Elimination of A-type inclusion formation enhances cowpox virus replication in mice: Implications for orthopoxvirus evolution

Kastenmayer, Robin J.; Maruri-Avidal, Liliana; Americo, Jeffrey L.; Earl, Patricia L.; Weisberg, Andrea S.; Moss, Bernard

doi:10.1016/j.virol.2013.12.030

Cited by 19 publications

(25 citation statements)

References 24 publications

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“…A26L, also named p4c or CPXV159 protein, is required to direct intracellular mature virions (IMVs) into ATIs (33); the protein has a bridging function between the A25L matrix protein and IMVs containing the membrane-associated A27L (CPXV162 protein) (34). In addition, the capability to embed mature virions in the ATIs was recently shown to influence the virulence of CPXV (35). We showed that the RatPox09 p4c amino acid sequence (A26; CPXV159 protein) results in a 59-amino-acid (aa) truncation at the N terminus, which likely is responsible for the observed V Ϫ phenotype; in contrast, FM2292 harbors a full-length p4c gene (Fig.…”

Section: Isolation Of a Cpxv From A Common Volementioning

confidence: 99%

Out of the Reservoir: Phenotypic and Genotypic Characterization of a Novel Cowpox Virus Isolated from a Common Vole

Hoffmann

Franke

Jenckel

et al. 2015

J Virol

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The incidence of human cowpox virus (CPXV) infections has increased significantly in recent years. Serological surveys have suggested wild rodents as the main CPXV reservoir. We characterized a CPXV isolated during a large-scale screening from a feral common vole. A comparison of the full-length DNA sequence of this CPXV strain with a highly virulent pet rat CPXV isolate showed a sequence identity of 96%, including a large additional open reading frame (ORF) of about 6,000 nucleotides which is absent in the reference CPXV strain Brighton Red. Electron microscopy analysis demonstrated that the vole isolate, in contrast to the rat strain, forms A-type inclusion (ATI) bodies with incorporated virions, consistent with the presence of complete ati and p4c genes. Experimental infections showed that the vole CPXV strain caused only mild clinical symptoms in its natural host, while all rats developed severe respiratory symptoms followed by a systemic rash. In contrast, common voles infected with a high dose of the rat CPXV showed severe signs of respiratory disease but no skin lesions, whereas infection with a low dose led to virus excretion with only mild clinical signs. We concluded that the common vole is susceptible to infection with different CPXV strains. The spectrum ranges from well-adapted viruses causing limited clinical symptoms to highly virulent strains causing severe respiratory symptoms. In addition, the low pathogenicity of the vole isolate in its eponymous host suggests a role of common voles as a major CPXV reservoir, and future research will focus on the correlation between viral genotype and phenotype/ pathotype in accidental and reservoir species. IMPORTANCEWe report on the first detection and isolation of CPXV from a putative reservoir host, which enables comparative analyses to understand the infection cycle of these zoonotic orthopox viruses and the relevant genes involved. In vitro studies, including whole-genome sequencing as well as in vivo experiments using the Wistar rat model and the vole reservoir host allowed us to establish links between genomic sequences and the in vivo properties (virulence) of the novel vole isolate in comparison to those of a recent zoonotic CPXV isolated from pet rats in 2009. Furthermore, the role of genes present only in a reservoir isolate can now be further analyzed. These studies therefore allow unique insights and conclusions about the role of the rodent reservoir in CPXV epidemiology and transmission and about the zoonotic threat that these viruses represent. C owpox virus (CPXV), a member of the genus Orthopoxvirus (OPV) in the Poxviridae family, is suspected to be widespread in Western Eurasian rodents, particularly vole species (1, 2). From the presumed reservoir hosts, spill-over infections to accidental hosts are regularly observed (3). The accidental hosts include domestic cats and also exotic animals in zoos, such as large felids and elephants, which regularly develop severe disease (3). As CPXV is a zoonotic virus, humans in direct contact wit...

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Section: Isolation Of a Cpxv From A Common Volementioning

confidence: 99%

Out of the Reservoir: Phenotypic and Genotypic Characterization of a Novel Cowpox Virus Isolated from a Common Vole

Hoffmann

Franke

Jenckel

et al. 2015

J Virol

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“…While many notable poxviruses, including monkeypox and variola virus, contain disrupted versions of the P4c protein (or its homolog), the lack of inclusion body formation may suggest a positive infection advantage. Interestingly, recent evidence has suggested that interruption of the cowpox P4c protein enhances the pathogenicity in the lungs of mice, as well as viral replication [35]. Given that the P4c gene is fragmented in the majority of the Farm 2 SwCRV viral isolates, a farm where we see increased presentation of poxvirus lesions, as well as enhanced pathogenicity and prolonged infection, one hypothesis might be that this gene interruption is driving this phenomenon.…”

Section: Discussionmentioning

confidence: 91%

Crocodilepox Virus Evolutionary Genomics Supports Observed Poxvirus Infection Dynamics on Saltwater Crocodile (Crocodylus porosus)

Sarker

Isberg

Moran³

et al. 2019

Viruses

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Saltwater crocodilepox virus (SwCRV), belonging to the genus Crocodylidpoxvirus, are large DNA viruses posing an economic risk to Australian saltwater crocodile (Crocodylus porosus) farms by extending production times. Although poxvirus-like particles and sequences have been confirmed, their infection dynamics, inter-farm genetic variability and evolutionary relationships remain largely unknown. In this study, a poxvirus infection dynamics study was conducted on two C. porosus farms. One farm (Farm 2) showed twice the infection rate, and more concerningly, an increase in the number of early- to late-stage poxvirus lesions as crocodiles approached harvest size, reflecting the extended production periods observed on this farm. To determine if there was a genetic basis for this difference, 14 complete SwCRV genomes were isolated from lesions sourced from five Australian farms. They encompassed all the conserved genes when compared to the two previously reported SwCRV genomes and fell within three major clades. Farm 2′s SwCRV sequences were distributed across all three clades, highlighting the likely mode of inter-farm transmission. Twenty-four recombination events were detected, with one recombination event resulting in consistent fragmentation of the P4c gene in the majority of the Farm 2 SwCRV isolates. Further investigation into the evolution of poxvirus infection in farmed crocodiles may offer valuable insights in evolution of this viral family and afford the opportunity to obtain crucial information into natural viral selection processes in an in vivo setting.

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“…Sequences rendered nonfunctional due to the accumulation of mutations following decreased or negative selection pressure for protein function may be removed from the genome to reduce the burden of replicating nonfunctional DNA (63). The decrease in genome size of some poxviruses such as variola virus, ectromelia virus, and molluscum contagiosum virus has been hypothesized to be an important mechanism of adaptation toward a narrower host range (19,20,64,65). Genes required for replication within a particular host are maintained, perhaps with minor modifications most suited to that particular host, while genes required for replication in alternative hosts are inactivated and removed.…”

Section: Discussionmentioning

confidence: 99%

Identification of Nucleotide-Level Changes Impacting Gene Content and Genome Evolution in Orthopoxviruses

Hatcher

Hendrickson

Lefkowitz

2014

J Virol

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Poxviruses are composed of large double-stranded DNA (dsDNA) genomes coding for several hundred genes whose variation has supported virus adaptation to a wide variety of hosts over their long evolutionary history. Comparative genomics has suggested that the Orthopoxvirus genus in particular has undergone reductive evolution, with the most recent common ancestor likely possessing a gene complement consisting of all genes present in any existing modern-day orthopoxvirus species, similar to the current Cowpox virus species. As orthopoxviruses adapt to new environments, the selection pressure on individual genes may be altered, driving sequence divergence and possible loss of function. This is evidenced by accumulation of mutations and loss of protein-coding open reading frames (ORFs) that progress from individual missense mutations to gene truncation through the introduction of early stop mutations (ESMs), gene fragmentation, and in some cases, a total loss of the ORF. In this study, we have constructed a whole-genome alignment for representative isolates from each Orthopoxvirus species and used it to identify the nucleotide-level changes that have led to gene content variation. By identifying the changes that have led to ESMs, we were able to determine that short indels were the major cause of gene truncations and that the genome length is inversely proportional to the number of ESMs present. We also identified the number and types of protein functional motifs still present in truncated genes to assess their functional significance. IMPORTANCEThis work contributes to our understanding of reductive evolution in poxviruses by identifying genomic remnants such as single nucleotide polymorphisms (SNPs) and indels left behind by evolutionary processes. Our comprehensive analysis of the genomic changes leading to gene truncation and fragmentation was able to detect some of the remnants of these evolutionary processes still present in orthopoxvirus genomes and suggests that these viruses are under continual adaptation due to changes in their environment. These results further our understanding of the evolutionary mechanisms that drive virus variation, allowing orthopoxviruses to adapt to particular environmental niches. Understanding the evolutionary history of these virus pathogens may help predict their future evolutionary potential.

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Elimination of A-type inclusion formation enhances cowpox virus replication in mice: Implications for orthopoxvirus evolution

Cited by 19 publications

References 24 publications

Out of the Reservoir: Phenotypic and Genotypic Characterization of a Novel Cowpox Virus Isolated from a Common Vole

Out of the Reservoir: Phenotypic and Genotypic Characterization of a Novel Cowpox Virus Isolated from a Common Vole

Crocodilepox Virus Evolutionary Genomics Supports Observed Poxvirus Infection Dynamics on Saltwater Crocodile (Crocodylus porosus)

Identification of Nucleotide-Level Changes Impacting Gene Content and Genome Evolution in Orthopoxviruses

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