Review
Poxviruses and the evolution of host range and virulence

https://doi.org/10.1016/j.meegid.2013.10.014Get rights and content

Highlights

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    Review of poxvirus families and poxvirus genes that influence poxvirus host range.

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    Molecular mechanisms poxviruses use to subvert the host innate immune system.

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    Evolution of poxvirus host range genes and their role in the virulence of poxviruses.

Abstract

Poxviruses as a group can infect a large number of animals. However, at the level of individual viruses, even closely related poxviruses display highly diverse host ranges and virulence. For example, variola virus, the causative agent of smallpox, is human-specific and highly virulent only to humans, whereas related cowpox viruses naturally infect a broad spectrum of animals and only cause relatively mild disease in humans. The successful replication of poxviruses depends on their effective manipulation of the host antiviral responses, at the cellular-, tissue- and species-specific levels, which constitutes a molecular basis for differences in poxvirus host range and virulence. A number of poxvirus genes have been identified that possess host range function in experimental settings, and many of these host range genes target specific antiviral host pathways. Herein, we review the biology of poxviruses with a focus on host range, zoonotic infections, virulence, genomics and host range genes as well as the current knowledge about the function of poxvirus host range factors and how their interaction with the host innate immune system contributes to poxvirus host range and virulence. We further discuss the evolution of host range and virulence in poxviruses as well as host switches and potential poxvirus threats for human and animal health.

Section snippets

Poxvirus host range factors

Poxviruses are large double-stranded DNA viruses, which exclusively replicate in the cytoplasm of their host cells. The genomes of currently sequenced poxviruses contain between 135 and 360 kb and contain up to 328 predicted open reading frames (ORFs). Poxviruses can be grouped into 2 subfamilies: chordopoxvirinae, which infect vertebrates and entomopoxvirinae, which infect insects. Among chordopoxvirinae, 10 genera are currently recognized: orthopoxviruses, yatapoxviruses, leporipoxviruses,

Orthopoxviruses

The orthopoxvirus genus comprises some of the best-studied poxviruses. The genomes of many orthopoxvirus species and strains have been completely sequenced, which provides valuable insights into the evolution of orthopoxviruses. Orthopoxviruses are closely related to one another antigenetically, which results in cross-reactivity and cross-protection against recurrent orthopoxvirus infection. Among the orthopoxviruses are two of the most renowned viruses: Variola virus (VARV), which caused human

Variola virus

Variola virus (VARV), the causative agent of smallpox, is thought to have caused more human fatalities throughout history than all other infectious diseases combined (McFadden, 2005). It was likely the first pathogen used for immunization by a process known as variolation, and is the only human virus that has been successfully eliminated from nature through mass vaccinations. VARV was most frequently transmitted in nature by droplet infection, usually requiring close contact, and caused a

Camelpox and taterapox viruses

CMLV and TATV viruses are the closest identified extant relatives of VARV. CMLV is a widespread pathogen of old world camels and causes an infection that resembles smallpox in humans (reviewed in Duraffour et al., 2011). It is characterized by fever, rash, the formation of vesicles and pustules concentrated on the head, neck and extremities, and the infection often spreads to the respiratory system. Depending on strain-specific and regional differences, mortality can reach up to 50%. As in

Vaccinia virus, horsepox virus and rabbitpox virus

Vaccinia virus (VACV) is the best studied of the poxviruses. It has been studied extensively as a model to understand the basic biology, virulence, and host range of poxviruses as well as its induction of host immune responses. Due to the fact that it usually causes only mild infections in humans and can induce protective immunity against other orthopoxviruses, it was used successfully in the campaign to eliminate smallpox (reviewed in Smith, 2007).

Currently available VACV strains have been

Cowpox viruses

Historically, the designation cowpox virus (CPXV) was used to describe orthopoxviruses that infect cows and were occasionally transmitted to humans who had close contact with infected cows. Characteristics of CPXV, although not specific, are the formation of cytoplasmic A-type inclusions, which contain mature virions embedded in a matrix formed by the late viral protein ATI, and the formation of large hemorrhagic pocks on the chorioallantoic membrane (reviewed in Essbauer and Meyer, 2007).

Monkeypox virus

Human monkeypox is an emerging zoonotic disease in humans, which clinically resembles smallpox. It is caused by monkeypox virus (MPXV), which is endemic to central and western African countries and possesses one of the broadest host ranges among poxviruses. The natural host reservoirs of MPXV are probably rodents including rope squirrels (Funisciurus sp.), sun squirrels (Heliosciurus sp.) and Gambian giant rats (Cricetomys sp.), as indicated by the isolation of virus from these species and the

Ectromelia virus

Ectromelia virus (ECTV) causes mousepox in laboratory mice (M. musculus) (reviewed in Esteban and Buller, 2005). The complete genomes of two ECTV strains are available: ECTV-Mos and ECTV-Nav, which contain 210 and 208 kb, respectively (Chen et al., 2003) (complete sequence of ECTV-Nav can be found at: http://www.sanger.ac.uk/Projects/Ectromelia_virus/EV.seq). Sequence identity between the two strains is approximately 99.5%, with only three ORFs showing disruptions between strains (Esteban and

North American orthopoxviruses

North American (NA) orthopoxviruses, including raccoonpox virus (RACV), skunkpox virus (SKPV) and volepox virus (VPXV), are presumed to be endemic to North America and can be described as “new world” orthopoxviruses as opposed to the previously characterized “old world” orthopoxviruses (Emerson et al., 2009). The characteristics of these viruses, such as geographic distribution, host range and taxonomic position have not yet been determined in detail. Phylogenetic analysis with selected genes,

Yoka poxvirus

Yoka poxvirus (YKV) was isolated in 1972 from Aedes simpsoni mosquitoes in the Central African Republic. It was identified as a poxvirus in 1989 by electron microscopy (Zeller et al., 1989), however, it was not until recently that its genetic and evolutionary relationship to other poxviruses has been investigated (Zhao et al., 2011). The host range of this virus is currently unknown and there has been very little work to explore the host range function of its genes. It has been shown to cause a

Yatapoxviruses

The genus yatapoxvirus comprises three viruses that have been completely sequenced: Yaba-like disease virus (YLDV), Tanapox virus (TPV) and Yaba monkey tumor virus (YMTV), the genomes of which comprise 145 kb (YLDV and TPV) 135 kb (YMTV) (Brunetti et al., 2003, Lee et al., 2001, Nazarian et al., 2007). All of these viruses infect primate species. YLDV and TPV are closely related to one another. A pairwise comparison of their genomes using blastn shows 98.6% identity on the nucleotide level. YMTV

Leporipoxviruses

Leporipoxviruses include the completely sequenced Myxoma virus (MXYV) and rabbit fibroma virus (RFV, also known as Shope fibroma virus) (Cameron et al., 1999, Willer et al., 1999). The natural hosts of MXYV and RFV are rabbits of the Sylvilagus species in America. MYXV infections appear to be limited to lagomorphs with two major groups currently recognized: Californian and South American strains. The natural host of Californian strains of MYXV is the brush rabbit (S. bachmani), which is endemic

Capripoxviruses

The genus Capripoxvirus contains three closely related members: Sheeppox virus (SPPV), Goatpox (GTPV) and Lumpy skin disease virus (LSDV), which naturally infect sheep, goats and cattle, respectively. The currently known capripoxviruses cannot be distinguished by serological tests. Survival of infection or vaccination with one capripoxvirus species usually confers resistance to the others. Species distinction is made according to the infected host species from which the virus was isolated and

Deerpox virus

Deerpoxvirus (DPV) is the sole recognized member of the genus Cervidpoxvirus. Two strains have been completely sequenced W-848-83 (DPV-W83) and W-1170-84 (DPV-W83) and contain 166 and 171 kb, respectively. W83 and W84 strains show 95% nucleotide identity (Afonso et al., 2005). They were isolated from free ranging mule deer (Odocoileus hemionus) fawns in Wyoming in 1983 and 1984, respectively. Both fawns were seriously ill (one died spontaneously and the other had to be euthanized) and displayed

Swinepox virus

Swinepox virus (SWPV) is the only member of the genus Suipoxvirus and infection is entirely restricted to pigs (Datt, 1964, Delhon et al., 2007). Swinepox occurs worldwide and is a common skin disease in pigs. Piglets are usually more severely affected. SWPV is thought to be predominantly transmitted mechanically by the hog louse, Haematopinus suis, but it can also be transmitted through direct contact and congenitally (House and House, 1992, Thibault et al., 1998). The genome of SWPV comprises

Cotia virus

Cotia virus (COTV) was isolated in 1961 during an arbovirus surveillance program at Cotia field station near São Paulo, Brazil, which used sentinel mice to detect novel viruses in the environment (Lopesode et al., 1965). Although there was initially some controversy over the classification of COTV, a comprehensive study of the fully sequenced genome including a phylogenetic analysis along with an examination of replication kinetics in different cell lines has indicated that COTV represents a

Parapoxviruses

Parapoxviruses are widespread pathogens that can infect a variety of different mammals including humans. Prototypic members of this genus are Orf virus (ORFV), Bovine papular stomatitis virus (BPSV) and Pseudocowpoxvirus (PCPV), the genomes of which have been completely sequenced and contain 134 to 140 kb (four ORFV strains), 134 kb and 135–145 kb (PCPV), respectively (Delhon et al., 2004, Hautaniemi et al., 2010). In phylogenetic analyses parapoxviruses form a sister-clade to orthopoxviruses and

Squirrelpox virus

Squirrelpox virus (SQPV) was identified as the causative agent of a lethal disease of red squirrels (Sciurus vulgaris) in the United Kingdom. It was initially described as a parapoxvirus due to similar morphology observed by electron microscopy (Scott et al., 1981, Thomas et al., 2003). However, phylogenetic analyses with sequences from the partially sequenced SQPV genome showed that the SQPV branch was well separated from that formed by parapoxviruses. This finding together with relatively low

Avipoxviruses

Avipoxviruses are common bird pathogens. Bolte et al. summarized avipoxvirus infections in 232 bird species, in which they can cause serious infections (Bolte et al., 1999). The genomes the two fowlpoxvirus (FWPV) strains Iowa (I) and HP-438/Munich (M) and one Canarypoxvirus (CNPV) have been completely sequenced and contain 289, 266 and 360 kb respectively (Afonso et al., 2000, Laidlaw and Skinner, 2004, Tulman et al., 2004). The large genome sizes of avipoxviruses can be attributed to multiple

Molluscum contagiosum virus

Molluscum contagiosum virus (MOCV) is the only identified member of the genus Molluscipoxvirus and displays the narrowest host range and tissue tropism of all known poxviruses. It is specific to humans and is only known to replicate in basal keratinocytes. MOCV causes molluscum contagiosum, which is a common skin disease characterized by wart-like skin lesions that affects mainly children and immunocompromised people (reviewed in Bugert, 2007). The genome of MOCV comprises 190 kb, codes for an

Crocodilepox virus

Poxvirus infections have also been reported from reptiles, including many crocodilian species. Poxviruses can cause serious infections in young farmed crocodiles and caimans, whereas adults remain largely asymptomatic (as referenced in (Afonso et al., 2006, Huchzermeyer, 2002)). The genome of a crocodilepox virus (CRV) isolated from a Nile crocodile (Crocodylus niloticus) was completely sequenced. The 190 kb genome encodes for 173 predicted proteins, of which 62 do not contain recognizable

Entomopoxviruses

Entomopoxvirinae constitute a subfamily of Poxviridae, which specifically infect insects. Based on the host species, morphology and genomic characteristics, three entomopoxvirus genera are recognized: alphaentomopoxviruses, which infect beetles, betaentomopoxviruses, which infect butterflies and moths, and gammaentomopoxviruses, which infect flies and mosquitos. Additionally, some entomopoxviruses have not yet been classified (reviewed in Becker and Moyer, 2007). The genomes of six

PKR inhibitors K3L and E3L

The host double-stranded (ds) RNA-activated protein kinase PKR is activated upon infection by of many viruses and initiates an antiviral response by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α). Many viruses in turn have evolved mechanisms that subvert this antiviral response (reviewed in Langland et al., 2006). As a consequence, PKR has evolved rapidly throughout the vertebrate lineage due to positive selection (Elde et al., 2009, Rothenburg et al.,

Poxvirus host switches

Our current knowledge is insufficient to accurately predict the outcomes and consequences of poxvirus host switches such as virulence, transmissibility and whether persistence within a new host species can be established. This is complicated by the problem that for many poxviruses, the reservoir host-species have not been unequivocally identified. Many poxviruses cause only mild disease in their respective reservoir hosts, probably reflecting sufficient time for host–virus coevolution. Notable

Eminent poxvirus threats

Poxviruses face stiff inter-species competition. Because VARV was so prevalent in human populations and smallpox survivors gained immunity against other orthopoxviruses, the latter likely never had a chance to establish themselves in the human population. However, with the eradication of VARV from nature and the cessation of mass vaccinations with vaccinia virus, we are left vulnerable to infection by other orthopoxviruses. One major threat would be the emergence of a human-adapted MPXV with

Evolution of poxvirus virulence

Viruses can have intricate relationships with their hosts that can lead to the coevolution of virus and host genes, which can influence the virulence and transmissibility of the viruses. Evolution of virulence for a certain host is probably influenced by the effectiveness and route of transmission of the virus, the immune status of host species, the availability of additional reservoir hosts, intra- and inter-species competition with other viruses and the positive selection for hosts that are

Conclusions

Our current knowledge is insufficient to predict the outcomes of poxvirus host-switches. Every animal or human that comes into contact with poxvirus-infected animals or arthropod vectors of poxviruses is at risk for productive infection. Whether productive infection can be established depends on the effective manipulation of the host immune response by the querying virus. It is likely that both gene loss and the acquisition of new genes, through gene duplication, recombination, horizontal

Acknowledgements

This work was supported by NIH grant P20 RR016475 from the INBRE program of the National Center for Research Resources to S.R. G.M.’s lab is supported by NIH R01 grants AI080607, CA138541, and AI100987.

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