How host genetics dictates successful viral zoonosis

Warren, Cody J.; Sawyer, Sara L.

doi:10.1371/journal.pbio.3000217

Cited by 71 publications

(68 citation statements)

References 115 publications

(146 reference statements)

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“…VACV K3 has well-defined species-specific differences in its ability to inhibit PKR across the mammalian phylogeny, defined by both LBR assays and yeast-based studies [8,9,17]. The data presented here support and extend this species-specific sensitivity of PKR to VACV K3L and add to a growing body of evidence that virus-specific differences play an important role in viral host range, as do species-specific differences in host genes [22,23]. Consistent with this concept, in this study we showed that the VACV K3 orthologs from four different orthopoxviruses display dramatic differences in their ability to inhibit PKR from different species, including different sensitivities in closely related species such as mice and rats.…”

Section: Discussionsupporting

confidence: 63%

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Park

Chen

Rahman

et al. 2020

Preprint

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The antiviral protein kinase R (PKR) is an important restriction factor, which poxviruses must overcome to productively infect host cells. Many poxviruses encode a pseudosubstrate mimic of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), designated K3 in vaccinia virus, to inhibit PKR. Although the interaction between PKR and eIF2a is highly conserved, some K3 orthologs were previously shown to inhibit PKR in a species-specific manner. To better define this host range function, we compared the sensitivity of PKR from 17 mammals to inhibition by K3 orthologs from closely related orthopoxviruses. The K3 orthologs showed species-specific inhibition of PKR and exhibited three distinct inhibition profiles. In some cases, PKR from closely related species showed dramatic differences in their sensitivity to K3 orthologs. Vaccinia virus expressing the camelpox virus K3 ortholog replicated more than three orders of magnitude better in human and sheep cells than a virus expressing vaccinia virus K3, but both viruses replicated comparably well in cow cells. Strikingly, in site-directed mutagenesis experiments between the variola virus and camelpox virus K3 orthologs, we found that the amino acid combinations needed to mediate improved or diminished inhibition of PKR varied between different species. The data presented here show that even closely related species can display drastically different sensitivities to orthopoxvirus PKR inhibitors, and that orthologs from closely related poxviruses can show strong differences in their function. Furthermore, there is likely to be a limited number of possible mutations that disrupt K3-interactions but still maintain PKR/eIF2a interactions. Thus, by chance some potential new hosts may be susceptible to K3-mediated inhibition from a virus it has never previously encountered. We conclude that neither the sensitivity of host proteins to virus inhibition nor the effectiveness of viral host antagonists can be inferred from their phylogenetic relatedness but must be experimentally determined.

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Section: Discussionsupporting

confidence: 63%

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Park

Chen

Rahman

et al. 2020

Preprint

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“…By 7 February, the number of cases had increased to 29, including individuals without travel history to China, prompting Singaporean authorities to implement control measures aimed at reducing the community spread of the virus ( 3 ). Successful zoonotic viral transmission from animals to humans is often associated with the ability of viruses to adapt to a new host, via genetic mutation events, and cause sustained transmission ( 4 – 6 ). A variety of genomic changes, including mutations, deletions, and recombinations, have been frequently observed in the other two documented zoonotic coronaviruses, SARS-CoV and Middle East respiratory syndrome-coronavirus (MERS-CoV) ( 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

Discovery and Genomic Characterization of a 382-Nucleotide Deletion in ORF7b and ORF8 during the Early Evolution of SARS-CoV-2

Anderson

Young

et al. 2020

mBio

269

254

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To date, limited genetic changes in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome have been described. Here, we report a 382-nucleotide (nt) deletion in SARS-CoV-2 that truncates open reading frame 7b (ORF7b) and ORF8, removing the ORF8 transcription regulatory sequence (TRS) and eliminating ORF8 transcription. The earliest 382-nt deletion variant was detected in Singapore on 29 January 2020, with the deletion viruses circulating in the country and accounting for 23.6% (45/191) of SARS-CoV-2 samples screened in this study. SARS-CoV-2 with the same deletion has since been detected in Taiwan, and other ORF7b/8 deletions of various lengths, ranging from 62 nt to 345 nt, have been observed in other geographic locations, including Australia, Bangladesh, and Spain. Mutations or deletions in ORF8 of SARS-CoV have been associated with reduced replicative fitness and virus attenuation. In contrast, the SARS-CoV-2 382-nt deletion viruses showed significantly higher replicative fitness in vitro than the wild type, while no difference was observed in patient viral load, indicating that the deletion variant viruses retained their replicative fitness. A robust antibody response to ORF8 has been observed in SARS-CoV-2 infection, suggesting that the emergence of ORF8 deletions may be due to immune-driven selection and that further deletion variants may emerge during the sustained transmission of SARS-CoV-2 in humans. IMPORTANCE During the SARS epidemic in 2003/2004, a number of deletions were observed in ORF8 of SARS-CoV, and eventually deletion variants became predominant, leading to the hypothesis that ORF8 was an evolutionary hot spot for adaptation of SARS-CoV to humans. However, due to the successful control of the SARS epidemic, the importance of these deletions for the epidemiological fitness of SARS-CoV in humans could not be established. The emergence of multiple SARS-CoV-2 strains with ORF8 deletions, combined with evidence of a robust immune response to ORF8, suggests that the lack of ORF8 may assist with host immune evasion. In addition to providing a key insight into the evolutionary behavior of SARS-CoV-2 as the virus adapts to its new human hosts, the emergence of ORF8 deletion variants may also impact vaccination strategies.

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“…In general, viruses are usually well adapted to their host, and cross-species transmissions can be limited by host factor incompatibilities and restriction factors ( 3 ). Tropism and pathogenesis depend on exploitation of host factors supporting infection and evasion of cellular antiviral mechanisms ( 4 , 5 ). HCV naturally infects only humans, preventing studies of progressive immunopathogenesis or preclinical testing of novel therapeutics in an immunocompetent animal model.…”

Section: Introductionmentioning

confidence: 99%

Liver-expressed Cd302 and Cr1l limit hepatitis C virus cross-species transmission to mice

et al. 2020

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Hepatitis C virus (HCV) has no animal reservoir, infecting only humans. To investigate species barrier determinants limiting infection of rodents, murine liver complementary DNA library screening was performed, identifying transmembrane proteins Cd302 and Cr1l as potent restrictors of HCV propagation. Combined ectopic expression in human hepatoma cells impeded HCV uptake and cooperatively mediated transcriptional dysregulation of a noncanonical program of immunity genes. Murine hepatocyte expression of both factors was constitutive and not interferon inducible, while differences in liver expression and the ability to restrict HCV were observed between the murine orthologs and their human counterparts. Genetic ablation of endogenous Cd302 expression in human HCV entry factor transgenic mice increased hepatocyte permissiveness for an adapted HCV strain and dysregulated expression of metabolic process and host defense genes. These findings highlight human-mouse differences in liver-intrinsic antiviral immunity and facilitate the development of next-generation murine models for preclinical testing of HCV vaccine candidates.

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How host genetics dictates successful viral zoonosis

Cited by 71 publications

References 115 publications

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Discovery and Genomic Characterization of a 382-Nucleotide Deletion in ORF7b and ORF8 during the Early Evolution of SARS-CoV-2

Liver-expressed Cd302 and Cr1l limit hepatitis C virus cross-species transmission to mice

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