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Ultra-deep sequencing of intra-host rabies virus populations during cross-species transmission.

ABSTRACT: One of the hurdles to understanding the role of viral quasispecies in RNA virus cross-species transmission (CST) events is the need to analyze a densely sampled outbreak using deep sequencing in order to measure the amount of mutation occurring on a small time scale. In 2009, the California Department of Public Health reported a dramatic increase (350) in the number of gray foxes infected with a rabies virus variant for which striped skunks serve as a reservoir host in Humboldt County. To better understand the evolution of rabies, deep-sequencing was applied to 40 unpassaged rabies virus samples from the Humboldt outbreak. For each sample, approximately 11 kb of the 12 kb genome was amplified and sequenced using the Illumina platform. Average coverage was 17,448 and this allowed characterization of the rabies virus population present in each sample at unprecedented depths. Phylogenetic analysis of the consensus sequence data demonstrated that samples clustered according to date (1995 vs. 2009) and geographic location (northern vs. southern). A single amino acid change in the G protein distinguished a subset of northern foxes from a haplotype present in both foxes and skunks, suggesting this mutation may have played a role in the observed increased transmission among foxes in this region. Deep-sequencing data indicated that many genetic changes associated with the CST event occurred prior to 2009 since several nonsynonymous mutations that were present in the consensus sequences of skunk and fox rabies samples obtained from 20032010 were present at the sub-consensus level (as rare variants in the viral population) in skunk and fox samples from 1995. These results suggest that analysis of rare variants within a viral population may yield clues to ancestral genomes and identify rare variants that have the potential to be selected for if environment conditions change.

SUBMITTER: Borucki MK

PROVIDER: S-EPMC3836733 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Project description:Most emerging viruses are spilled over from mammals. Understanding the mechanism of virus cross-species transmission and identifying zoonotic viruses before their emergence are critical for the prevention and control of newly emerging viruses. This study systematically investigated the host proteins associated with the cross-species transmission of mammalian viruses based on 1,271 pairs of virus-mammal interactions including 382 viruses from 33 viral families and 73 mammal species from 11 orders. Numerous host proteins were found to contribute to the cross-species transmission of mammalian viruses. Host proteins potentially contributing to virus cross-species transmission are specific to viral families, and few overlaps of such host proteins are observed in different viral families. Based on these host proteins, the random-forest (RF) models were built to predict the cross-species transmission potential of mammalian viruses. Moderate performance was obtained when using all viruses together. However, when modeling by viral family, the performance of the RF models varied much among viral families. In 13 viral families such as Flaviviridae, Retroviridae, and Poxviridae, the AUC of the RF model was greater than 0.8. Finally, the contribution of virus receptors to cross-species transmission was evaluated, and the virus receptor was found to have a minor effect in predicting the cross-species transmission of mammalian viruses. The study deepens our understanding of the mechanism of virus cross-species transmission and provides a framework for predicting the cross-species transmission of mammalian viruses. IMPORTANCE Emerging viruses pose serious threats to humans. Understanding the mechanism of virus cross-species transmission and identifying zoonotic viruses before their emergence are critical for the prevention and control of emerging viruses. This study systematically identified host factors associated with cross-species transmission of mammalian viruses and further built machine-learning models for predicting cross-species transmission of the viruses based on host factors including virus receptors. The study not only deepens our understanding of the mechanism of virus cross-species transmission but also provides a framework for predicting the cross-species transmission of mammalian viruses based on host factors.

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Ultra-deep sequencing of intra-host rabies virus populations during cross-species transmission.

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