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At least 19 recordsLinked to original sources
PubMed1999

Selenium and viral virulence.

A mouse model of coxsackievirus-induced myocarditis is being used to investigate nutritional determinants of viral virulence. This approach was suggested by research carried out in China which showed that mice fed diets composed of low selenium ingredients from a Keshan disease area suffered more extensive heart damage when infected with a coxsackie B4 virus than infected mice fed the same diet but supplemented with selenium by esophageal intubation. Selenium deficiency in our mice increased the virulence of an already virulent strain of coxsackievirus B3 (CVB3/20) and also allowed conversion of a non-virulent strain (CVB3/0) to virulence. Such conversion of CVB3/0 was accompanied by a change in the viral genome to more closely match that of the virulent virus, CVB3/20. As far as the authors are aware, this is the first report of host nutrition influencing the genetic make-up of an invading pathogen. Nutritionists may need to consider this mechanism of increased viral virulence in order to gain a better understanding of diet/infection relationships.

Animals↗
PubMed2000

A deletion in the gI and gE genes of equine herpesvirus type 4 reduces viral virulence in the natural host and affects virus transmission during cell-to-cell spread.

In order to identify the role of the equine herpesvirus type 4 (EHV-4) glycoprotein I (gI) and E (gE) genes in determining viral virulence and their affect on the infection cycle, we constructed an EHV-4 recombinant strain containing a deletion in both gI and gE genes and its revertant. The recombinant was assayed in vitro in order to compare its growth kinetics with the parent and revertant viruses. Our results indicated that a deletion in the genes encoding gI and gE affected cell-to-cell spread of the virus in vitro. In order to assess the pathogenicity and vaccine efficacy of the recombinant in a natural host, colostrum-deprived foals were inoculated intranasally with the recombinant. Clinical signs obtained in foals upon the inoculation with the recombinant were milder than that for the revertant. This suggests that intact gI and/or gE genes are important factors in the expression of virulence in EHV-4 as in seen in the case of other herpesviruses. In addition, full protection against challenge infection was observed in foals, which had undergone a previous inoculation of the recombinant.

Animals↗
PubMed2004

Viral virulence protein suppresses RNA silencing-mediated defense but upregulates the role of microrna in host gene expression.

Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are processed by the ribonuclease Dicer from distinct precursors, double-stranded RNA (dsRNA) and hairpin RNAs, respectively, although either may guide RNA silencing via a similar complex. The siRNA pathway is antiviral, whereas an emerging role for miRNAs is in the control of development. Here, we describe a virulence factor encoded by turnip yellow mosaic virus, p69, which suppresses the siRNA pathway but promotes the miRNA pathway in Arabidopsis thaliana. p69 suppression of the siRNA pathway is upstream of dsRNA and is as effective as genetic mutations in A. thaliana genes involved in dsRNA production. Possibly as a consequence of p69 suppression, p69-expressing plants contained elevated levels of a Dicer mRNA and of miRNAs as well as a correspondingly enhanced miRNA-guided cleavage of two host mRNAs. Because p69-expressing plants exhibited disease-like symptoms in the absence of viral infection, our findings suggest a novel mechanism for viral virulence by promoting the miRNA-guided inhibition of host gene expression.

Arabidopsis↗
PubMed2000

Group B coxsackievirus myocarditis and pancreatitis: connection between viral virulence phenotypes in mice.

The group B coxsackieviruses (CVB) induce experimental pancreatitis and myocarditis in mice and are established agents of human myocarditis, especially in children. We tested the hypothesis that the development of CVB-induced myocarditis is linked to CVB-induced pancreatitis by studying the replication of different CVB strains in mice. Eight of nine genotypically different type 3 CVB (CVB3) strains induced acute pancreatitis in mice; of these, three viruses also induced acute myocarditis. One CVB3 strain was avirulent for both organs. Myocarditis was not observed in the absence of pancreatitis. The results obtained by inoculation of mice with strains of other CVB serotypes were consistent with these data. Infectious virus titers were measured in serum, pancreas, and heart as a function of time after inoculation of mice with three CVB3 strains. Each strain was representative of one of the three viral virulence phenotypes: avirulent, pancreovirulent only, and cardiovirulent. All strains replicated well and persisted in the pancreas through 8 days post-inoculation, but the cardiovirulent CVB3 strain tended to replicate to higher titer earlier and persist longer in sera, pancreatic, and cardiac tissues than the noncardiovirulent strains. Replication of the CVB3 strains were studied in two human pancreatic tumor lines and in primary human endothelial cell cultures derived from cardiac artery. Cardiovirulent strains, both individually and as a group, tended to replicate to titers as high as, or higher than, noncardiovirulent strains did in cell culture. The data are consistent with the possibility of an etiologic link between CVB-induced pancreatic and heart disease.

Acute Disease↗
PubMed2004

The avirulence domain of Cauliflower mosaic virus transactivator/viroplasmin is a determinant of viral virulence in susceptible hosts.

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.

Brassica napus↗
PubMed1997

A BIR motif containing gene of African swine fever virus, 4CL, is nonessential for growth in vitro and viral virulence.

An African swine fever virus (ASFV) gene with similarity to viral and cellular inhibitor of apoptosis genes (iap) has been described in the African isolate Malawi Lil-20/1 (ORF 4CL) and a cell-culture-adapted European virus, BA71V (ORF A224L). The similarity of the ASFV gene to genes involved in inhibiting cellular apoptosis suggested the gene may regulate apoptosis in ASFV-infected cells and thus may function in ASFV virulence and/or host range. Sequence analysis of additional African and European pathogenic isolates demonstrates that this gene is highly conserved among both pig and tick ASFV isolates and that its similarity to iap genes is limited to the presence of a single IAP repeat motif (BIR motif) in the ASFV gene. To study gene function, a 4CL gene deletion mutant, delta 4CL, was constructed from the pathogenic Malawi Lil-20/1 isolate. Growth characteristics of delta 4CL in swine macrophage cell cultures were indistinguishable from those of parental virus. Infected macrophage survival time and the induction and magnitude of apoptosis in virus-infected macrophages were comparable for cells infected with either delta 4CL or parental virus. In infected swine, delta 4CL exhibited an unaltered Malawi Lil-20/1 virulence phenotype. These data indicate that, although highly conserved among ASFV isolates, the 4CL gene is nonessential for growth in macrophage cell cultures in vitro and for pig virulence. Additionally, despite its limited similarity to JAP genes, 4CL exhibits no anti-apoptotic function in infected macrophage cell cultures. The high degree of gene conservation among ASFV isolates, together with the apparent lack of function in the swine host, suggests 4CL may be a host range gene involved in aspects of infection in the arthropod host, ticks of the genus Ornithodoros.

African Swine Fever↗
PubMed1995

Effects of viral virulence on intrauterine growth in SIV-infected fetal rhesus macaques (Macaca mulatta).

Studies with a simian immunodeficiency virus (SIV)-infected fetal monkey model were conducted with a focus on fetal growth and viral pathogenesis. Twenty-six fetuses were inoculated in utero via ultrasound guidance with an uncloned pathogenic strain of SIV or vehicle during the second or third trimesters [gestational day (GD) 65, 110, or 130], sonographically monitored weekly (biometrics, blood flow), then necropsied at incremental time points postinfection. Peripheral blood hematologic (complete blood counts, clinical chemistries), immunologic (immunophenotyping), and endocrine studies [insulin-like growth factor (IGF), IGF-binding proteins (IGFBP)] were conducted. Severe intrauterine growth restriction (IUGR), oligohydramnios, and altered lymphocyte counts were noted for fetuses infected on GD 65. Less severe effects were detected for fetuses inoculated at the later time points, with severity dependent upon the length of SIV infection in utero. IGF studies indicated significant reductions in IGF-I and elevated immunoreactive levels of IGFBP-3 in infected fetuses during the third trimester. Parallel studies conducted with four fetuses infected on GD 65 with a nonpathogenic, molecularly cloned virus (SIVmac1A11) resulted in normal fetal growth, with no effects on hematopoiesis or IGF/IGFBP levels, and no evidence of clinical disease. Taken together, these studies show that (1) infection of fetuses during the early second trimester with an uncloned pathogenic strain of SIV results in severe IUGR and a disruption in the molar ratio of IGF:IGFBP-3, and (2) outcome of fetal SIV infection is determined by the timing of infection and the virulence of the viral inoculum.

Animals↗
PubMed1991

Myxoma virus expresses a secreted protein with homology to the tumor necrosis factor receptor gene family that contributes to viral virulence.

Poxviruses are known to contain a large number of open reading frames, particularly near the termini of the viral genome, that are not required for growth in tissue culture. However, many of these gene products are believed to play important roles in determining the virulence of the virus by modulating the host immune response to the infection. Recently it has been shown that Shope fibroma virus encodes, within the terminal inverted repeats, a protein (T2) related to the cellular tumor necrosis factor receptor (TNFR) and which specifically binds both TNF alpha and TNF beta. We have sequenced the terminal regions of two other Leporipoxviruses (myxoma virus and malignant rabbit fibroma virus) that are extremely invasive and capable of inducing extensive immunosuppression in rabbits and demonstrate that they also encode a closely related T2 homolog with all the structural motifs predicted for a secreted TNF binding protein. To investigate the biological role of the T2 protein, we have inactivated the myxoma virus T2 gene within each copy of the viral TIR by the insertion of a dominant selectable marker (Escherichia coli guanosine phosphoribosyltransferase) and selection of the recombinant virus in the presence of mycophenolic acid. The success of the inactivation of both copies of T2 was confirmed by the loss a broad protein band (52-56 kDa) of the predicted size for T2 from the profile of proteins secreted from mutant virus-infected BGMK cells at early times after infection. Although the T2-minus recombinant myxoma virus grew normally in tissue culture, upon infection of susceptible rabbits the viral disease was observed to be significantly attenuated. The majority of infected rabbits were able to mount an effective immune response to the infection and completely recovered. These survivor rabbits became immune to subsequent challenge with wild type myxoma virus. We conclude that the T2 viral protein is an important secreted virulence factor and that it in all likelihood functions by compromising the antiviral effects of TNF. We propose the term "viroceptor" to describe viral-encoded homologs of cellular lymphokine receptors whose function is to intercept the activity of the cognate lymphokine in order to short circuit the host immune response to the viral infection.

Amino Acid Sequence↗
PubMed1992

Myxoma virus M11L ORF encodes a protein for which cell surface localization is critical in manifestation of viral virulence.

Myxoma virus (MYX) induces extensive immunosuppression in infected rabbits and is associated with high levels of mortality. The virus encodes multiple gene products designed to circumvent the cellular immune response to the viral infection. Deletion analysis has shown that the M11L open reading frame (ORF) is an important virulence factor which downregulates leukocyte infiltration of MYX-induced tumors. To investigate the role of the M11L protein in viral pathogenesis, we sequenced the MYX M11L ORF and showed that the sequence has motifs consistent with a 166-aa class III membrane-spanning molecule possessing a single transmembrane helix near the C-terminus and a 142-aa N-terminal extracellular domain that has six cysteine residues plus two consensus N-glycosylation sites. Transcription analysis indicates that M11L is expressed as an early gene, and surface immunofluorescence studies with anti-M11L antibodies reveal that M11L protein is transported to the infected cell surface. Immunoprecipitation analysis of an attenuated viral recombinant, vMYX-GF-delta M11L, indicates that an M11L variant protein with an altered C-terminus is synthesized at about 45% of wild type levels; however, it is not detectable on the cell surface, suggesting that proper M11L function requires localization at the infected cell membrane. We propose that M11L is a virulence factor whose function is to recognize an extracellular ligand essential for the cellular inflammatory response.

Amino Acid Sequence↗
PubMed1988

Antigenic site II of the rabies virus glycoprotein: structure and role in viral virulence.

Twelve monoclonal antibodies neutralizing the CVS strain of rabies virus were used to characterize antigenic site II of the viral glycoprotein. Nineteen antigenic mutants resistant to neutralization by some of these antibodies were selected; some continued to normally or partially bind the antibody, whereas others did not. Mutations conferring resistance to neutralization by site II-specific monoclonal antibodies were localized into two clusters, the first between amino acids 34 and 42 (seven groups of mutants) and the second at amino acids 198 and 200 (three groups of mutants). Two intermediate mutations were identified at positions 147 and 184. Four mutations resulted in reduced pathogenicity after intramuscular inoculation of the virus in adult mice. One of the mutants, M23, was 300 times and the others were 10 to 30 times less pathogenic than CVS. In three cases the attenuated phenotype was related to an important modification of antigenic site II, whereas the other known antigenic sites were unchanged.

Amino Acid Sequence↗
PubMed2006

[The deletion of nucleotides of NS gene from 263 to 277 of H5N1 increases viral virulence in chicken].

Since 2000, more and more NS fragment of H5N1 subtype influenza A virus had a unique deletion of nuleotides from 263 to 277. In order to investigate the biological significance of the mutation, four recombinants, RWSN-848, RWSN-m848, RWSN-248 and RWSN-m248, were generated via eight-plasmid reverse genetic system. These reassortants had the same inner gene and outer gene derived from A/WSN/33(H1N1) and A/D/SD/04(H5N1), respectively. But their NS genes were different. RWSN-m248 and RWSN-848 were isogenic with RWSN-248 and RWSN-m848 respectively, except for the NS gene, the formers encoded a mutant NS with a deletion from 263 - 277 nucleotides. All of the four recombinants could grow well in embryonated chicken eggs and had the similar viral titer, EID50 and MDT. Infections were done with the same Multiplicity of infection (MOI, 0.001), and the viruses in supernatants from infected cells were titrated at 12, 24, 36, and 48 h post-infection by plaque assay in fresh MDCK. The results show that four viruses grown well and had the same viral title in Vero cell, a non-IFN-responsive cell system. But in MDCK and COS-1, the cell lines can produce IFN, RWSN-248 and RWSN-m848 had a higher viral titer (two fold) than RWSN-m248 and RWSN-848. It revealed that the deletion of nucleotides of NS from 263 - 277 of H5N1 influences decreases viral growth ability in IFN producing cell line. IVPI were done for the virulence test of reassorted H5N1 viruses. Ten six-week-old SPF White Leghorn chickens were inoculated intravenously with 0.2mL of a 1:10 dilution of allantoic fluid containing each of the four recombinant viruses. The chickens were daily monitored for disease signs and death for 10 days post-inoculation. Finally, IVPI was counted for each virus. RWSN-m248 caused 4 chickens died in 10 days and its index was 1.63. RWSN-248 only caused one chicken died and its index was 0.45. RWSN848 caused 3 chickens died in 10 days and its index was 0.81. RWSN-m848 caused one of the ten chickens died and its' index was only 0.175. The results revealed that the deletion of nucleotides of NS gene from 263 to 277 sites increases H5N1 pathogenesis in chicken.

Animals↗
PubMed2005

Mutation of E1 glycoprotein of classical swine fever virus affects viral virulence in swine.

Transposon linker insertion mutagenesis of a full-length infectious clone (IC) (pBIC) of the pathogenic classical swine fever virus (CSFV) strain Brescia was used to identify genetic determinants of CSFV virulence and host range. Here, we characterize a virus mutant, RB-C22v, possessing a 19-residue insertion at the carboxyl terminus of E1 glycoprotein. Although RB-C22v exhibited normal growth characteristics in primary porcine macrophage cell cultures, the major target cell of CSFV in vivo, it was markedly attenuated in swine. All RB-C22v-infected pigs survived infection remaining clinically normal in contrast to the 100% mortality observed for BICv-infected animals. Comparative pathogenesis studies demonstrated a delay in RB-C22v spread to, and decreased replication in the tonsils, a 10(2) to 10(7) log10 reduction in virus titers in lymphoid tissues and blood, and an overall delay in generalization of infection relative to BICv. Notably, RB-C22v-infected animals were protected from clinical disease when challenged with pathogenic BICv at 3, 5, 7, and 21 days post-RB-C22v inoculation. Viremia, viral replication in tissues, and oronasal shedding were reduced in animals challenged at 7 and 21 DPI. Notably BICv-specific RNA was not detected in tonsils of challenged animals. These results indicate that a carboxyl-terminal domain of E1 glycoprotein affects virulence of CSFV in swine, and they demonstrate that mutation of this domain provides the basis for a rationally designed and efficacious live-attenuated CSF vaccine.

Amino Acid Sequence↗
PubMed2000

An African swine fever virus ERV1-ALR homologue, 9GL, affects virion maturation and viral growth in macrophages and viral virulence in swine.

The African swine fever virus (ASFV) genome contains a gene, 9GL, with similarity to yeast ERV1 and ALR genes. ERV1 has been shown to function in oxidative phosphorylation and in cell growth, while ALR has hepatotrophic activity. 9GL encodes a protein of 119 amino acids and was highly conserved at both nucleotide and amino acid levels among all ASFV field isolates examined. Monospecific rabbit polyclonal antibody produced to a glutathione S-transferase-9GL fusion protein specifically immunoprecipitated a 14-kDa protein from macrophage cell cultures infected with the ASFV isolate Malawi Lil-20/1 (MAL). Time course analysis and viral DNA synthesis inhibitor experiments indicated that p14 was a late viral protein. A 9GL gene deletion mutant of MAL (Delta9GL), exhibited a growth defect in macrophages of approximately 2 log(10) units and had a small-plaque phenotype compared to either a revertant (9GL-R) or the parental virus. 9GL affected normal virion maturation; virions containing acentric nucleoid structures comprised 90 to 99% of all virions observed in Delta9GL-infected macrophages. The Delta9GL virus was markedly attenuated in swine. In contrast to 9GL-R infection, where mortality was 100%, all Delta9GL-infected animals survived infection. With the exception of a transient fever response in some animals, Delta9GL-infected animals remained clinically normal and exhibited significant 100- to 10,000-fold reductions in viremia titers. All pigs previously infected with Delta9GL survived infection when subsequently challenged with a lethal dose of virulent parental MAL. Thus, ASFV 9GL gene deletion mutants may prove useful as live-attenuated ASF vaccines.

African Swine Fever↗
PubMed2006

Reduction of the rate of poliovirus protein synthesis through large-scale codon deoptimization causes attenuation of viral virulence by lowering specific infectivity.

Exploring the utility of de novo gene synthesis with the aim of designing stably attenuated polioviruses (PV), we followed two strategies to construct PV variants containing synthetic replacements of the capsid coding sequences either by deoptimizing synonymous codon usage (PV-AB) or by maximizing synonymous codon position changes of the existing wild-type (wt) poliovirus codons (PV-SD). Despite 934 nucleotide changes in the capsid coding region, PV-SD RNA produced virus with wild-type characteristics. In contrast, no viable virus was recovered from PV-AB RNA carrying 680 silent mutations, due to a reduction of genome translation and replication below a critical level. After subcloning of smaller portions of the AB capsid coding sequence into the wt background, several viable viruses were obtained with a wide range of phenotypes corresponding to their efficiency of directing genome translation. Surprisingly, when inoculated with equal infectious doses (PFU), even the most replication-deficient viruses appeared to be as pathogenic in PV-sensitive CD155tg (transgenic) mice as the PV(M) wild type. However, infection with equal amounts of virus particles revealed a neuroattenuated phenotype over 100-fold. Direct analysis indicated a striking reduction of the specific infectivity of PV-AB-type virus particles. Due to the distribution effect of many silent mutations over large genome segments, codon-deoptimized viruses should have genetically stable phenotypes, and they may prove suitable as attenuated substrates for the production of poliovirus vaccines.

Animals↗