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Key genomic changes necessary for an in vivo lethal mouse marburgvirus variant selection process.

ABSTRACT: Marburgvirus (MARV) infections are generally lethal in humans and nonhuman primates but require in vivo lethal mouse variant selection by the serial transfer (passage) of the nonlethal virus into naïve mice to propagate a lethal infection. The passage of progenitor (wild-type) MARV or Ravn virus (RAVV) from infected scid BALB/c mouse liver homogenates into immunocompetent BALB/c mice results in the selection of lethal mouse viruses from within the quasispecies sufficient to establish lethality in immunocompetent mice. Genomic analysis in conjunction with the passage history of each mutation detailed the altered primary and secondary structures of the viral genomic RNA throughout the process. Key findings included the following: (i) a VP40:D184N mutation previously identified in the lethal guinea pig MARV genome was the first mutation to occur during the passage of both the MARV and RAVV variants; (ii) there was biased hypermutagenesis in the RAVV variant genome; (iii) there were two identical mutations in lethal mouse MARV and RAVV variants, VP40:Y19H in the PPPY motif and VP40:D184N in a loop structure between the two VP40 domains; (iv) the passage of wild-type MARV and RAVV in mice resulted in the selection of viral variants from among the quasispecies with different genotypes than those of the wild-type viruses; and (v) a lethal mouse RAVV variant had different tissue tropisms distinct from those of its wild-type virus. These studies provide insights into how marburgviruses manipulate the host for enzymes, metabolites, translation regulators, and effectors of the innate immune response to serve as potential viral countermeasures.

SUBMITTER: Lofts LL

PROVIDER: S-EPMC3126133 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Key genomic changes necessary for an in vivo lethal mouse marburgvirus variant selection process.

Lofts Loreen L LL Wells Jay B JB Bavari Sina S Warfield Kelly L KL

Journal of virology 20110202 8

Marburgvirus (MARV) infections are generally lethal in humans and nonhuman primates but require in vivo lethal mouse variant selection by the serial transfer (passage) of the nonlethal virus into naïve mice to propagate a lethal infection. The passage of progenitor (wild-type) MARV or Ravn virus (RAVV) from infected scid BALB/c mouse liver homogenates into immunocompetent BALB/c mice results in the selection of lethal mouse viruses from within the quasispecies sufficient to establish lethality i ...[more]

PMID: 21289122

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Project description:Previous studies demonstrated that a single intramuscular (i.m.) dose of an attenuated recombinant vesicular stomatitis virus (rVSV) vector (VesiculoVax vector platform; rVSV-N4CT1) expressing the glycoprotein (GP) from the Mayinga strain of Zaire ebolavirus (EBOV) protected nonhuman primates (NHPs) from lethal challenge with EBOV strains Kikwit and Makona. Here, we studied the immunogenicities of an expanded range of attenuated rVSV vectors expressing filovirus GP in mice. Based on data from those studies, an optimal attenuated trivalent rVSV vector formulation was identified that included rVSV vectors expressing EBOV, Sudan ebolavirus (SUDV), and the Angola strain of Marburg marburgvirus (MARV) GPs. NHPs were vaccinated with a single dose of the trivalent formulation, followed by lethal challenge 28 days later with each of the three corresponding filoviruses. At day 14 postvaccination, a serum IgG response specific for all three GPs was detected in all the vaccinated macaques. A modest and balanced cell-mediated immune response specific for each GP was also detected in a majority of the vaccinated macaques. No matter the level of total GP-specific immune response detected postvaccination, all the vaccinated macaques were protected from disease and death following lethal challenge with each of the three filoviruses. These findings indicate that vaccination with a single dose of attenuated rVSV-N4CT1 vectors each expressing a single filovirus GP may provide protection against the filoviruses most commonly responsible for outbreaks of hemorrhagic fever in sub-Saharan Africa.IMPORTANCE The West African Ebola virus Zaire outbreak in 2013 showed that the disease was not only a regional concern, but a worldwide problem, and highlighted the need for a safe and efficacious vaccine to be administered to the populace. However, other endemic pathogens, like Ebola virus Sudan and Marburg, also pose an important health risk to the public and therefore require development of a vaccine prior to the occurrence of an outbreak. The significance of our research was the development of a blended trivalent filovirus vaccine that elicited a balanced immune response when administered as a single dose and provided complete protection against a lethal challenge with all three filovirus pathogens.

Project description:BackgroundGenomic selection makes it possible to reduce pedigree-based inbreeding over best linear unbiased prediction (BLUP) by increasing emphasis on own rather than family information. However, pedigree inbreeding might not accurately reflect loss of genetic variation and the true level of inbreeding due to changes in allele frequencies and hitch-hiking. This study aimed at understanding the impact of using long-term genomic selection on changes in allele frequencies, genetic variation and level of inbreeding.MethodsSelection was performed in simulated scenarios with a population of 400 animals for 25 consecutive generations. Six genetic models were considered with different heritabilities and numbers of QTL (quantitative trait loci) affecting the trait. Four selection criteria were used, including selection on own phenotype and on estimated breeding values (EBV) derived using phenotype-BLUP, genomic BLUP and Bayesian Lasso. Changes in allele frequencies at QTL, markers and linked neutral loci were investigated for the different selection criteria and different scenarios, along with the loss of favourable alleles and the rate of inbreeding measured by pedigree and runs of homozygosity.ResultsFor each selection criterion, hitch-hiking in the vicinity of the QTL appeared more extensive when accuracy of selection was higher and the number of QTL was lower. When inbreeding was measured by pedigree information, selection on genomic BLUP EBV resulted in lower levels of inbreeding than selection on phenotype BLUP EBV, but this did not always apply when inbreeding was measured by runs of homozygosity. Compared to genomic BLUP, selection on EBV from Bayesian Lasso led to less genetic drift, reduced loss of favourable alleles and more effectively controlled the rate of both pedigree and genomic inbreeding in all simulated scenarios. In addition, selection on EBV from Bayesian Lasso showed a higher selection differential for mendelian sampling terms than selection on genomic BLUP EBV.ConclusionsNeutral variation can be shaped to a great extent by the hitch-hiking effects associated with selection, rather than just by genetic drift. When implementing long-term genomic selection, strategies for genomic control of inbreeding are essential, due to a considerable hitch-hiking effect, regardless of the method that is used for prediction of EBV.

Dataset Information

Key genomic changes necessary for an in vivo lethal mouse marburgvirus variant selection process.

Publications

Key genomic changes necessary for an in vivo lethal mouse marburgvirus variant selection process.

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