Extracellular HSP70, Neuroinflammation and Protection Against Viral Virulence

2019 ◽  
pp. 23-55 ◽  
Author(s):  
Michael Oglesbee ◽  
Mi Young Kim ◽  
Yaoling Shu ◽  
Sonia Longhi
Keyword(s):  
Viral Virulence

scholarly journals Structural Glycoprotein E2 of Classical Swine Fever Virus Interacts with Host Protein Dynactin Subunit 6 (DCTN6) during the Virus Infectious Cycle

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
M. V. Borca ◽  
E. A. Vuono ◽  
E. Ramirez-Medina ◽  
P. Azzinaro ◽  
K. A. Berggren ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Interaction ◽  
Hybrid Approach ◽  
Classical Swine Fever ◽  
Host Protein ◽  
Yeast Two Hybrid ◽  
Protein Protein Interaction ◽  
Viral Virulence ◽  
Glycoprotein E2 ◽  
Two Hybrid

ABSTRACT The E2 protein in classical swine fever (CSF) virus (CSFV) is the major virus structural glycoprotein and is an essential component of the viral particle. E2 has been shown to be involved in several functions, including virus adsorption, induction of protective immunity, and virulence in swine. Using the yeast two-hybrid system, we previously identified a swine host protein, dynactin subunit 6 (DCTN6) (a component of the cell dynactin complex), as a specific binding partner for E2. We confirmed the interaction between DCTN6 and E2 proteins in CSFV-infected swine cells by using two additional independent methodologies, i.e., coimmunoprecipitation and proximity ligation assays. E2 residues critical for mediating the protein-protein interaction with DCTN6 were mapped by a reverse yeast two-hybrid approach using a randomly mutated E2 library. A recombinant CSFV mutant, E2ΔDCTN6v, harboring specific substitutions in those critical residues was developed to assess the importance of the E2-DCTN6 protein-protein interaction for virus replication and virulence in swine. CSFV E2ΔDCTN6v showed reduced replication, compared with the parental virus, in an established swine cell line (SK6) and in primary swine macrophage cultures. Remarkably, animals infected with CSFV E2ΔDCTN6v remained clinically normal during the 21-day observation period, which suggests that the ability of CSFV E2 to bind host DCTN6 protein efficiently during infection may play a role in viral virulence. IMPORTANCE Structural glycoprotein E2 is an important component of CSFV due to its involvement in many virus activities, particularly virus-host interactions. Here, we present the description and characterization of the protein-protein interaction between E2 and the swine host protein DCTN6 during virus infection. The E2 amino acid residues mediating the interaction with DCTN6 were also identified. A recombinant CSFV harboring mutations disrupting the E2-DCTN6 interaction was created. The effect of disrupting the E2-DCTN6 protein-protein interaction was studied using reverse genetics. It was shown that the same amino acid substitutions that abrogated the E2-DCTN6 interaction in vitro constituted a critical factor in viral virulence in the natural host, domestic swine. This highlights the potential importance of the E2-DCTN6 protein-protein interaction in CSFV virulence and provides possible mechanisms of virus attenuation for the development of improved CSF vaccines.

scholarly journals The Vaccinia Virus O1 Protein Is Required for Sustained Activation of Extracellular Signal-Regulated Kinase 1/2 and Promotes Viral Virulence

2011 ◽  
Vol 86 (4) ◽  
pp. 2323-2336 ◽  
Author(s):  
M. Schweneker ◽  
S. Lukassen ◽  
M. Spath ◽  
M. Wolferstatter ◽  
E. Babel ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Viral Virulence ◽  
Sustained Activation

In silico approach to predict the SARS-CoV2 derived candidate miRNAs as potential antiviral therapy

2021 ◽  
Vol 16 ◽  
Author(s):  
Soudabeh Kavousi Pour ◽  
Shiva Mohammadi ◽  
Ebrahim Eftekhar ◽  
Sajad Jalili ◽  
Elham Arabizadeh ◽  
...  
Keyword(s):  
Viral Infection ◽  
Immune Escape ◽  
Genome Structure ◽  
Antiviral Agents ◽  
Experimental Studies ◽  
Viral Disease ◽  
Potential Candidate ◽  
Viral Mirnas ◽  
Host Interaction ◽  
Viral Virulence

Background: The coronavirus disease 2019 (COVID-19) pandemic is a contagious disease originating from severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Previous experimental studies indicate that viral miRNAs (vMirs) have essential functions in pathogen-host interaction, immune escape, host cell death, and tumorigenesis during viral infection. MiRNAs are small, single-stranded RNAs that exist in viruses as well as in animals. Thus, these molecules can play a pivotal role in viral disease pathogenesis. Objective: Since no approved drugs or vaccines currently exist for SARS-CoV2 and its pathogenic mechanism is unknown, we explored and proposed viral microRNAs (vmiRNAs) platforms as potential antiviral therapeutic agents against its SARS-CoV2. Therefore, the development of antiviral drugs to target vmiRNAs may result in down-regulation of viral virulence genes expression and suppression of viral proliferation. Methods: In this study, to attain insight into the potential role of SARS-CoV2 derived miRNAs in the viral infection background, we used a set of computational methods to scan the SARS-CoV2 genome that finally led to computationally predicted 13 potential candidate viral microRNAs. Furthermore, we expected the potential genes in a human host that were the target of these candidate vmiRNAs by applying mirPath software. Results: Our study proposed a theory indicating that these predicted viral miRNAs might have a plausible role in altering human target gene expression, mainly contributing to the viral infectious state, inflammation, and immune system escape. This vmiRNAs maight have therapeutic trends as antiviral agents against Covid-19 infection. Conclusion: These findings offer a reference idea for a supplementary study on miRNA identification as a drug target and the necessity to increase understanding of SARS-CoV2 genome structure for better combat against the virus.

scholarly journals The Avirulence Domain of Cauliflower mosaic virus Transactivator/Viroplasmin Is a Determinant of Viral Virulence in Susceptible Hosts

2004 ◽  
Vol 17 (5) ◽  
pp. 475-483 ◽  
Author(s):  
Kappei Kobayashi ◽  
Thomas Hohn
Keyword(s):  
Mosaic Virus ◽  
Host Plants ◽  
Datura Stramonium ◽  
Cauliflower Mosaic Virus ◽  
Wild Type Virus ◽  
Wild Type ◽  
Multifunctional Protein ◽  
Viral Virulence ◽  
Host Defense Response ◽  
Solanaceous Plants

Cauliflower mosaic virus (CaMV) transactivator/viroplasmin (Tav) is a multifunctional protein essential for basic replication of CaMV. It also plays a role in viral pathogenesis in crucifer and solanaceous host plants. Deletion mutagenesis revealed that N- and C-terminal parts of Tav are not essential for CaMV replication in transfected protoplasts. Two deletion mutants having only minimal defects in basic replication were infectious in turnips but only with highly attenuated virulence. This was shown to be due to delayed virus spread within the inoculated leaves and to the upper leaves. Unlike the wild-type virus, the mutant viruses successfully spread locally without inducing a host defense response in inoculated Datura stramonium leaves, but did not spread systemically. These results provide the first evidence that a Tav domain required for avirulence function in solanaceous plants is not essential for CaMV infectivity but has a role in viral virulence in susceptible hosts.

scholarly journals Single amino acid mutations effect Zika virus replication in vitro and virulence in vivo

2020 ◽  
Author(s):  
Nicole M. Collette ◽  
Victoria H.I. Lao ◽  
Dina R. Weilhammer ◽  
Barbara Zingg ◽  
Shoshana D. Cohen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Zika Virus ◽  
Model Systems ◽  
Single Amino Acid ◽  
Replication Rate ◽  
Adult Mice ◽  
Naturally Occurring ◽  
Viral Virulence

AbstractThe 2014-2016 Zika virus (ZIKV) epidemic in the Americas resulted in large deposits of next-generation sequencing data from clinical samples. This resource was mined to identify emerging mutations and trends in mutations as the outbreak progressed over time. Information on transmission dynamics, prevalence and persistence of intra-host mutants, and the position of a mutation on a protein were then used to prioritize 544 reported mutations based on their ability to impact ZIKV phenotype. Using this criteria, six mutants (representing naturally occurring mutations) were generated as synthetic infectious clones using a 2015 Puerto Rican epidemic strain PRVABC59 as the parental backbone. The phenotypes of these naturally occurring variants were examined using both cell culture and murine model systems. Mutants had distinct phenotypes, including changes in replication rate, embryo death, and decreased head size. In particular, a NS2B mutant previously detected during in vivo studies in rhesus macaques was found to cause lethal infections in adult mice, abortions in pregnant females, and increased viral genome copies in both brain tissue and blood of female mice. Additionally, mutants with changes in the region of NS3 that interfaces with NS5 during replication displayed reduced replication in the blood of adult mice. This analytical pathway, integrating both bioinformatic and wet lab experiments, provides a foundation for understanding how naturally occurring single mutations affect disease outcome and can be used to predict the of severity of future ZIKV outbreaks.Author summaryTo determine if naturally occurring individual mutations in the Zika virus epidemic genotype effect viral virulence or replication rate in vitro or in vivo, we generated an infectious clone representing the epidemic genotype of stain Puerto Rico, 2015. Using this clone, six mutants were created by changing nucleotides in the genome to cause one to two amino acid substitutions in the encoded proteins. The six mutants we generated represent mutations that differentiated the early epidemic genotype from genotypes that were either ancestral or that occurred later in the epidemic. We assayed each mutant for changes in growth rate, and for virulence in adult mice and pregnant mice. Three of the mutants caused catastrophic embryo effects including increased embryonic death or significant decrease in head diameter. Three other mutants that had mutations in a genome region associated with replication resulted in changes in in vitro and in vivo replication rates. These results illustrate the potential impact of individual mutations in viral phenotype.

scholarly journals Immune stimulation and antibody response of chicks to different doses/units of the Nigerian live infectious bursa disease vaccine

2021 ◽  
pp. 20-24
Keyword(s):  
Body Weight ◽  
Immune System ◽  
Antibody Response ◽  
Disease Control ◽  
Immune Stimulation ◽  
Viral Virulence ◽  
Antibody Titres ◽  
And Control ◽  
Higher Doses ◽  
Different Doses

Vaccination failure is one of the major constraints to disease control in poultry. To investigate Infectious bursa disease (IBD)-vaccination failures (frequently/globally reported), batches of the Nigerian live-vaccine were tested for viral units before vaccinating following chick-groups: 16 doses (65,536 units), 8 doses (32,768 units), 4 doses (6,384 units), 2 doses (8,192 units), 1 dose (4,096 units), 1:2 dose (2,048 units), 1:4 dose (1,024 units), 1:8 dose (512 units), 1:16 dose (256 units) and control. Each batch gave 4,096 viral units. Mean bursa weight/body weight ratios (immune stimulation) and mean antibody titres of the chick-groups were 47.40 ±5.45 and 51.20 ±7.83; 44.25 ±7.28 & 48.00 ±9.24; 45.25 ± 4.28 and 64.00 ± 0.00; 43.00 ±7.58 and 101.60 ± 35.05; 44.60 ± 5.51 and 128.00 ± 0.00; 42.60 ± 6.23 and 268.80 ± 16.00; 40.50 ± 1.76 and 80.00 ±16.00; 31.40 ± 3.80 and 80.00 ± 27.71; 37.18 ± 4.07 and 89.60 ± 15.68 and 26.20 ± 3.31 and 19.20 ± 5.99, respectively. Half (2,048 units) of the recommended 1-dose gave optimal antibody-titre. The higher doses gave lower antibody-titres like the lower doses but immune stimulation continued to increase as doses/units increased. Both over-stimulating the immune system (too high vaccine-doses/viral-units/viral-virulence) and under-stimulation cause vaccination failure.

Virulence of enterovirus-A71 fluctuates depending on the phylogenetic clade formed in the epidemic year and epidemic region

2021 ◽  
Author(s):  
Kyousuke Kobayashi ◽  
Hidekazu Nishimura ◽  
Katsumi Mizuta ◽  
Tomoha Nishizawa ◽  
Son T. Chu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Foot And Mouth Disease ◽  
Virus Genome ◽  
Mouth Disease ◽  
Asia Pacific ◽  
Enterovirus A71 ◽  
Viral Virulence ◽  
Foot And Mouth ◽  
Potential Risks ◽  
A Minor

Although epidemics of hand, foot, and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) have occurred worldwide, the Asia-Pacific region has seen large sporadic outbreaks with many severe neurological cases. This suggests that the virulence of the circulating viruses fluctuates in each epidemic and that HFMD outbreaks with many severe cases occur when highly virulent viruses are circulating predominantly, which has not been experimentally verified. Here, we analyzed 32 clinically isolated strains obtained in Japan from 2002 to 2013, along with 27 Vietnamese strains obtained from 2015 to 2016 that we characterized previously using human SCARB2 transgenic mice. Phylogenetic analysis of the P1 region classified them into five clades belonging to subgenogroup B5 (B5-I to B5-V) and five clades belonging to subgenogroup C4 (C4-I to C4-V) according to the epidemic year and region. Interestingly, the clade B5-I and B5-II were very virulent, while clades B5-III, B5-IV, and B5-V were less virulent. Clades C4-II, C4-III, C4-IV, and C4-V were virulent, while clade C4-I was not. The result experimentally showed for the first time that several clades with different virulence levels emerged one after another. The experimental virulence evaluation of circulating viruses using SCARB2 transgenic mice is helpful to assess potential risks of circulating viruses. These results also suggest that a minor nucleotide or amino acid substitution in the EV-A71 genome during circulation may cause fluctuations in virulence. The data presented herein may increase our understanding of the dynamics of viral virulence during epidemics. IMPORTANCE Outbreaks of hand, foot, and mouth disease (HFMD) with severe enterovirus A71 (EV-A71) cases have occurred repeatedly, mainly in Asia. In severe cases, central nervous system complications can lead to death, making it an infectious disease of importance to public health. An unanswered question about this disease is why outbreaks of HFMD with many severe cases sometimes occur. Here, we collected EV-A71 strains that were prevalent in Japan and Vietnam over the past 20 years and evaluated their virulence in a mouse model of EV-A71 infection. This method clearly revealed that viruses belonging to different clades have different virulence, indicating that the method is powerful to assess the potential risks of the circulating viruses. The results also suggested that factors in the virus genome may potentially cause an outbreak with many severe cases and that further studies may facilitate the prediction of large epidemics of EV-A71 in the future.

Determinants of Viral Virulence and Host Resistance/Susceptibility

1999 ◽  
pp. 111-125
Author(s):  
Frederick A. Murphy ◽  
E. Paul J. Gibbs ◽  
Marian C. Horzinek ◽  
Michael J. Studdert
Keyword(s):  
Host Resistance ◽  
Viral Virulence

Viral Virulence and Stress

2007 ◽  
pp. 842-849
Author(s):  
A MACARIO ◽  
E CONWAYDEMACARIO
Keyword(s):  
Viral Virulence

scholarly journals Characterization of Human Influenza Virus Variants Selected In Vitro in the Presence of the Neuraminidase Inhibitor GS 4071

1998 ◽  
Vol 42 (12) ◽  
pp. 3234-3241 ◽  
Author(s):  
Chun Y. Tai ◽  
Paul A. Escarpe ◽  
Robert W. Sidwell ◽  
Matthew A. Williams ◽  
Willard Lew ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Neuraminidase Inhibitor ◽  
H3n2 Virus ◽  
Wild Type Virus ◽  
Type Virus ◽  
Human Influenza ◽  
Wild Type ◽  
Viral Virulence ◽  
High Level

ABSTRACT An oral prodrug of GS 4071, a potent and selective inhibitor of influenza neuraminidases, is currently under clinical development for the treatment and prophylaxis of influenza virus infections in humans. To investigate the potential development of resistance during the clinical use of this compound, variants of the human influenza A/Victoria/3/75 (H3N2) virus with reduced susceptibility to the neuraminidase inhibitor GS 4071 were selected in vitro by passaging the virus in MDCK cells in the presence of inhibitor. After eight passages, variants containing two amino acid substitutions in the hemagglutinin (A28T in HA1 and R124M in HA2) but no changes in the neuraminidase were isolated. These variants exhibited a 10-fold reduction in susceptibility to GS 4071 and zanamivir (GG167) in an in vitro plaque reduction assay. After 12 passages, a second variant containing these hemagglutinin mutations and a Lys substitution for the conserved Arg292 of the neuraminidase was isolated. The mutant neuraminidase enzyme exhibited high-level (30,000-fold) resistance to GS 4071, but only moderate (30-fold) resistance to zanamivir and 4-amino-Neu5Ac2en, the amino analog of zanamivir. The mutant enzyme had weaker affinity for the fluorogenic substrate 2′-(4-methylumbelliferyl)-α-d- N -acetylneuraminic acid and lower enzymatic activity compared to the wild-type enzyme. The viral variant containing the mutant neuraminidase did not replicate as well as the wild-type virus in culture and was 10,000-fold less infectious than the wild-type virus in a mouse model. These results suggest that although the R292K neuraminidase mutation confers high-level resistance to GS 4071 in vitro, its effect on viral virulence is likely to render this mutation of limited clinical significance.

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