. How the emerging ORF3a mutations alter the function of SARS-CoV-2 ORF3a and its role in viral pathogenesis and COVID-19 is largely unknown. This review provides an in-depth analysis of ORF3a protein’s structure, origin, evolution, and mutant variants, and how these characteristics affect its functional role in viral pathogenesis and COVID-19.read more
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SARS-CoV-2 protein ORF3a is pathogenic in Drosophila and causes phenotypes associated with COVID-19 post-viral syndrome
TL;DR: In this article, the authors used Drosophila to develop an in vivo model that characterizes mechanisms of SARS-CoV-2 pathogenicity, and found ORF3a adversely affects longevity and motor function by inducing apoptosis and inflammation in the nervous system.
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Evolution of ACE2-independent SARS-CoV-2 infection and mouse adaption after passage in cells expressing human and mouse ACE2
TL;DR: ACE2-independent entry reveals a SARS-CoV-2 infection mechanism that has potential implications for disease pathogenesis, evolution, tropism, and perhaps also intervention development.
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Evolution of the SARS-CoV-2 mutational spectrum
TL;DR: In this article , the relative rates of different types of single nucleotide mutations at fourfold degenerate sites in the viral genome across millions of human SARS-CoV-2 sequences were quantified.
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Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics
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TL;DR: In this paper , the authors highlight target hotspots and their potential agents, with the ultimate goal of using rational design of new therapeutics to not only end this pandemic but also uncover a generalizable platform for use in future pandemics.
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A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
David E. Gordon,Gwendolyn M. Jang,Mehdi Bouhaddou,Jiewei Xu,Kirsten Obernier,Kris M. White,Matthew J. O’Meara,Veronica V. Rezelj,Jeffrey Z. Guo,Danielle L. Swaney,Tia A. Tummino,Ruth Hüttenhain,Robyn M. Kaake,Alicia L. Richards,Beril Tutuncuoglu,Helene Foussard,Jyoti Batra,Kelsey M. Haas,Maya Modak,Minkyu Kim,Paige Haas,Benjamin J. Polacco,Hannes Braberg,Jacqueline M. Fabius,Manon Eckhardt,Margaret Soucheray,Melanie J. Bennett,Merve Cakir,Michael McGregor,Qiongyu Li,Bjoern Meyer,Ferdinand Roesch,Thomas Vallet,Alice Mac Kain,Lisa Miorin,Elena Moreno,Zun Zar Chi Naing,Yuan Zhou,Shiming Peng,Ying Shi,Ziyang Zhang,Wenqi Shen,Ilsa T Kirby,James E. Melnyk,John S. Chorba,Kevin Lou,Shizhong Dai,Inigo Barrio-Hernandez,Danish Memon,Claudia Hernandez-Armenta,Jiankun Lyu,Christopher J.P. Mathy,Tina Perica,Kala Bharath Pilla,Sai J. Ganesan,Daniel J. Saltzberg,Rakesh Ramachandran,Xi Liu,Sara Brin Rosenthal,Lorenzo Calviello,Srivats Venkataramanan,Jose Liboy-Lugo,Yizhu Lin,Xi Ping Huang,Yongfeng Liu,Stephanie A. Wankowicz,Markus Bohn,Maliheh Safari,Fatima S. Ugur,Cassandra Koh,Nastaran Sadat Savar,Quang Dinh Tran,Djoshkun Shengjuler,Sabrina J. Fletcher,Michael C. O’Neal,Yiming Cai,Jason C.J. Chang,David J. Broadhurst,Saker Klippsten,Phillip P. Sharp,Nicole A. Wenzell,Duygu Kuzuoğlu-Öztürk,Hao-Yuan Wang,Raphael Trenker,Janet M. Young,Devin A. Cavero,Devin A. Cavero,Joseph Hiatt,Joseph Hiatt,Theodore L. Roth,Ujjwal Rathore,Ujjwal Rathore,Advait Subramanian,Julia Noack,Mathieu Hubert,Robert M. Stroud,Alan D. Frankel,Oren S. Rosenberg,Kliment A. Verba,David A. Agard,Melanie Ott,Michael Emerman,Natalia Jura,Mark von Zastrow,Eric Verdin,Eric Verdin,Alan Ashworth,Olivier Schwartz,Christophe d'Enfert,Shaeri Mukherjee,Matthew P. Jacobson,Harmit S. Malik,Danica Galonić Fujimori,Trey Ideker,Charles S. Craik,Stephen N. Floor,James S. Fraser,John D. Gross,Andrej Sali,Bryan L. Roth,Davide Ruggero,Jack Taunton,Tanja Kortemme,Pedro Beltrao,Marco Vignuzzi,Adolfo García-Sastre,Kevan M. Shokat,Brian K. Shoichet,Nevan J. Krogan +128 more
TL;DR: A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.