Poxviruses and the evolution of host range and virulence

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.

Keywords: Antiviral response; Host range; Host response; Host–pathogen interactions; Poxviruses; Virus evolution.

Figure 1. Presence of host range gene families in poxviruses

The shown schematic poxvirus phylogeny is based on a recently published phylogenetic analysis (Bratke et al., 2013) and incorporates the phylogenetic positions of PCPV, YKV and COTV as published (Afonso et al., 2012; Hautaniemi et al., 2010; Zhao et al., 2011). Branch lengths are not drawn to scale. Approximate extent of virus host range, as discussed in this manuscript, is indicated by circles. A small circle indicates a very limited host range. Large circles indicate a broad host range. No circle indicates insufficient data to project host range. Human-specific viruses are marked by red circles. Viruses that can cause zoonotic infections in humans are marked by orange circles. Presence of likely functional host range genes or gene families are indicated by numbers (see (Bratke et al., 2013) and this manuscript). Asterisks (*) mark E3L orthologs that don't encode for a functional Zα domain. The number (#) sign denotes an additional serpin gene in YKV that is probably non-functional (see YKV section). Abreviations for poxvirus genera are: EPV = Entomopoxvirus B; APV = Avipoxvirus; CrPV = Crocodylidpoxvirus; MOPV = Molluscipoxvirus; PPV = Parapoxvirus; YPV = Yatapoxvirus; LPV = Leporipoxvirus; CePV = Cervidpoxvirus; CaPV = Capripoxvirus; SPV = Suipoxvirus.

Figure 2. Molecular basis for poxvirus host range

Potential molecular mechanisms of how genetic differences of both the virus (left) and host (right) contribute to the host range of poxviruses.

Figure 3. Molecular interactions of poxvirus host-range factors with host proteins

The host range function of proteins encoded by poxviruses can be attributed to several interactions with specific host proteins. Some poxviruses encode proteins that use the host's machinery to their own benefit to promote viral spread or degrade unwanted host proteins. Many also encode inhibitors of proteins involved in antiviral responses, such as apoptosis or translational shut-off, ultimately reducing the inflammatory or interferon response mediated by the cell to promote viral replication. The specificity of these interactions with their host targets can either restrict or expand the range of hosts in which the virus can replicate. Abbreviations used: dsRNA = double-stranded RNA; MAVS = mitochondrial antiviral signaling protein (also known as IPS-1/Cardiff/VISA); TNFR = tumor necrosis factor receptor; IRF (1,3,7) = interferon response factor; CEV = cell associated enveloped virus; EEV = extracellular enveloped virus; Ub = ubiquitin; SCF-1 = Skp1:Cullin-1:F-box ubiquitin ligase complex; eIF2 = eukaryotic translation initiation factor 2; IFNAR = interferon receptor; IFN = interferon; Bcl-xL = B-cell lymphoma extra large; FADD = Fas-associated Death domain protein; TRADD = TNFR-1 associated Death domain protein; Organelles and proteins not drawn to scale. * B5 is present on both cellular and EEV membranes (here shown in two sizes) and promotes the transition from CEV to EEV during viral replication.