Rna Binding Is A Determinant For Zinc Finger Antiviral Protein Zap Inhibition Of Alphaviruses
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Rna Binding Is A Determinant For Zinc Finger Antiviral Protein Zap Inhibition Of Alphaviruses
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Author : LeAnn Pham Nguyen
language : en
Publisher:
Release Date : 2023
Rna Binding Is A Determinant For Zinc Finger Antiviral Protein Zap Inhibition Of Alphaviruses written by LeAnn Pham Nguyen and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2023 with categories.
As the potential for viral epidemics grows, so does the need to understand host antiviral mechanisms and the ways in which viruses evade these defenses. Alphaviruses are positive-sense single-stranded RNA viruses that cause serious disease in humans and whose geographic distributions continue to expand. The type I interferon (IFN) response controls the acute phase of alphavirus infection by stimulating expression of antiviral effectors including zinc finger antiviral protein (ZAP). ZAP restricts certain alphaviruses by translational inhibition. While the ability of ZAP to bind RNA is critical for its antiviral activity against a broad spectrum of viruses, it is unclear how ZAP RNA binding is linked to its ability to inhibit viral RNA translation. The precise determinants of ZAP recognition of viral and host RNA also remain uncertain. In this dissertation, we aimed to elucidate the principles and functional consequences of ZAP RNA recognition during alphavirus infection. First, we characterized how RNA binding by ZAP and its co-factor TRIM25 affects their abilities to inhibit viral RNA translation. We demonstrated that mutations targeting the ability of ZAP to bind CpG dinucleotides also compromises its ability to restrict viral replication and translation. Additionally, we found a negative correlation between the ability of ZAP to bind RNA and its ability to interact with TRIM25, suggesting that these interactions may form distinct determinants for ZAP antiviral activity against different viruses. Next, we leveraged a panel of related alphaviruses with different sensitivities to ZAP to investigate the molecular determinants of how some alphaviruses can evade ZAP restriction. Previous work from our lab found that Ross River virus (RRV) and Sindbis virus (SINV) are sensitive to ZAP inhibition, while o'nyong'nyong virus (ONNV) and the particularly pathogenic chikungunya virus (CHIKV) are resistant to ZAP. We identified a 500-bp window within the genomes of these viruses where in vitro ZAP CpG-specific binding correlates with ZAP sensitivity. However, upon testing ZAP binding to other windows with CpG contents correlating to ZAP sensitivity, we found that ZAP preferentially binds CpG dinucleotides only in certain alphavirus RNA contexts. Our results suggest a potential strategy of immune evasion by ZAP-resistant alphaviruses by suppression or masking of CpG dinucleotides in regions important for ZAP recognition and/or inhibition. Finally, we investigated ZAP binding to virus and host RNA in a cellular context during infection with a ZAP-sensitive alphavirus virus, SINV, and a ZAP-resistant alphavirus, CHIKV. We found that ZAP binds distinct regions of the SINV and CHIKV genomes and that ZAP binding sites on host mRNAs also shift during infection with these two viruses. These findings provide a basis for evaluating strategies by which a highly pathogenic virus like CHIKV may evade recognition and remodel the host cellular environment during infection. The work presented in this dissertation broadens our understanding of the molecular mechanisms underlying immune recognition of alphaviruses, as well as how some alphaviruses have developed strategies to subvert this recognition. Our results will provide targets for the development of antivirals to reinforce weak points in the immune response.
Ubiquitination And Rna Binding In The Host Antiviral Response To Alphaviruses
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Author : Emily Yang
language : en
Publisher:
Release Date : 2022
Ubiquitination And Rna Binding In The Host Antiviral Response To Alphaviruses written by Emily Yang and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2022 with categories.
Humanity is plagued by myriad viruses, most of which have no vaccines nor antiviral therapeutics. In order to address this pressing need and stave off future viral pandemics, basic science is required to illuminate both virulence determinants and host defenses. Alphaviruses are arthropod-borne, positive-sense RNA viruses that can cause febrile rashes, debilitating arthritis, and encephalomyelitis, which can prove fatal. The acute phase of their infection is controlled by the type I interferon (IFN) response, wherein host detection of invading pathogens induces expression of IFN and subsequent IFN-stimulated genes (ISGs) to establish an antiviral environment. In this dissertation, I present a study on the roles of ubiquitination and RNA binding in antiviral mechanisms utilized by two ISGs, the ubiquitin E3 ligase tripartite motif-containing protein 25 (TRIM25) and the RNA CpG sensor zinc finger antiviral protein (ZAP), to restrict alphavirus translation. While both TRIM25 and ZAP are potent antiviral factors individually, whether through direct or indirect means of viral inhibition, attention has turned in recent years to their cooperative inhibition of varied viruses. Previous work done by our lab suggests that TRIM25-mediated ubiquitination is essential for ZAP inhibition of alphavirus translation, but the exact substrates that mediate this antiviral activity are unknown. Moreover, not only do both TRIM25 and ZAP bind RNA, but also RNA binding is critical to their cellular function. For TRIM25, RNA binding stimulates its ligase activity; for ZAP, RNA binding is required for its detection and inhibition of viral RNA. However, the requirement for ZAP and TRIM25 RNA binding in their synergistic inhibition of viral translation remains unknown. Here, we utilized a "substrate trapping" approach to elucidate TRIM25 ubiquitination substrates involved in diverse and antiviral cellular processes. We generated a point mutation in the TRIM25 RING catalytic domain that abolishes TRIM25 ligase activity and traps substrates, enabling us to identify and characterize bona fide TRIM25 substrates involved in translation and nucleic acid metabolism. Moreover, our results suggest that several of these substrates contribute to TRIM25 antiviral activity. Together, these findings lay the groundwork for understanding how TRIM25-mediated ubiquitination of diverse substrates may modulate translation, nucleic acid metabolism, and antiviral activity. We also characterized the effects of ZAP and TRIM25 RNA binding on inhibiting viral translation. We demonstrate that mutations affecting ZAP RNA binding to CpG motifs significantly impact its ability to restrict viral replication and translation, and that the ability of ZAP to bind viral RNA is significantly negatively correlated with its ability to associate with TRIM25. These results suggest that ZAP RNA binding and interaction with TRIM25 may form two distinct determinants for ZAP antiviral mechanisms dependent on the viral context. Finally, I conclude with our collaborative work in characterizing the ability of novel antifusion peptides induce positive Gaussian curvature, thus remodeling membranes and restricting alphavirus replication. The work presented in this dissertation represents a multifaceted examination of the multiple determinants of TRIM25 and ZAP antiviral activity against alphaviruses, and includes a forward-looking development of antiviral therapeutics
Fields Virology
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Author : David Mahan Knipe
language : en
Publisher: Lippincott Williams & Wilkins
Release Date : 2007
Fields Virology written by David Mahan Knipe and has been published by Lippincott Williams & Wilkins this book supported file pdf, txt, epub, kindle and other format this book has been release on 2007 with Science categories.
Accompanying CD-ROM has same title as book.
Desk Encyclopedia Animal And Bacterial Virology
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Author : Brian W.J. Mahy
language : en
Publisher: Academic Press
Release Date : 2010-04-06
Desk Encyclopedia Animal And Bacterial Virology written by Brian W.J. Mahy and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2010-04-06 with Medical categories.
This volume contains 81 chapters that relate to veterinary and bacterial virology. The first section describes general features of farm and other animals of agricultural importance. The following three sections detail other animal viruses, avian viruses, and viruses affecting aquatic species such as fish and crustaceans. The Section five deals with viruses which infect bacteria. The most comprehensive single-volume source providing an overview of virology issues related to animal and bateria Bridges the gap between basic undergraduate texts and specialized reviews Concise and general overviews of important topics within the field will help in preparation of lectures, writing reports, or drafting grant applications
American Society For Virology 22nd Annual Meeting
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Author : American Society for Virology. Meeting
language : en
Publisher:
Release Date : 2003
American Society For Virology 22nd Annual Meeting written by American Society for Virology. Meeting and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2003 with Virology categories.
Ebola And Marburg Viruses
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Author : Elena Ryabchikova
language : en
Publisher:
Release Date : 2004
Ebola And Marburg Viruses written by Elena Ryabchikova and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2004 with Medical categories.
Electron microscopy has a special place among the wide range of techniques available for viral research. With electron microscopy, a virologist can follow the course of viral infections by visualizing cell damage and viral replication. Each virus family has its own structural and functional attributes, but attention is usually focused on the pathogenic and health-threatening viruses. The Ebola and Marburg filoviruses are notorious among these. The work was done at Vector in Novosibirsk, Russia, by Dr. Ryabchikova. Dr. Price has made it possible for Dr. Ryabchikova to explain her experiments and insights by expanding the descriptions and making the book readable by professionals who are not steeped in the intricacies of virology. In the course of writing this book, Dr. Price has incorporated more complete references of work done by other laboratories so that the story of the filoviruses is a compilation of the research done internationally, but told from the Russian perspective. In Ebola and Marburg Viruses: A View of Infection Using Electron Microscopy, the authors combine recent published and unpublished literature with the insight developed in over 30 years in electron microscopy and 15 years in virology to tell the story of filoviruses and how they invade and conquer their hosts. The book describes the dynamic properties of these viruses, follows the stages of filoviral infection from the individual cell to the whole organism, and reconstructs the sequential events that occur in filoviral infections. The book also demonstrates that, rather than a curiosity, the electron micrograph is an integral tool in studies of viral infection and the pathological process. Ebola and MarburgViruses: A View of Infection Using Electron Microscopy includes over 100 outstanding electron micrographs of filoviruses and the cell and tissue damage they cause during infection. Ebola and Marburg Viruses: A View of Infection Using Electron Microscopy is addressed to investigators in the widely diversified fields of medicine and biology. For this reason, Ryabchikova and Price have carefully elucidated concepts familiar to virologists that may be unfamiliar to nonvirolgists. The book is also designed to provide opportunities for investigators specializing in viruses to correlate their findings with the work of electron microscopists.
Microbial Pathogenesis
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Author : Bruce A. McClane
language : en
Publisher: Wiley-Blackwell
Release Date : 1999-09
Microbial Pathogenesis written by Bruce A. McClane and has been published by Wiley-Blackwell this book supported file pdf, txt, epub, kindle and other format this book has been release on 1999-09 with Medical categories.
The fact that infectious diseases claim over 17 million victims worldwide each year, along with the regular emergence of new drug resistance pathogens, signals that infectious diseases will continue to be a daily concern of the Physician well into the future. This reality requires that today's medical students develop a solid foundation in medical microbiology -- a foundation they can achieved by using IMS: Microbial Pathogenesis. This book is developed in response to the changing field of medical microbiology. The number of diseases and the diversity of microbial pathogens that cause these diseases are far too many for simple taxonomic organization. As a result, IMS Microbial Pathogenesis focuses on the common principles of infection rather than the old taxonomic organization, enabling a better long term retention of relevant material, and minimizing the short-term memorization of specific "factoids," many of which may become out-dated in a short time.
Viral Immunology And Immunopathology
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Author : Abner Louis Notkins
language : en
Publisher: Academic Press
Release Date : 2014-06-28
Viral Immunology And Immunopathology written by Abner Louis Notkins and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014-06-28 with Medical categories.
Viral Immunology and Immunopathalogy covers topics concerning the role of cellular and humoral immunity in viral infections, factors responsible for the persistence and recurrence of viral infections in the presence of immunity, mechanisms of viral immunopathology, and concepts in the development of vaccines. The book describes the history of viral immunology; the synthesis and properties of viral antigens; and the humoral immune response to viruses. The text also discusses the mechanisms of viral neutralization; cellular immunity; the role of inflammatory cells and effector molecules in combating viral infections; and the genetic control of resistance. The book concludes with chapters on herd immunity; viral immunopathology; and viral immunology and immunopathology. Immunologists, pathologists, virologists, and microbiologists will find the book useful.
Encyclopedia Of Virology D H
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Author :
language : en
Publisher:
Release Date : 2008
Encyclopedia Of Virology D H written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2008 with Virology categories.
A reference source that deals with the research in virology. It covers biological, molecular, and medical topics concerning viruses in animals, plants, bacteria and insects. It also offers coverage on AIDS and HIV, viral immunology and vaccines, and the origin, history, evolution and phylogeny of viruses. "Encyclopedia of Virology, Third Edition" continues its success as the largest single reference source of current research in virology. Unique in its use of concise 'mini-review' articles, this praised work covers biological, molecular, and medical topics concerning viruses in animals, plants, bacteria and insects. Now in five volumes, this new edition has been extensively revised and updated to reflect the 50 per cent increase in identified and accepted viruses since the year 2000. With over 25 per cent new chapters and over 1000 illustrations, this edition takes into account the new developments in virology research by including information on new emerging diseases such as avian flu, SARS and West Nile and the ability of some viruses to be used as agents of bioterrorism. Edited by leading Virologists Mahy and van Regenmortel, this third edition remains the number one all-inclusive source of information for virology researchers, students, and reference departments of academic, medical, and corporate libraries. This title offers extensive coverage on AIDS and HIV, viral immunology and vaccines, the economic importance and control of virus diseases, and the origin, history, evolution and phylogeny of viruses. It features: four color throughout; sections on future perspectives that show the direction of current research; 25 per cent articles; glossary of key terms for easy referencing; information on viruses of human clinical interest, including the virus causing SARS; more than 20 per cent virus classifications. It offers the most recent information from the 8th International Committee on Taxonomy and Classification of Viruses. It includes recommendations for further reading and a list of other relevant entries.
Medical Aspects Of Biological Warfare
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Author : Zygmunt F. Dembek
language : en
Publisher: U.S. Government Printing Office
Release Date : 2008-02
Medical Aspects Of Biological Warfare written by Zygmunt F. Dembek and has been published by U.S. Government Printing Office this book supported file pdf, txt, epub, kindle and other format this book has been release on 2008-02 with History categories.
NOTE: NO FURTHER DISCOUNT FOR THIS PRINT PRODUCT-- OVERSTOCK SALE -- Significantly reduced list price while supplies last Addresses weaponization of biological agents. Categorizes potential agents as food, waterborne, or agricultural toxins and discusses the respective epidemiology.