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The Alphavirus Trifecta: How Replication, Assembly, and Virus-Host Interactions Modulate...
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The Alphavirus Trifecta: How Replication, Assembly, and Virus-Host Interactions Modulate Alphavirus Pathogenesis

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Viral Pathogens".

Deadline for manuscript submissions: closed (20 August 2021) | Viewed by 20029

Special Issue Editors

Prof. Dr. Tuli Mukhopadhyay

E-Mail Website
Guest Editor
Department of Biology, Indiana University, Bloomington, United States
Interests: alphavirus structure; assembly; spread
Prof. Dr. Tem Morrison

E-Mail Website
Guest Editor
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
Interests: arbovirus pathogenesis and immunity; viral evasion of host immune responses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alphaviruses are responsible for diseases that range from arthritis to encephalitis, and have global distribution as both endemic and emerging pathogens. Despite the worldwide prevalence of alphaviruses, no approved therapeutics or vaccines for these infections are commercially available. Typically characterized as positive-strand RNA viruses that are transmitted to vertebrate hosts by arthropod vectors, alphaviruses that remain in an insect-restricted transmission cycle or that infect marine animals via horizontal transmission have been identified and continue to be discovered. Thus, the viral vectors, their hosts, and disease mechanisms for alphaviruses are continuously expanding. 

In this Special Issue of Pathogens, our overall goal is to bring together a body of research on different aspects of alphavirus biology, virulence, and pathogenesis. Traditionally, we have studied stages of a virus lifecycle as individual entities—replication factors or innate immunity antagonists or virion structure. It is becoming clear there are no distinct lines between these stages and a single viral protein often has multiple functions throughout the virus lifecycle and in different hosts. We want to learn about these multi-functional factors, and how they contribute to alphavirus replication, transmission, and pathogenesis. We encourage submissions from new investigators who are establishing their laboratories and research programs and mid-career investigators who are expanding their research programs. The questions being asked and approaches being used by the current generation include single-cell analysis, high-resolution microscopy, and interdisciplinary perspectives. These are essential to understand the mechanisms behind viral infections, pathogenesis, anti-viral treatments, and vaccine development. Having researchers who share common interests contribute to this Special issue of Pathogens will foster collaborations that make research more productive and enjoyable.

Prof. Dr. Tuli Mukhopadhyay
Prof. Dr. Tem Morrison
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • RNA replication
  • particle assembly
  • innate host response
  • virion structure
  • host factors
  • viral antagonists
  • transmission and spread

Published Papers (5 papers)

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Research

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16 pages, 2158 KiB  
Article
Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections
by Michael D. Barrera, Victoria Callahan, Ivan Akhrymuk, Nishank Bhalla, Weidong Zhou, Catherine Campbell, Aarthi Narayanan and Kylene Kehn-Hall
Pathogens 2021, 10(3), 283; https://doi.org/10.3390/pathogens10030283 - 02 Mar 2021
Cited by 8 | Viewed by 3369
Abstract
Alphaviruses are a genus of the Togaviridae family and are widely distributed across the globe. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV), cause encephalitis and neurological sequelae while chikungunya virus (CHIKV) and Sindbis virus (SINV) cause arthralgia. There are [...] Read more.
Alphaviruses are a genus of the Togaviridae family and are widely distributed across the globe. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV), cause encephalitis and neurological sequelae while chikungunya virus (CHIKV) and Sindbis virus (SINV) cause arthralgia. There are currently no approved therapeutics or vaccines available for alphaviruses. In order to identify novel therapeutics, a V5 epitope tag was inserted into the N-terminus of the VEEV E2 glycoprotein and used to identify host-viral protein interactions. Host proteins involved in protein folding, metabolism/ATP production, translation, cytoskeleton, complement, vesicle transport and ubiquitination were identified as VEEV E2 interactors. Multiple inhibitors targeting these host proteins were tested to determine their effect on VEEV replication. The compound HA15, a GRP78 inhibitor, was found to be an effective inhibitor of VEEV, EEEV, CHIKV, and SINV. VEEV E2 interaction with GRP78 was confirmed through coimmunoprecipitation and colocalization experiments. Mechanism of action studies found that HA15 does not affect viral RNA replication but instead affects late stages of the viral life cycle, which is consistent with GRP78 promoting viral assembly or viral protein trafficking. Full article
(This article belongs to the Special Issue The Alphavirus Trifecta: How Replication, Assembly, and Virus-Host Interactions Modulate Alphavirus Pathogenesis)
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Review

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19 pages, 2111 KiB  
Review
Alphavirus-Induced Membrane Rearrangements during Replication, Assembly, and Budding
by Zeinab Elmasri, Benjamin L. Nasal and Joyce Jose
Pathogens 2021, 10(8), 984; https://doi.org/10.3390/pathogens10080984 - 04 Aug 2021
Cited by 6 | Viewed by 4628
Abstract
Alphaviruses are arthropod-borne viruses mainly transmitted by hematophagous insects that cause moderate to fatal disease in humans and other animals. Currently, there are no approved vaccines or antivirals to mitigate alphavirus infections. In this review, we summarize the current knowledge of alphavirus-induced structures [...] Read more.
Alphaviruses are arthropod-borne viruses mainly transmitted by hematophagous insects that cause moderate to fatal disease in humans and other animals. Currently, there are no approved vaccines or antivirals to mitigate alphavirus infections. In this review, we summarize the current knowledge of alphavirus-induced structures and their functions in infected cells. Throughout their lifecycle, alphaviruses induce several structural modifications, including replication spherules, type I and type II cytopathic vacuoles, and filopodial extensions. Type I cytopathic vacuoles are replication-induced structures containing replication spherules that are sites of RNA replication on the endosomal and lysosomal limiting membrane. Type II cytopathic vacuoles are assembly induced structures that originate from the Golgi apparatus. Filopodial extensions are induced at the plasma membrane and are involved in budding and cell-to-cell transport of virions. This review provides an overview of the viral and host factors involved in the biogenesis and function of these virus-induced structures. Understanding virus–host interactions in infected cells will lead to the identification of new targets for antiviral discovery. Full article
(This article belongs to the Special Issue The Alphavirus Trifecta: How Replication, Assembly, and Virus-Host Interactions Modulate Alphavirus Pathogenesis)
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17 pages, 2202 KiB  
Review
Alphavirus Virulence Determinants
by Margarita V. Rangel and Kenneth A. Stapleford
Pathogens 2021, 10(8), 981; https://doi.org/10.3390/pathogens10080981 - 03 Aug 2021
Cited by 5 | Viewed by 3676
Abstract
Alphaviruses are important pathogens that continue to cause outbreaks of disease in humans and animals worldwide. Diseases caused by alphavirus infections include acute symptoms of fever, rash, and nausea as well as chronic arthritis and severe-to-fatal conditions including myocarditis and encephalitis. Despite their [...] Read more.
Alphaviruses are important pathogens that continue to cause outbreaks of disease in humans and animals worldwide. Diseases caused by alphavirus infections include acute symptoms of fever, rash, and nausea as well as chronic arthritis and severe-to-fatal conditions including myocarditis and encephalitis. Despite their prevalence and the significant public health threat they pose, there are currently no effective antiviral treatments or vaccines against alphaviruses. Various genetic determinants of alphavirus virulence, including genomic RNA elements and specific protein residues and domains, have been described by researchers to play key roles in the development of disease, the immune response to infection, and virus transmissibility. Here, we focus on the determinants that are currently described in the literature. Understanding how these molecular determinants shape viral infections can lead to new strategies for the development of therapies and vaccines to combat these viruses. Full article
(This article belongs to the Special Issue The Alphavirus Trifecta: How Replication, Assembly, and Virus-Host Interactions Modulate Alphavirus Pathogenesis)
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20 pages, 3904 KiB  
Review
The Structural Biology of Eastern Equine Encephalitis Virus, an Emerging Viral Threat
by S. Saif Hasan, Debajit Dey, Suruchi Singh and Matthew Martin
Pathogens 2021, 10(8), 973; https://doi.org/10.3390/pathogens10080973 - 31 Jul 2021
Cited by 1 | Viewed by 3601
Abstract
Alphaviruses are arboviruses that cause arthritis and encephalitis in humans. Eastern Equine Encephalitis Virus (EEEV) is a mosquito-transmitted alphavirus that is implicated in severe encephalitis in humans with high mortality. However, limited insights are available into the fundamental biology of EEEV and residue-level [...] Read more.
Alphaviruses are arboviruses that cause arthritis and encephalitis in humans. Eastern Equine Encephalitis Virus (EEEV) is a mosquito-transmitted alphavirus that is implicated in severe encephalitis in humans with high mortality. However, limited insights are available into the fundamental biology of EEEV and residue-level details of its interactions with host proteins. In recent years, outbreaks of EEEV have been reported mainly in the United States, raising concerns about public safety. This review article summarizes recent advances in the structural biology of EEEV based mainly on single-particle cryogenic electron microscopy (cryoEM) structures. Together with functional analyses of EEEV and related alphaviruses, these structural investigations provide clues to how EEEV interacts with host proteins, which may open avenues for the development of therapeutics. Full article
(This article belongs to the Special Issue The Alphavirus Trifecta: How Replication, Assembly, and Virus-Host Interactions Modulate Alphavirus Pathogenesis)
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18 pages, 2876 KiB  
Review
De-Coding the Contributions of the Viral RNAs to Alphaviral Pathogenesis
by Autumn T. LaPointe and Kevin J. Sokoloski
Pathogens 2021, 10(6), 771; https://doi.org/10.3390/pathogens10060771 - 19 Jun 2021
Cited by 1 | Viewed by 3368
Abstract
Alphaviruses are positive-sense RNA arboviruses that are capable of causing severe disease in otherwise healthy individuals. There are many aspects of viral infection that determine pathogenesis and major efforts regarding the identification and characterization of virulence determinants have largely focused on the roles [...] Read more.
Alphaviruses are positive-sense RNA arboviruses that are capable of causing severe disease in otherwise healthy individuals. There are many aspects of viral infection that determine pathogenesis and major efforts regarding the identification and characterization of virulence determinants have largely focused on the roles of the nonstructural and structural proteins. Nonetheless, the viral RNAs of the alphaviruses themselves play important roles in regard to virulence and pathogenesis. In particular, many sequences and secondary structures within the viral RNAs play an important part in the development of disease and may be considered important determinants of virulence. In this review article, we summarize the known RNA-based virulence traits and host:RNA interactions that influence alphaviral pathogenesis for each of the viral RNA species produced during infection. Overall, the viral RNAs produced during infection are important contributors to alphaviral pathogenesis and more research is needed to fully understand how each RNA species impacts the host response to infection as well as the development of disease. Full article
(This article belongs to the Special Issue The Alphavirus Trifecta: How Replication, Assembly, and Virus-Host Interactions Modulate Alphavirus Pathogenesis)
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