scholarly journals Bat IFITM3 restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain

2019 ◽  
Vol 3 (1) ◽  
pp. e201900542 ◽  
Author(s):  
Camilla TO Benfield ◽  
Farrell MacKenzie ◽  
Markus Ritzefeld ◽  
Michela Mazzon ◽  
Stuart Weston ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Adaptive Evolution ◽  
Broad Spectrum ◽  
Transmembrane Proteins ◽  
Cysteine Residues ◽  
Restriction Factors ◽  
Emerging Viruses ◽  
Molecular Determinant ◽  
Natural Hosts ◽  
Important Site

Host interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral restriction factors. Of these, IFITM3 potently inhibits viruses that enter cells through acidic endosomes, many of which are zoonotic and emerging viruses with bats (order Chiroptera) as their natural hosts. We previously demonstrated that microbat IFITM3 is antiviral. Here, we show that bat IFITMs are characterized by strong adaptive evolution and identify a highly variable and functionally important site—codon 70—within the conserved CD225 domain of IFITMs. Mutation of this residue in microbat IFITM3 impairs restriction of representatives of four different virus families that enter cells via endosomes. This mutant shows altered subcellular localization and reduced S-palmitoylation, a phenotype copied by mutation of conserved cysteine residues in microbat IFITM3. Furthermore, we show that microbat IFITM3 is S-palmitoylated on cysteine residues C71, C72, and C105, mutation of each cysteine individually impairs virus restriction, and a triple C71A-C72A-C105A mutant loses all restriction activity, concomitant with subcellular re-localization of microbat IFITM3 to Golgi-associated sites. Thus, we propose that S-palmitoylation is critical for Chiropteran IFITM3 function and identify a key molecular determinant of IFITM3 S-palmitoylation.

scholarly journals Comparative analysis reveals adaptive evolution of bat IFITMs and a novel antiviral determinant

2019 ◽  
Author(s):  
Camilla T O Benfield ◽  
Farrell MacKenzie ◽  
Markus Ritzefeld ◽  
Michela Mazzon ◽  
Stuart Weston ◽  
...  
Keyword(s):  
Comparative Analysis ◽  
Adaptive Evolution ◽  
Transmembrane Proteins ◽  
Cysteine Residue ◽  
Cysteine Residues ◽  
Restriction Factors ◽  
Emerging Viruses ◽  
Molecular Determinant ◽  
Natural Hosts ◽  
Important Site

ABSTRACTHost interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral restriction factors. Of these, IFITM3 potently inhibits viruses that enter cells through acidic endosomes, many of which are zoonotic and emerging viruses with bats (order Chiroptera) as natural hosts. We previously demonstrated that microbat IFITM3 is antiviral. Here we show that bat IFITMs are characterized by strong adaptive evolution and identify a highly variable and functionally important site - codon 70 - within the conserved CD225 domain of IFITMs. Mutation of this residue in microbat IFITM3 impairs restriction of four different virus families that enter cells via endosomes. This mutant shows altered subcellular localization and reduced S-palmitoylation, a phenotype copied by mutation of conserved cysteine residues in microbat IFITM3. Furthermore, we show that microbat IFITM3 is S-palmitoylated on cysteine residues C71, C72 and C105, mutation of each cysteine residue individually impairs virus restriction, and a triple C71-C72-C105 mutant loses all restriction, concomitant with subcellular re-localization of microbat IFITM3 to Golgi-associated sites. Thus, we propose that S-palmitoylation is critical for Chiropteran IFITM3 function and identify a key molecular determinant of IFITM3 S-palmitoylation.

Therapeutic Exploitation of Viral Interference

2020 ◽  
Vol 20 (4) ◽  
pp. 423-432 ◽  
Author(s):  
Imre Kovesdi ◽  
Tibor Bakacs
Keyword(s):  
Broad Spectrum ◽  
Viral Infections ◽  
Viral Vector ◽  
Antiviral Treatment ◽  
Type I ◽  
Virus Infections ◽  
Emerging Viruses ◽  
Viral Interference ◽  
Pathogenic Virus ◽  
Hepatitis C Rna

: Viral interference, originally, referred to a state of temporary immunity, is a state whereby infection with a virus limits replication or production of a second infecting virus. However, replication of a second virus could also be dominant over the first virus. In fact, dominance can alternate between the two viruses. Expression of type I interferon genes is many times upregulated in infected epithelial cells. Since the interferon system can control most, if not all, virus infections in the absence of adaptive immunity, it was proposed that viral induction of a nonspecific localized temporary state of immunity may provide a strategy to control viral infections. Clinical observations also support such a theory, which gave credence to the development of superinfection therapy (SIT). SIT is an innovative therapeutic approach where a non-pathogenic virus is used to infect patients harboring a pathogenic virus. : For the functional cure of persistent viral infections and for the development of broad- spectrum antivirals against emerging viruses a paradigm shift was recently proposed. Instead of the virus, the therapy should be directed at the host. Such a host-directed-therapy (HDT) strategy could be the activation of endogenous innate immune response via toll-like receptors (TLRs). Superinfection therapy is such a host-directed-therapy, which has been validated in patients infected with two completely different viruses, the hepatitis B (DNA), and hepatitis C (RNA) viruses. SIT exerts post-infection interference via the constant presence of an attenuated non-pathogenic avian double- stranded (ds) RNA viral vector which boosts the endogenous innate (IFN) response. SIT could, therefore, be developed into a biological platform for a new “one drug, multiple bugs” broad-spectrum antiviral treatment approach.

scholarly journals Fludarabine Inhibits Infection of Zika Virus, SFTS Phlebovirus, and Enterovirus A71

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 774
Author(s):  
Chengfeng Gao ◽  
Chunxia Wen ◽  
Zhifeng Li ◽  
Shuhan Lin ◽  
Shu Gao ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Zika Virus ◽  
Therapeutic Agent ◽  
Viral Infections ◽  
Rna Virus ◽  
Emerging Viruses ◽  
Enterovirus A71 ◽  
Ic50 Values ◽  
High Doses ◽  
Severe Fever

Viral infections are one of the leading causes in human mortality and disease. Broad-spectrum antiviral drugs are a powerful weapon against new and re-emerging viruses. However, viral resistance to existing broad-spectrum antivirals remains a challenge, which demands development of new broad-spectrum therapeutics. In this report, we showed that fludarabine, a fluorinated purine analogue, effectively inhibited infection of RNA viruses, including Zika virus, Severe fever with thrombocytopenia syndrome virus, and Enterovirus A71, with all IC50 values below 1 μM in Vero, BHK21, U251 MG, and HMC3 cells. We observed that fludarabine has shown cytotoxicity to these cells only at high doses indicating it could be safe for future clinical use if approved. In conclusion, this study suggests that fludarabine could be developed as a potential broad-spectrum anti-RNA virus therapeutic agent.

scholarly journals Foamy Viruses, Bet, and APOBEC3 Restriction

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Ananda Ayyappan Jaguva Vasudevan ◽  
Daniel Becker ◽  
Tom Luedde ◽  
Holger Gohlke ◽  
Carsten Münk
Keyword(s):  
Current Knowledge ◽  
Regulatory Protein ◽  
Host Population ◽  
Life Cycles ◽  
Restriction Factors ◽  
Host Restriction ◽  
Open Questions ◽  
Foamy Viruses ◽  
Natural Hosts ◽  
Hiv 1

Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and HTLV-1 emerged as retroviral pathogens in humans, a unique class of retroviruses called foamy viruses (FV) with zoonotic potential are occasionally detected in bushmeat hunters or zookeepers. Various FVs are endemic in numerous mammalian natural hosts, such as primates, felines, bovines, and equines, and other animals, but not in humans. They are apathogenic, and significant differences exist between the viral life cycles of FV and other retroviruses. Importantly, FVs replicate in the presence of many well-defined retroviral restriction factors such as TRIM5α, BST2 (Tetherin), MX2, and APOBEC3 (A3). While the interaction of A3s with HIV-1 is well studied, the escape mechanisms of FVs from restriction by A3 is much less explored. Here we review the current knowledge of FV biology, host restriction factors, and FV–host interactions with an emphasis on the consequences of FV regulatory protein Bet binding to A3s and outline crucial open questions for future studies.

scholarly journals Tilorone: A Broad-Spectrum Antiviral For Emerging Viruses

2020 ◽  
Author(s):  
Sean Ekins ◽  
Peter Madrid
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Chikungunya Virus ◽  
Middle Eastern ◽  
Emerging Viruses

Tilorone demonstrates in vitro antiviral activity against Chikungunya virus (CHIK) and Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV).

scholarly journals Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations

2020 ◽  
Vol 8 (12) ◽  
pp. 1965
Author(s):  
Guney Boso ◽  
Christine A. Kozak
Keyword(s):  
Adaptive Evolution ◽  
Restriction Factors ◽  
Complex Interactions ◽  
Evolutionary Conflict ◽  
Accelerated Evolution ◽  
Multiple Virus ◽  
Vertebrate Hosts ◽  
Cellular Pathways ◽  
Retroviral Replication ◽  
Viral Antagonists

The evolutionary conflict between retroviruses and their vertebrate hosts over millions of years has led to the emergence of cellular innate immune proteins termed restriction factors as well as their viral antagonists. Evidence accumulated in the last two decades has substantially increased our understanding of the elaborate mechanisms utilized by these restriction factors to inhibit retroviral replication, mechanisms that either directly block viral proteins or interfere with the cellular pathways hijacked by the viruses. Analyses of these complex interactions describe patterns of accelerated evolution for these restriction factors as well as the acquisition and evolution of their virus-encoded antagonists. Evidence is also mounting that many restriction factors identified for their inhibition of specific retroviruses have broader antiviral activity against additional retroviruses as well as against other viruses, and that exposure to these multiple virus challenges has shaped their adaptive evolution. In this review, we provide an overview of the restriction factors that interfere with different steps of the retroviral life cycle, describing their mechanisms of action, adaptive evolution, viral targets and the viral antagonists that evolved to counter these factors.

scholarly journals Regulators of Vps4 ATPase Activity at Endosomes Differentially Influence the Size and Rate of Formation of Intralumenal Vesicles

2010 ◽  
Vol 21 (6) ◽  
pp. 1023-1032 ◽  
Author(s):  
Daniel P. Nickerson ◽  
Matthew West ◽  
Ryan Henry ◽  
Greg Odorizzi
Keyword(s):  
Subcellular Localization ◽  
Atpase Activity ◽  
Transmembrane Proteins ◽  
Regulatory Proteins ◽  
Multivesicular Bodies ◽  
Unique Role ◽  
Vesicle Size ◽  
Endosomal Sorting ◽  
Membrane Scission

Recruitment of endosomal sorting complexes required for transport (ESCRTs) to the cytosolic face of endosomes regulates selective inclusion of transmembrane proteins into the lumenal vesicles of multivesicular bodies (MVBs). ESCRT-0, -I, and -II bind directly to ubiquitinated transmembrane cargoes of the MVB pathway, whereas polymerization of ESCRT-III at endosomes is thought to bend the membrane and/or provide the energetic force that drives membrane scission and detachment of vesicles into the endosome lumen. Disassembly of the ESCRT-III polymer and dissociation of its subunits from endosomes requires the Vps4 ATPase, the activity of which is controlled in vivo by regulatory proteins. We identify distinct spatiotemporal roles for Vps4-regulating proteins through examinations of subcellular localization and endosome morphology. Did2 plays a unique role in the regulation of MVB lumenal vesicle size, whereas Vtal and Vps60 promote efficient membrane scission and delivery of membrane to the endosome lumen. These morphological effects probably result from Vps4-mediated manipulations of ESCRT-III, because we show dissociation of ESCRT-0, -I, and -II from endosomes is not directly dependent on Vps4 activity.

scholarly journals Cysteine residues in the C-terminal tail of connexin32 regulate its trafficking

2020 ◽  
Author(s):  
Anuttoma Ray ◽  
Parmender P. Mehta
Keyword(s):  
Molecular Mechanisms ◽  
Genetic Diseases ◽  
Transmembrane Proteins ◽  
Cysteine Residues ◽  
Post Translational Modifications ◽  
Polarized Cells ◽  
Carboxyl Terminal ◽  
First Time ◽  
Caax Motif ◽  
Assembly Defect

ABSTRACTGap junctions (GJ)s are formed by the assembly of constituent transmembrane proteins called connexins (Cxs). Aberrations in this assembly of Cxs are observed in several genetic diseases as well as in cancers. Hence it becomes imperative to understand the molecular mechanisms underlying such assembly defect. The polarized cells in the epithelia express Connexin32 (Cx32). The carboxyl-terminal tail (CT) of Cx32 orchestrates several aspects of GJ dynamics, function and growth. The study here was aimed at determining if post-translational modifications, specifically, palmitoylation of cysteine residues, present in the CT of Cx32, has any effect on GJ assembly. The CT of Cx32 was found to harbor three cysteine residues, which are likely to be modified by palmitoylation. The study here has revealed for the first time that Cx32 is palmitoylated at cysteine 217 (C217). However, it was found that mutating C217 to alanine affected neither the trafficking nor the ability of Cx32 to assemble into GJs. Intriguingly, it was discovered that mutating cysteine 280 and 283 in combination, blocked the transport of Cx32 from the Golgi to the cell surface. Overall, the findings reveal the importance of the two terminal cysteine residues of Cx32 in regulating its trafficking and stability and hence is ability to assemble into GJs, possibly as being part of a CAAX motif in its CT.

scholarly journals Tilorone, a Broad-Spectrum Antiviral for Emerging Viruses

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Sean Ekins ◽  
Peter B. Madrid
Keyword(s):  
Broad Spectrum ◽  
Chikungunya Virus ◽  
Ebola Virus ◽  
Middle Eastern ◽  
Emerging Viruses ◽  
Small Molecule Compound ◽  
The Russian Federation ◽  
Synthetic Small Molecule

ABSTRACT Tilorone is a 50-year-old synthetic small-molecule compound with antiviral activity that is proposed to induce interferon after oral administration. This drug is used as a broad-spectrum antiviral in several countries of the Russian Federation. We have recently described activity in vitro and in vivo against the Ebola virus. After a broad screening of additional viruses, we now describe in vitro activity against Chikungunya virus (CHIK) and Middle Eastern respiratory syndrome coronavirus (MERS-CoV).

scholarly journals Broad-Spectrum In Vitro Activity and In Vivo Efficacy of the Antiviral Protein Griffithsin against Emerging Viruses of the Family Coronaviridae

2010 ◽  
Vol 84 (10) ◽  
pp. 5456-5456 ◽  
Author(s):  
B. R. O'Keefe ◽  
B. Giomarelli ◽  
D. L. Barnard ◽  
S. R. Shenoy ◽  
P. K. S. Chan ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Emerging Viruses ◽  
Antiviral Protein ◽  
In Vivo Efficacy ◽  
The Family
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