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Article

Comparative Genomic Analysis of Two Bat Poxviruses in the Genus Vespertilionpoxvirus

by
Chi Zhang
1,
Kyle Heye
1,
Davide Lelli
2,
Loubna Tazi
1 and
Stefan Rothenburg
1,*
1
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616, USA
2
Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), Via Bianchi 9, 25124 Brescia, Italy
*
Author to whom correspondence should be addressed.
Viruses 2026, 18(7), 706; https://doi.org/10.3390/v18070706
Submission received: 16 May 2026 / Revised: 16 June 2026 / Accepted: 24 June 2026 / Published: 26 June 2026
(This article belongs to the Special Issue Animal Virus Discovery and Genetic Diversity: 2nd Edition)
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Abstract

Poxviruses are large double-stranded DNA (dsDNA) viruses that cause important human and animal diseases, including smallpox and mpox. Poxviruses have also been identified in diverse bat populations; however, their potential for zoonotic transmission and adaptation to other mammalian hosts remains poorly understood. Poxviruses encode numerous immunomodulatory proteins that contribute to virulence, immune evasion, and host range. In this study, we performed a comparative genomic analysis of two bat-associated poxviruses belonging to the genus Vespertilionpoxvirus: hypsugopox virus (HYPV) and eptesipox virus (EPTV). Our analyses revealed 24 novel putative ORFs in HYPV and three in EPTV, thereby substantially expanding the inferred coding capacity of these viruses. Comparative analyses further revealed gene duplication and fragmentation events affecting several virulence and host range factors, as well as other unusual genomic features, including the presence of two divergent E3L homologs in EPTV. Together, our findings provide new insights into the genome evolution and potential host adaptation of bat-associated poxviruses and establish a foundation for future functional studies of Vespertilionpoxvirus biology, host–virus interactions, and zoonotic potential.

1. Introduction

Bats are known or suspected reservoirs of many important zoonotic viruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Middle East respiratory syndrome coronavirus (MERS-CoV), as well as Ebola virus (EBOV), Marburg virus (MARV), Nipah virus (NiV), and Hendra virus (HeV). These viruses can cause severe diseases with high fatality rates in humans [1,2,3,4,5,6]. Increased interest in bat-borne viruses has led to the identification of many previously unknown viruses in recent years, including poxviruses [7,8,9,10,11].
Poxviruses are large double-stranded DNA viruses that replicate exclusively in the cytoplasm of cells. The family Poxviridae comprises two subfamilies: Entomopoxvirinae, which infect insects, and Chordopoxvirinae, which infect vertebrates and currently include 18 recognized genera [12]. They contain several important human pathogens, including variola virus (VARV), the causative agent of smallpox, monkeypox virus (MPXV), the causative agent of mpox, vaccinia virus (VACV), which is used as a smallpox and mpox vaccine, and cowpox viruses (CPXV) [13]. In addition, many poxviruses are important animal pathogens, including myxoma virus (MYXV), which has been instrumental in shaping our understanding of virus–host co-evolution and host switches [14].
Poxvirus genomes range from approximately 122 to 460 kb and contain densely packed genes. Genes essential for replication and virion formation are highly conserved and located near the center of the genome, whereas genes involved in host interactions and virulence are more frequently located towards the termini [15]. The two termini of the poxvirus genome are covalently closed and contain inverted terminal repeats (ITRs) with identical sequences in inverted orientation. Poxvirus genomes are highly adaptable. Common mechanisms of poxvirus evolution include point mutations, gene loss, gene duplication and consequent neofunctionalization, expansion, and contraction of their ITR regions, which often lead to differences in gene copy number, homologous and non-homologous recombination, and horizontal gene transfer from their hosts or other microorganisms [16,17,18].
Poxvirus entry into host cells is generally mediated by highly conserved cellular surface molecules rather than species-specific receptors, and successful replication largely depends on post-entry interactions with the host antiviral immune defenses [19,20]. The host range of poxviruses varies greatly, from viruses that productively infect only a single species, such as VARV (human-specific), to others, sometimes closely related viruses, such as CPXVs, which have naturally caused disease in more than 60 different host species [21]. Although the precise mechanisms determining poxvirus host range are not fully understood, a group of genes has been described that influences host and cell line tropism, collectively referred to as host range genes [22,23,24]. In orthopoxviruses, the number of host range genes roughly correlates with the size of their host range [24]. In addition, sequence variations in poxvirus host range genes have been shown to be important to virus replication and host tropism [23].
Although several bat poxvirus species have been recently identified, their host ranges and potential for spillover into other mammals remain largely unknown [7,8,9]. The recent report of a laboratory-confirmed human infection with Israeli Rousettus aegyptiacus poxvirus highlights the importance of investigating bat poxviruses and evaluating their zoonotic potential [25]. Comparative genomic analyses on conserved and unique genes can provide important insights into the putative virulence and host-range determinants of these viruses. However, genomic information on bat poxviruses remains limited, as only three bat poxviruses have had their nearly complete genomes sequenced [8,9,26]. Among these are eptesipox virus (EPTV) and hypsugopox virus (HYPV), the only known members of the genus Vespertilionpoxvirus, which are found in a sister clade (clade II poxviruses) to Orthopoxvirus and Centapoxvirus genera. EPTV was initially identified from the wings and joints of several sick big brown bats (Eptesicus fuscus) with progressive joint swelling and inability to fly in Washington, USA [7]. Its genome was subsequently sequenced and found to be 176,688 nucleotides in length and to contain 191 open reading frames (ORFs), 11 of which lacked homologs in other known poxviruses [26]. EPTV was later isolated from lesions in infected big brown bats in Saskatchewan, Canada, which shared 99.7% sequence identity with the Washington isolate [27]. HYPV was detected in deceased insectivorous bats (Hypsugo savii) during viral surveillance programs in Italy. Necropsy showed lymphoplasmacytic pneumonia in two bats, while no apparent pathological lesions were observed in another infected bat [9,28]. A total of 161 ORFs were annotated in the 166,600 bp HYPV genome, while the precise extent of the ITR region was not resolved [9]. However, because the original annotation relied on sequence similarity to EPTV, potentially divergent ORFs may have been overlooked. The incomplete annotation may lead to inaccurate conclusions regarding Vespertilionpoxvirus gene content and genome organization.
In this study, we reannotated the HYPV genome and performed a comparative genomic analysis of the two vespertilionpoxviruses. We identified multiple previously unannotated ORFs in HYPV and three small ORFs in EPTV, characterized gene deletions, fragmentations, and duplication events. These findings provide a more comprehensive view of the genomic architecture of the two bat poxviruses, which offer a foundation for further studies of their infection phenotypes, host range, and protein functions.

2. Materials and Methods

2.1. Genome Annotation and Comparative Analysis

The partially sequenced HYPV genome was downloaded from GenBank (accession number: MK860688.1) and subjected to genome annotation. ORFs longer than 50 amino acids (aa) and overlapping with less than 25% with existing ORFs were considered putative genes unless supported otherwise by experimental evidence. Homology searches were initially performed using the EPTV genome (accession number: KY747497) as a reference. If no homologs were identified in EPTV, additional searches were conducted against poxviruses and vertebrates using BLASTp, PSI-BLAST and tBLASTn (https://blast.ncbi.nlm.nih.gov/Blast.cgi accessed between 9 February 2025 and 2 April 2026). Orthopoxvirus gene (OPG) numbers [17] were assigned based on homology to orthopoxvirus genes.
The genome sequences of the two EPTV isolates, the Washington and Saskatoon strains, were compared using MegaBLAST alignment (https://blast.ncbi.nlm.nih.gov/Blast.cgi accessed on 27 February 2026). Regions containing suspected repeat sequences were further analyzed using Tandem Repeat Finder (TRF v4.09) [29] with default parameters.

2.2. dN/dS Analysis

Homologous amino acid sequences from EPTV and HYPV were aligned using Clustal Omega (version 1.2.4) [30]. Positive selection analysis was performed using JCoDA v1.4 [31], which generated codon-delimited alignments and calculated dN/dS values through sliding window analysis.

2.3. Sequence Alignment and Phylogeny

The homologs of EPTV and HYPV proteins in other poxviruses were identified through BLASTp searches (https://blast.ncbi.nlm.nih.gov/Blast.cgi accessed between 9 February 2025 and 2 April 2026) against representative poxvirus genomes (Table 1). In some cases, in which the homologous genes were not annotated as such, tBLASTn searches and gene synteny analyses were used to identify potential homologs.
The dsRBDs of E3L homologs were identified using InterProScan v109.0 [32] and manually curated. Amino acid sequence alignments were generated using Clustal Omega [30] and MUSCLE v3.8 [33] and visualized in JalView v2.11.5.1 [34].
Maximum-likelihood phylogenetic trees were constructed using PhyML v3.0 with automatic substitution model selection [35,36]. Branch support was assessed using the non-parametric bootstrap analysis with 100 bootstrap replicates. The resulting phylogenetic trees were visualized using FigTree v1.4.3 (https://tree.bio.ed.ac.uk/software/figtree/, accessed on 30 April 2025).

2.4. Structural Homology Search and Protein Structure Prediction

EPTV-010.5/181.5 and HYPV-013 were searched for structural homology using the sequence motif search tool in the RCSB Protein Data Bank (https://www.rcsb.org/ accessed on 13 October 2025). Protein structure predictions for VACV, EPTV, and HYPV proteins were generated using the AlphaFold online server powered by AlphaFold 3 [37].

3. Results and Discussion

3.1. Identification of Previously Unannotated Genes in HYPV

During an initial analysis of HYPV host range proteins, we noticed that several proteins appeared to be absent. Closer inspection revealed that the corresponding ORFs were not annotated in the original study, likely due to a conservative approach that included only ORFs with high sequence identity to EPTV homologs [9]. This resulted in the omission of many ORFs found across multiple other poxvirus species. Therefore, we systematically reanalyzed both genomes to identify additional ORFs. ORFs longer than 50 aa were considered candidate protein-coding regions. ORFs were classified based on a combination of sequence identities with other poxvirus proteins, conserved motifs or domains, gene synteny, and ORF length. ORFs shorter than 50 aa were considered when prior evidence from homologs in other poxviruses indicated the expression and function of the encoded proteins.
We identified 24 previously unannotated ORFs in HYPV (indicated in bold letters in Figure 1), 21 of which have homologs in EPTV or in other poxviruses. The putatively encoded proteins range from 30 to 672 aa, with an average length of 148 aa. ORFs in the HYPV genome were renamed according to their relative position in the genome (HYPV-001 through HYPV-185) (Figure 1, Table 2). The originally identified HYPV ORF names, as well as orthologous ORF names in EPTV, are also shown for reference (Table 2). Three ORFs, HYPV-011 (95 aa), HYPV-147 (95 aa), and HYPV-175 (123 aa), appear to be unique to HYPV since no homologs could be detected in BLASTp or tBLASTn searches. Nine ORFs are specific to the genus Vespertilionpoxvirus: HYPV-009, HYPV-015, HYPV-024, HYPV-027, HYPV-034, HYPV-140, HYPV-146, HYPV-154, and HYPV-157.
Three HYPV ORFs lack homologs in EPTV but are found in other poxviruses. HYPV-17 shares 33.67% aa sequence identity with sheeppox virus (SPPV) protein 012, an interleukin-18 binding protein [38]. HYPV-166 shares 26.09% aa sequence identity with MYXV m135, a transmembrane virulence factor [39]. The N-terminal 55 aa of HYPV-181 share 44% aa sequence identity with swinepox virus (SWPV) 009. However, it is restricted to the encoded LAP/PHD finger-like domain; beyond this region, HYPV-181 shows higher sequence identity to other E3 ubiquitin-protein ligases, e.g., Silurus meridionalis MARCH1 (accession number: KAI5087763.1).
The original HYPV genome annotation relied on an automated pipeline that only compared homology to EPTV and chose a conservative approach to avoid over-annotating ORFs, by excluding ORFs smaller than 50 codons [9]. However, 22 of the 24 putative ORFs identified here exceed this threshold, and 21 have homologs in other poxviruses.
EPTV contains three unique ORFs not found in other poxviruses, including HYPV: EPTV-143 (74 aa), EPTV-145 (74 aa), and EPTV-176 (62 aa). EPTV-145 consists of 50-nt long tandem repeats containing the consensus pattern 5′-ATG GAC ATG TTT TTT AAA AAG TTT ATT AAT TGT TTT TTT AAA AAA ATT AC-3′, which extend into the adjacent intergenic regions and have a total of five repeat units. In the EPTV isolate Saskatoon/01/2020, this region contains 11 repeat units. Because of the repetitive origin and minor differences in the repeat motif, the predicted aa identity of EPTV-145 between both EPTV isolates is only 53%. Overall, the Washington and Saskatchewan EPTV isolates share 99.7% nucleotide sequence identity and a conserved gene content. Sequence variations are distributed across the genome and no large-scale genomic rearrangements were detected.
In order to analyze if positive selection could be detected in HYPV and EPTV genes, we performed a sliding window analysis with all ORFs pairs in HYPV and EPTV to determine the ratios of non-synonymous to synonymous nucleotide substitutions (dN/dS) (Table 2). dN/dS ratios above 1 are suggestive of positive selection. All the determined dN/dS ratios were found to be below 1, with the highest ratios having values ranging between 0.1 and 0.4. The majority of the ORFs displayed very low dN/dS ratios ranging between 0.003 and 0.09, indicating that a majority of HYPV and EPTV genes have been under strong purifying selection.

3.2. Identification of Three Previously Unannotated ORFs in EPTV

We have identified three previously unannotated ORFs in EPTV, which we termed EPTV-010.5/181.5, 031.5, and 045.5 based on their genomic positions between previously annotated genes [26]. The predicted encoded proteins are shorter than 75 aa and have conserved homologs in multiple poxviruses, including HYPV.

3.2.1. Vespertilionpoxviruses Encode Homologs of the STAT1 Antagonist VACV 018

EPTV-010.5/181.5 and its ortholog HYPV-013 are located near the genomic termini, with the EPTV copies residing within the ITR regions. BLAST searches (v2.17) matched these ORFs to the VACV Western Reserve strain 018 (OPG 024). VACV 018 was shown to antagonize IFN-I- and -II-induced signaling by binding directly to the SH2 domain of signal transducer and activator of transcription 1 (STAT1). The interaction blocks STAT1 phosphorylation, thereby inhibiting its activation and downstream induction of interferon-stimulated genes (ISGs). Although a recombinant VACV Δ018 strain replicated at comparable levels to the WT virus in cell culture, it was attenuated in mice [40]. Many poxviruses encode VACV 018 homologs, which contain a STAT1 binding motif (corresponding to amino acids 11–31 in VACV 018) (Figure 2A). A crystal structure of the STAT1 core and the binding motif of VACV 018 was previously reported and showed that this motif forms a β-hairpin [40]. Prediction of the N-terminal structures of EPTV-010.5 and HYPV-013 using AlphaFold3 is consistent with the reported structure (Figure 2B).

3.2.2. F14.5L Homologs Are Conserved Across Multiple Chordopoxvirus Genera

EPTV-031.5 and its HYPV ortholog HYPV-035 encode proteins of 53 aa in length. To identify the orthologous genes in other species, we first performed BLAST searches with the two proteins, which showed no hits. However, examination of corresponding genomic loci in other poxviruses revealed ORFs of similar length. In the VACV Copenhagen strain, this gene is annotated as F14.5L (OPG 059), located between F14L and F15L. F14.5L has orthologs in other orthopoxviruses [41]. Previous studies showed that the protein product of VACV F14.5L was incorporated into the mature virion (MV) membrane with the C-terminus of the protein exposed on the virion surface, contributing to virion morphology and adhesion of infected cells. Its deletion did not affect VACV replication and MV/EEV production in cell culture but contributed to the virus’s virulence in vivo [41].
Homologous ORFs of F14.5L have not been well defined and annotated outside of orthopoxviruses. After identifying homologs in the two vespertilionpoxvirus genomes, we examined the same genomic locus in other chordopoxvirus genera. ORFs of similar length were identified at the syntenic loci in multiple poxviruses (Figure 3A), which share a hydrophobic N-terminus corresponding to a transmembrane region. Structural prediction of VACV, EPTV, and HYPV homologs using AlphaFold3 showed similar α-helical structures at the N-terminus and a more variable C-terminus (Figure 3B). Further studies are needed to determine whether these ORFs encode functional proteins and whether they are expressed and incorporated into MV particles similarly to VACV F14.5L. Although the C-terminus has been implicated in cell morphology and adhesion, its role in virus replication remains unclear.

3.2.3. Entry-Fusion Complex (EFC) Component O3L Homologs

EPTV-045.5 and HYPV-049 are homologs of VACV O3L (OPG 076), whose product, O3, is an integral component of the virus entry-fusion complex (EFC) and the smallest known VACV protein, containing only 35 aa. It is incorporated into the mature virions and is required for virus entry and membrane fusion of infected cells [42]. Deletion of O3L in VACV did not affect progeny virion morphology but significantly reduced infectivity [42]. O3 orthologs exhibit a more conserved N-terminus (aa 1–26) and a more variable C-terminal region (Figure 4A). Of note is a highly conserved proline at position 24, which separates the two α-helices [43,44]. EPTV-045.5 and HYPV-049 are found at genomic locations syntenic to O3L. Hydropathy plots of VACV O3, EPTV-045.5, and HYPV-049 revealed similar profiles, with hydrophobic N-termini and hydrophilic C-termini (Figure 4B). AlphaFold3 structural prediction of VACV O3, EPTV-045.5, and HYPV-049 further indicates similar folding patterns (Figure 4C) and agrees well with the resolved structure of O3 in the EFC [44]. Given that a highly attenuated O3L-deficient VACV could be rescued by O3 homologs from other poxviruses, such as MYXV, SPPV, and fowlpox virus (FWPV) [45], EPTV-045.5 and HYPV-049 are also likely functional components of the EFC.

3.3. Gene Fragmentations in Vespertilionpoxviruses

Gene loss through fragmentation is a common theme in poxvirus evolution and may contribute to a more restricted host range [17,18]. Comparison of the HYPV and EPTV genomes revealed four genes that are fragmented in HYPV relative to EPTV: EPTV-002, EPTV-146, EPTV-149, and EPTV-010/182 (corresponding to HYPV-002, HYPV-149, HYPV-152, and HYPV-184, respectively) (Figure 5). These genes encode proteins involved in antagonizing host immune responses and represent potential virulence and host range factors.
EPTV-002 encodes a serine protease inhibitor (serpin). Serpins belong to a large and broadly distributed protein family involved in regulating diverse proteolytic cascades [46]. The number of serpin genes in chordopoxviruses varies from zero in parapoxviruses to four in avipoxviruses [23]. These proteins exhibit anti-apoptotic and anti-inflammatory functions and target host proteins such as cathepsin G, caspases 1, 8 and 10, and granzyme B [47,48,49,50]. Both EPTV and HYPV encode an additional serpin homolog (EPTV-164 and HYPV-168).
EPTV-146 is homologous to the C-terminal regulatory domain of metazoan gasdermins, as demonstrated by the crystal structure of EPTV-146 [51]. Gasdermins are pore-forming effector proteins that act as executioners of pyroptosis, an inflammatory form of induced cell death. Upon activation, inflammasome complexes recruit and cleave gasdermins, releasing the N-terminal lipophilic domain from the C-terminal autoinhibitory domain [52]. The VACV homolog of EPTV-146 was shown to prevent noncanonical pyroptotic cell death and dampen inflammasome signaling by hindering caspase-mediated substrate processing [51]. However, the contribution of these proteins to virus host range and virulence remains unclear. Gene fragmentation or pseudogenization of this locus has also been observed in other poxviruses like CPXV and camelpox virus (CMLV) [51].
EPTV-149 is a BTB kelch-domain protein homologous to VACV A55R. In poxvirus BTB kelch-domain proteins, the N-terminal BTB domain mediates interaction with the Cullin-3-based E3 ubiquitin ligase complex [53], whereas the C-terminal kelch repeats can inhibit NF-κB signaling by targeting host importin α1 [54]. Although fragmented, the corresponding HYPV ORFs retain the full BTB domain and several kelch repeats, making it possible that they are functional. Both EPTV and HYPV encode a second BTB kelch-domain protein (EPTV-155 and HYPV-158).
EPTV-010/182 is an ankyrin repeat-containing protein and homologous to CPXV CP77 and MYXV MT5, two previously identified host range genes [55,56]. CP77 is required for CPXV replication in hamster CHO cells and has been associated with multiple immunomodulatory functions, including inhibition of NF-κB activation and antagonism of the restriction factors SAMD9 and SAMD9L [55,57,58]. In addition to the fragmented HYPV-184, HYPV encodes two additional CP77 homologs, HYPV-012 and HYPV-173. Notably, EPTV-010/182 and HYPV-012 are approximately 100 aa shorter at the C-terminus than their CPXV homolog and thus lack carboxy-terminal F-box-like domains, whereas HYPV-173 is full length.

3.4. Gene Duplications in Vespertilionpoxviruses

Gene duplications in poxviruses contribute to functional diversification and adaptation. Two EPTV genes in the same genomic region, EPTV-007 and EPTV-008, are duplicated in HYPV (Figure 6A).

3.4.1. Gene Duplications in HYPV

EPTV-007, HYPV-007, and HYPV-008 are homologs of M-T4-like apoptosis inhibitors. The MYXV ortholog, M-T4, is a recognized host range factor because induced apoptosis was observed in rabbit RL5 cells and peripheral blood lymphocytes infected with T4-deleted MYXV, but not in RK13 cells [59]. The cowpox ortholog, CPXV203 (OPG 195), binds fully assembled MHC I proteins and retrieves them to the ER via its C-terminal ER retrieval sequence (KTEL). Therefore, it could downregulate MHC I and reduce detection of infected cells by CD8+ T cells [60,61]. The C-terminal ER retrieval signal is retained in EPTV-007 and HYPV-007 (Figure 6B). This motif mediates retention of proteins in the ER through continuous retrieval of proteins from the Golgi apparatus [62,63]. In contrast, HYPV-008 lacks the C-terminal 13 aa and has lost this signal peptide (Figure 6B). Phylogenetic analysis shows that EPTV and HYPV M-T4 orthologs cluster more closely with those of other clade-II poxviruses, forming a clade distinct from orthopoxvirus and centapoxvirus homologs (Figure 6C).
The other duplicated HYPV ORFs, HYPV-009 and HYPV-015, share 29.7% aa sequence identity and show no detectable matches in BLAST analyses (v2.17) other than their EPTV ortholog, but are predicted to contain Bcl-2-like domains (Figure 6D). Bcl-2-like domains are present in several poxvirus proteins, including VACV B14, A46, A52, C1, K7, N1, and N2. These proteins are involved in inhibiting the Toll-like receptor signaling pathway and exhibit anti-apoptotic and anti-inflammatory activities [64,65]. However, due to low sequence similarity, the precise relationship between vespertilionpoxvirus proteins and other poxvirus Bcl-2-like proteins remains unclear.

3.4.2. Presence of Two E3L Homologs in EPTV

A unique genomic feature of EPTV among currently characterized poxviruses is the presence of two homologs of the dsRNA-binding protein kinase R (PKR) inhibitor E3L (OPG 65) (EPTV-037 and EPTV-163) in distinct regions of the genome [26]. VACV E3L is a well-established virulence and host range gene. It consists of an N-terminal Zα domain and a C-terminal dsRNA-binding domain (dsRBD), which bind Z-form nucleic acids and dsRNA, respectively. E3 inhibits multiple innate immunity pathways triggered by viral nucleic acids, including the PKR pathway, the 2′-5′-oligoadenylate synthetase (OAS)/RNase L pathway, RIG-I/MDA5-mediated IFN induction, and Z-DNA binding protein 1 (ZBP1)-mediated IFN signaling and necroptosis [66,67,68]. While the Zα domain of VACV E3L is dispensable for virus replication in cell culture, both domains are necessary for virus full pathogenesis in mouse models [69,70,71]. E3L homologs are found in many poxviruses. However, some of them lack a functional Zα domain, as observed in MYXV, rabbit fibroma virus (RFV), and MPXV [23]. In addition to its role in virulence, E3L has been described as a host range gene, because it is dispensable for VACV infection in Syrian hamster cells but required in human cells [72]. A molecular explanation for this difference is that Syrian hamster PKR is resistant to E3 inhibition but sensitive to the alternative VACV PKR inhibitor K3, whereas human PKR is sensitive to E3 but resistant to K3 [73]. The only other poxvirus known to have two E3 orthologs is cetacean poxvirus 1 (CePV-1), which contains two closely related, tandemly arranged homologs (CePV-TA-20 and CePV-TA-21). Whereas CePV-TA-21 encodes both Zα and dsRBDs, CePV-TA-20 contains a dsRBD but lacks the Zα domain [74]. In contrast, the two EPTV E3 homologs are located in distinct regions of the genome. Although both homologs contain Zα and dsRBD domains, they share only 22% aa sequence identity. Uniquely among E3 homologs, EPTV-163 contains an 80 aa C-terminal extension with no detectable homology to known proteins.
Synteny analyses of the loci containing the two EPTV E3 homologs revealed that EPTV-037 occupies the same genomic location as E3 homologs in other clade II poxviruses (Figure 7A). We identified a single, previously unannotated E3L homolog in HYPV (HYPV-169), which is syntenic to EPTV-163 (Figure 7B). Phylogenetic analysis based on the conserved dsRBD of E3Ls shows that EPTV-037 and EPTV-163 cluster in distinct clades, confirming that they are not closely related (Figure 8). Consistent with the synteny analysis, EPTV-163 and HYPV-169 are closely related, indicating that they are orthologs. These observations indicate that the common ancestor of EPTV and HYPV acquired a second E3 homolog from an unidentified poxvirus rather than through duplication of the ancestral EPTV-037. HYPV subsequently lost the ancestral copy, leaving only HYPV-169. Future studies are required to determine whether the two EPTV E3L homologs have diverged functionally and whether retention of both copies confers adaptive advantages.

3.5. Other Host Range Genes in Vespertilionpoxviruses

As previously noted, EPTV contains 11 of 12 described host range factors, lacking only K1L, which is specific to orthopoxviruses and centapoxviruses [26]. HYPV also encodes orthologs of these proteins. However, in addition to those described above, several vespertilionpoxvirus host range genes exhibit distinct features compared with their counterparts in other poxviruses.
VACV K3 (encoded by K3L, OPG 041) is another inhibitor of the PKR pathway, and its ortholog is newly annotated in HYPV (HYPV-014 and EPTV-012). K3 acts as a structural mimic of eIF2α and antagonizes the PKR pathway by binding directly to activated PKR, thereby preventing its interaction with its substrate [76,77]. A K3L-deleted VACV strain showed reduced replication in mouse L929 cells and hamster BHK cells but was unaffected in human HeLa and rabbit RK13 cells [72,76,78]. Notably, the EPTV K3L homolog encodes an unusual C-terminal extension that is not observed in other poxviruses [79]. In contrast, the HYPV K3L homolog lacks this extension, indicating that it is unique to EPTV. Previous studies in yeast have shown that the C-terminal extension modulated the inhibitory activity of EPTV K3L in a species-specific manner [79]; however, its role in mediating interactions with PKR remains unclear.
EPTV-177 and HYPV-183 (199 aa and 131 aa in length, respectively) are homologs of cellular tumor necrosis factor receptors (TNFRs). Poxviral TNFR homologs can bind TNF cytokines, inhibiting the downstream signaling pathway involved in regulating host inflammatory responses and apoptosis [80,81]. Orthopoxviruses can encode up to four TNFRs, designated as CrmB, CrmC, CrmD, and CrmE in CPXV. Among clade II poxviruses, only leporipoxviruses encode TNFR homologs, called MT2 in MYXV. This protein contains four N-terminal cysteine-rich domains (CRDs) homologous to mammalian TNFR CRDs, as well as a poxvirus-specific C-terminal domain involved in the secretion of the protein [82]. EPTV-177 is truncated relative to the MYXV T2 homolog (326 aa), lacking the C-terminal domain, whereas HYPV-183 is further truncated and contains only two N-terminal CRDs. Similar truncations have been observed in some orthopoxvirus strains. Notably, a truncated MYXV T2 containing only two CRDs was unable to bind TNF but still inhibited apoptosis [82].
Another group of host range factors belongs to a family of poxviral proteins containing short consensus repeats (SCRs), also known as complement control protein modules, which are often involved in the regulation of the complement system. Most orthopoxviruses and centapoxviruses contain two SCR-encoding genes, called B5R (OPG 190) and C3L (OPG 32) in VACV [23]. B5R has four tandemly arranged SCRs and a C-terminal transmembrane domain (TM). It is expressed on the surface of the enveloped virion as a membrane glycoprotein and is essential for extracellular enveloped virus formation and actin tail-mediated virion repulsion [83,84]. C3L also contains four SCRs but lacks the TM domain. It is secreted and inhibits the complement system by interacting with C3b and C4b [85]. Clade II poxviruses typically encode a single B5R-like gene. In yatapoxviruses, leporipoxviruses, and deerpoxviruses, these proteins consist of three SCRs and a TM domain, whereas in capripoxviruses and suipoxviruses, they contain two SCRs and a TM domain [23]. Interestingly, both EPTV and HYPV encode two B5R-like proteins. EPTV-161 and HYPV-164 (237 aa and 235 aa, respectively) resemble the domain organization of B5R-like orthologs from capripoxviruses and suipoxviruses. On the other hand, the domain organization of EPTV-174 and HYPV-180 (263 aa and 260 aa, respectively) is more similar to that of VACV C3L, containing four SCRs and no TM domain. However, whether these proteins function similarly to C3L remains unknown. Phylogenetic and sequence analyses of the B5R-like protein family suggest that the two copies in orthopoxvirus originated through a duplication event early in the genus [23]. The presence of apparent C3L-like orthologs in vespertilionpoxviruses raises additional questions about their evolutionary history and warrants further investigation.

4. Conclusions

In this study, we analyzed the genomes of two bat-infecting poxviruses from the genus Vespertilionpoxvirus, identified previously unannotated ORFs, and conducted a comparative analysis of their gene content. We identified 24 previously unannotated ORFs in HYPV and three in EPTV, substantially expanding the number of ORFs encoded by their genomes. Comparative genomic analyses further revealed multiple gene duplication, deletion, and fragmentation events, especially in genes implicated in virulence and host range functions. These findings demonstrate that the genomes of vespertilionpoxviruses are more complex and dynamic than previously recognized and provide new insights into their genomic organization and evolutionary history. Some of these genomic changes may contribute to adaptation to their respective bat host.
Our results also highlighted the importance of thorough manual curation of poxvirus genomes to ensure accurate annotation. Although automated pipelines for poxvirus genome annotation are readily available [86], many poxvirus genes are highly divergent and subject to active adaptation during host–virus interactions. As a result, the assignment of homologous relationships should not solely rely on sequence identity but should integrate additional evidence, including genomic context (synteny), conserved domains, and structural similarity, taking advantage of the fast-developing protein structure prediction tools. This integrative approach is particularly important for identifying short ORFs and highly divergent genes that are often missed or misannotated by automated methods.
We also identified sequence variations in several host range genes in both HYPV and EPTV. These genes have been previously implicated in determining the range of host cells that poxviruses can infect and play a role in host tropism and viral adaptation [22,23,24]. Although no clear signs of positive selection were observed between HYPV and EPTV, the variation may reflect adaptation to specific bat hosts. Functional characterization of these genes will be important to determine how these genomic differences influence viral replication, immune evasion, and host specificity.
A major limitation in the study of bat poxviruses is the lack of well-established experimental systems. At present, most knowledge is derived from field observations, pathology reports, and full or partial genome sequences. The development of robust in vitro and in vivo models will be critical for validating the expression and functions of identified putative ORFs, understanding the biological significance of the genomic differences, and advancing our understanding of Vespertilionpoxvirus biology and zoonotic potential.

Author Contributions

Conceptualization, C.Z. and S.R.; methodology, C.Z., K.H., L.T. and S.R.; validation, D.L. and S.R.; formal analysis, C.Z., K.H., L.T. and S.R.; writing—original draft preparation, C.Z., L.T. and S.R.; writing—review and editing, C.Z., K.H., D.L., L.T. and S.R.; supervision, S.R.; funding acquisition, S.R. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by start-up funding from the University of California, Davis.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data necessary for the interpretation of the findings presented in this work are contained within the manuscript tables and figures.

Acknowledgments

We thank Priya S. Shah and Simon J. Anthony for helpful discussions.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
aaAmino acid(s)
dsDNADouble-stranded DNA
dN/dSratio of non-synonymous to synonymous nucleotide substitutions
dsRBDdsRNA-binding domain
EFCEntry-fusion complex
EREndoplasmic reticulum
ITRInverted terminal repeats
MVMature virion
OPGOrthopoxvirus gene
ORFOpen reading frame
PKRProtein kinase R
SCRShort consensus repeats
TMTransmembrane domain
TNFRTumor necrosis factor receptor

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Figure 1. HYPV genome organization. HYPV ORFs are shown as arrows indicating their transcription direction. Core genes involved in the basic replication of poxviruses are shown in red. ORFs whose encoded proteins are implicated in the interaction with the host immune system are shown in blue. Genes with undefined roles in the poxvirus life cycle are shown in purple. ORFs that were newly identified in this study are labeled with bold letters.
Figure 1. HYPV genome organization. HYPV ORFs are shown as arrows indicating their transcription direction. Core genes involved in the basic replication of poxviruses are shown in red. ORFs whose encoded proteins are implicated in the interaction with the host immune system are shown in blue. Genes with undefined roles in the poxvirus life cycle are shown in purple. ORFs that were newly identified in this study are labeled with bold letters.
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Figure 2. EPTV and HYPV orthologs of VACV WR018, a STAT1 inhibitor. (A) Sequence alignment of VACV WR018 orthologs in different poxviruses. Amino acids that are more than 50% conserved are highlighted in yellow, where the conservation is measured based on the number of conserved physicochemical properties for each column of the alignment. The stronger shadings indicate that residues are more conserved at the positions. (B) AlphaFold3 structural prediction of VACV, EPTV, and HYPV orthologs. N-termini are on the left. Colors represent the predicted Local Distance Difference Test (pLDDT) of the local regions. Dark blue—pLDDT > 90; light blue—90 > pLDDT > 70; yellow—70 > pLDDT > 50; red—pLDDT < 50.
Figure 2. EPTV and HYPV orthologs of VACV WR018, a STAT1 inhibitor. (A) Sequence alignment of VACV WR018 orthologs in different poxviruses. Amino acids that are more than 50% conserved are highlighted in yellow, where the conservation is measured based on the number of conserved physicochemical properties for each column of the alignment. The stronger shadings indicate that residues are more conserved at the positions. (B) AlphaFold3 structural prediction of VACV, EPTV, and HYPV orthologs. N-termini are on the left. Colors represent the predicted Local Distance Difference Test (pLDDT) of the local regions. Dark blue—pLDDT > 90; light blue—90 > pLDDT > 70; yellow—70 > pLDDT > 50; red—pLDDT < 50.
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Viruses 18 00706 g003
Figure 3. EPTV and HYPV F14.5 orthologs. (A) Sequence alignment of F14.5 orthologs in different poxviruses. The amino acids are colored using the Clustal X default coloring based on properties. Blue—hydrophobic; red—positive charge; purple—negative charge; green—polar; pink—cysteine; orange—glycine; yellow—proline; cyan—aromatic; white—non-conserved/gap. (B) AlphaFold3 structural prediction of VACV, EPTV, and HYPV F14.5 orthologs. The N-termini are at the bottom. Colors represent the predicted Local Distance Difference Test (pLDDT) of the local regions. Dark blue—pLDDT > 90; light blue—90 > pLDDT > 70; yellow—70 > pLDDT > 50; red—pLDDT < 50.
Figure 3. EPTV and HYPV F14.5 orthologs. (A) Sequence alignment of F14.5 orthologs in different poxviruses. The amino acids are colored using the Clustal X default coloring based on properties. Blue—hydrophobic; red—positive charge; purple—negative charge; green—polar; pink—cysteine; orange—glycine; yellow—proline; cyan—aromatic; white—non-conserved/gap. (B) AlphaFold3 structural prediction of VACV, EPTV, and HYPV F14.5 orthologs. The N-termini are at the bottom. Colors represent the predicted Local Distance Difference Test (pLDDT) of the local regions. Dark blue—pLDDT > 90; light blue—90 > pLDDT > 70; yellow—70 > pLDDT > 50; red—pLDDT < 50.
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Viruses 18 00706 g004
Figure 4. EPTV and HYPV O3 orthologs. (A) Sequence alignment of O3 orthologs from different poxviruses. Amino acids were colored using the Clustal X default coloring based on properties. Blue—hydrophobic; red—positive charge; purple—negative charge; green—polar; pink—cysteine; orange—glycine; yellow—proline; cyan—aromatic; white—unconserved/gap. Amino acid residues conserved in all sequences are denoted by asterisks. (B) Kyte/Doolittle hydropathy plots of VACV, EPTV, and HYPV O3 orthologs generated by ProtScale. (C) AlphaFold3 structural prediction of VACV, EPTV, and HYPV O3 orthologs. The N-termini are at the bottom. Colors represent the predicted Local Distance Difference Test (pLDDT) of the local regions. Dark blue—pLDDT > 90; light blue—90 > pLDDT > 70; yellow—70 > pLDDT > 50; red—pLDDT < 50.
Figure 4. EPTV and HYPV O3 orthologs. (A) Sequence alignment of O3 orthologs from different poxviruses. Amino acids were colored using the Clustal X default coloring based on properties. Blue—hydrophobic; red—positive charge; purple—negative charge; green—polar; pink—cysteine; orange—glycine; yellow—proline; cyan—aromatic; white—unconserved/gap. Amino acid residues conserved in all sequences are denoted by asterisks. (B) Kyte/Doolittle hydropathy plots of VACV, EPTV, and HYPV O3 orthologs generated by ProtScale. (C) AlphaFold3 structural prediction of VACV, EPTV, and HYPV O3 orthologs. The N-termini are at the bottom. Colors represent the predicted Local Distance Difference Test (pLDDT) of the local regions. Dark blue—pLDDT > 90; light blue—90 > pLDDT > 70; yellow—70 > pLDDT > 50; red—pLDDT < 50.
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Figure 5. Gene fragmentation in HYPV in comparison to EPTV. EPTV genes are shown in blue and fragmented HYPV genes are shown in orange. The direction of the arrow represent the direction of transcription.
Figure 5. Gene fragmentation in HYPV in comparison to EPTV. EPTV genes are shown in blue and fragmented HYPV genes are shown in orange. The direction of the arrow represent the direction of transcription.
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Figure 6. Gene duplications in HYPV. (A) A schematic representation of the genomic locations of the duplicated HYPV ORFs. The two sets of duplicated ORFs are shown in orange or purple. At the bottom are the percent aa identities of HYPV ORFs with their EPTV homologs. (B) Sequence alignment of EPTV-007 and its two HYPV homologs, HYPV-007 and HYPV-008. Amino acids that are 50% conserved are highlighted in yellow, where the conservation is measured based on the number of conserved physicochemical properties for each column of the alignment. The stronger shadings indicate the residues are more conserved at the positions. (C) Phylogenetic tree of MT4 homologs. The tree is midpoint-rooted, and bootstrap support of ≥50 is indicated above the branches. The EPTV and HYPV MT4 homologs are shown in bold. (D) Sequence alignment of EPTV-008 and its two HYPV homologs, HYPV-009 and HYPV-016, with the same highlight as in (B).
Figure 6. Gene duplications in HYPV. (A) A schematic representation of the genomic locations of the duplicated HYPV ORFs. The two sets of duplicated ORFs are shown in orange or purple. At the bottom are the percent aa identities of HYPV ORFs with their EPTV homologs. (B) Sequence alignment of EPTV-007 and its two HYPV homologs, HYPV-007 and HYPV-008. Amino acids that are 50% conserved are highlighted in yellow, where the conservation is measured based on the number of conserved physicochemical properties for each column of the alignment. The stronger shadings indicate the residues are more conserved at the positions. (C) Phylogenetic tree of MT4 homologs. The tree is midpoint-rooted, and bootstrap support of ≥50 is indicated above the branches. The EPTV and HYPV MT4 homologs are shown in bold. (D) Sequence alignment of EPTV-008 and its two HYPV homologs, HYPV-009 and HYPV-016, with the same highlight as in (B).
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Figure 7. Synteny conservation around the E3L homologs EPTV-037 (A) and EPTV-163 (B). The arrows on the horizontal line represent genes, with the direction corresponding to the transcription orientation. Homologous genes in different genomes are aligned vertically with the same color. E3L orthologs are highlighted in green. Genes without orthologs in the examined genomes are highlighted in white.
Figure 7. Synteny conservation around the E3L homologs EPTV-037 (A) and EPTV-163 (B). The arrows on the horizontal line represent genes, with the direction corresponding to the transcription orientation. Homologous genes in different genomes are aligned vertically with the same color. E3L orthologs are highlighted in green. Genes without orthologs in the examined genomes are highlighted in white.
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Viruses 18 00706 g008
Figure 8. Phylogenetic relationship between poxviral E3 homologs. The dsRBD regions of E3 homologs and crocodilepox virus 157, a distantly related dsRNA-binding protein [75], were aligned using MUSCLE and used for constructing the phylogenetic tree using PhyML. The tree was rooted to crocodilepox virus 157 and saltwater crocodilepox virus 198. Bootstrap support of ≥50 is indicated above the branches. The EPTV and HYPV E3 homologs are indicated in bold. The branches of clades were collapsed and shown as triangles for better clarity.
Figure 8. Phylogenetic relationship between poxviral E3 homologs. The dsRBD regions of E3 homologs and crocodilepox virus 157, a distantly related dsRNA-binding protein [75], were aligned using MUSCLE and used for constructing the phylogenetic tree using PhyML. The tree was rooted to crocodilepox virus 157 and saltwater crocodilepox virus 198. Bootstrap support of ≥50 is indicated above the branches. The EPTV and HYPV E3 homologs are indicated in bold. The branches of clades were collapsed and shown as triangles for better clarity.
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Table 1. Viruses used in the analysis and their genome accession number.
Table 1. Viruses used in the analysis and their genome accession number.
AbbreviationVirus NameAccession Number
BAVBeAn 58058 virusKY094066.1
BPSVBovine papular stomatitis virusAY386265.1
CNPVCanarypox virusAY318871.1
COTVCotia virusHQ647181.2
CPXVCowpox virusLT883663.1
DPVDeerpox virusAY689436.1
ECTVEctromelia virusNC_004105.1
EPTVEptesipox virusKY747497.1
FPVFowlpox virusAF198100.1
HYPVHypsugopox virusMK860688.1
MCVMolluscum contagiosum virusU60315.1
MPXVMonkeypox virusMT903340.1
MMPVMurmansk poxvirusMF001304.1
MYXVMyxoma virusAF170726.2
NY_014NY_014 poxvirusMF001305.1
PTPVPteropox virusKU980965.1
RAPVRaccoonpox virusKP143769.1
SOPVSea otterpox virusMH427217.1
SPPVSheeppox virusAY077832.1
SQPVSquirrelpox virusHE601899.1
BerSQPVSquirrelpox virus BerlinMF503315.1
SWPVSwinepox virusAF410153.1
VACVVaccinia virusAY243312.1
VARVVariola virusDQ441416.1
WKPVWestern grey kangaroopox virusMF467280.1
YMTVYaba monkey tumor virusAY386371.1
YKVYokapox virusHQ849551.1
Table 2. Updated HYPV genome annotation.
Table 2. Updated HYPV genome annotation.
HYPV
New HYPV ORF NameOld HYPV ORF NameORF
Position		aa LengthHomologous EPTV ORF 1% aa IdentityPutative Protein FunctiondN/dS RatioOPG 2
HYPV-001HYPV-1557-87157EPTV-00135.71Soluble IL-1β receptor, NF-kB signal inhibitor0.1202200
HYPV-002HYPV-21552-1037172EPTV-002 Serpin (SPI2) (host range), CrmA, anti-apoptosis (partial) 199
HYPV-003HYPV-32261-1581227EPTV-00369.47Bcl-2 domain, α-amanitin target protein, nuclear IRF3 inhibitor0.111836
HYPV-004HYPV-43316-2309336EPTV-00446.81IL-1 receptor-like protein0.1195
HYPV-005HYPV-53835-3356160EPTV-00575.95TLR-induced NF-κB pathway inhibitor0.0473
HYPV-006HYPV-64774-3872301EPTV-00676Tyrosine protein kinase-like protein0.0406
HYPV-007HYPV-75522-4842227EPTV-00748.23ER-localized apoptosis regulator (host range), retains MHC I in ER0.1436195
HYPV-008-6303-5620227EPTV-00742.79ER-localized apoptosis regulator (host range), retains MHC I in ER0.1325195
HYPV-009-6882-6373169EPTV-00831.65Hypothetical protein0.3381
HYPV-010HYPV-87481-7002159EPTV-00962.89Soluble IL-1β receptor, NF-kB signal inhibitor0.1522200
HYPV-011-7771-748495 Hypothetical protein
HYPV-012HYPV-99826-8141561EPTV-01042.24Ankyrin repeat-containing protein0.111223
HYPV-013-10,078-991753EPTV-010.5 *75.51STAT1 binding, type I IFN inhibitor0.109124
EPTV-011 Ankyrin repeat-containing protein
HYPV-014-10,421-10,13196EPTV-01240.62eIF2a-like PKR inhibitor (host range)0.159441
HYPV-015-10,992-10,465175EPTV-00830Hypothetical protein0.2229
EPTV-013 Ankyrin repeat-containing protein (partial)
HYPV-016HYPV-1011,913-11,053286EPTV-01488.3Monoglyceride lipase homolog0.020543
HYPV-017-12,336-12,03799SPPV-01233.67IL-18 binding protein
HYPV-018HYPV-1112,588-12,34082EPTV-01554.43Secreted EGF-like growth factor0.003519
HYPV-019HYPV-1213,100-12,594168EPTV-01647.27Anti-apoptotic factor, mitochondrial-associated (host range)0.114345
HYPV-020HYPV-1313,569-13,144141EPTV-01773.76dUTPase0.053146
HYPV-021HYPV-1414,004-13,597135EPTV-01869.4Pyrin-domain containing protein, inhibits inflammasome activation (host range)0.0716
HYPV-022HYPV-1515,034-14,060324EPTV-01988.54Ribonucleotide reductase small subunit0.018348
HYPV-023HYPV-1616,139-15,075354EPTV-02056.98Immunoglobulin domain, type I membrane protein0.077649
HYPV-024-16,361-16,16166EPTV-02134.85Hypothetical protein0.4167
HYPV-025-16,646-16,42573EPTV-02243.66Hypothetical protein0.176651
HYPV-026HYPV-1716,869-16,68760EPTV-02358.33Cytoplasmic protein, protein with iActA-like proline repeats0.067152
HYPV-027-17,327-16,941128EPTV-02449.58Hypothetical protein0.1281
HYPV-028HYPV-1818,008-17,361215EPTV-02580Entry-fusion complex (EFC) component, S-S bond formation pathway protein substrate0.042353
HYPV-029HYPV-1919,314-17,998438EPTV-02689.47Ser/Thr protein kinase0.022754
HYPV-030HYPV-2020,626-19,334430EPTV-02776.05RhoA-mDia signaling inhibitor0.036555
HYPV-031HYPV-2122,602-20,659647EPTV-02876.78EV maturation protein0.032356
HYPV-032HYPV-2223,755-22,640371EPTV-02995.69Palmitoylated enveloped virion membrane glycoprotein, phospholipase D-like0.006757
HYPV-033HYPV-2324,008-23,78175EPTV-03045.33NF-κB activation inhibitor0.23458
HYPV-034HYPV-2424,250-24,05066EPTV-03192.42Hypothetical protein0.0249
HYPV-035-24,414-24,25353EPTV-031.5 *47.17MV membrane protein, cell adhesion0.247259
HYPV-036HYPV-2524,917-24,471148EPTV-03280.41Hypothetical protein0.056760
HYPV-037HYPV-2625,654-24,992220EPTV-03367.27Non-functional serine recombinase0.125161
HYPV-038HYPV-2725,714-26,052112EPTV-03482.69DNA-binding phosphoprotein (VP11)0.040462
HYPV-039HYPV-2827,461-26,046471EPTV-03584.71Poly (A) polymerase catalytic subunit (VP55)0.026563
HYPV-040HYPV-2929,676-27,478732EPTV-03683.47EV formation, virus spread0.042964
EPTV-037 Z-DNA binding domain, dsRNA-binding, PKR inhibitor (host range) 65
HYPV-041HYPV-3030,455-29,733240EPTV-03886.25RNA polymerase 30 kDa subunit (RPO30)0.022266
HYPV-042HYPV-3130,760-32,463567EPTV-03988.54MV core protein, virion morphogenesis0.026868
HYPV-043HYPV-3232,490-33,302270EPTV-04091.48ER-localized membrane protein, virion core protein0.025770
HYPV-044HYPV-3336,319-33,2991006EPTV-04186.88DNA polymerase, catalytic subunit0.015671
HYPV-045HYPV-3436,352-36,64296EPTV-04287.5Sulfhydryl oxidase (FAD-linked), S-S bond formation pathway, virion protein0.024872
HYPV-046HYPV-3537,055-36,645136EPTV-04380.88MV core protein0.032673
HYPV-047HYPV-3639,117-37,039692EPTV-04481.91Virulence, membrane protein, activates of ERK1/2 signaling pathway0.023774
HYPV-048HYPV-3739,487-39,173104EPTV-04582.69Glutaredoxin, ribonucleotide reductase cofactor0.040475
HYPV-049-39,597-39,50530EPTV-045.5 *76.67MV membrane, Entry/fusion complex component0.057976
HYPV-050HYPV-3840,545-39,613310EPTV-04682.58DNA-binding core protein, virosomal protein, winged HTH domain0.027777
HYPV-051HYPV-3940,767-40,54673EPTV-04776.71MV membrane protein required for morphogenesis and entry0.090578
HYPV-052HYPV-4041,577-40,768269EPTV-04877.82ssDNA-binding phosphoprotein0.0479
HYPV-053HYPV-4143,925-41,640761EPTV-04986.58Ribonucleotide reductase large subunit0.017180
HYPV-054HYPV-4244,202-43,96678EPTV-05075.64MV protein (VP13)0.050881
HYPV-055HYPV-4345,371-44,220383EPTV-05176.9Telomere binding protein, DNA packaging0.032182
HYPV-056HYPV-4446,650-45,364428EPTV-05280.84Virion core cysteine protease, required for morphogenesis0.026583
HYPV-057HYPV-4546,656-48,686676EPTV-05385.8Core DNA/RNA-dependent NTPase (NPH-II), DNA and RNA helicase0.018484
HYPV-058HYPV-4650,465-48,678595EPTV-05483.87Metalloprotease-like protein0.021385
HYPV-059HYPV-4750,794-50,462110EPTV-05590MV membrane, Entry/fusion complex component0.090986
HYPV-060HYPV-4850,788-51,456222EPTV-05677.48Late transcription elongation factor (VLTF)0.048487
HYPV-061HYPV-4951,800-51,423125EPTV-05768Glutaredoxin S-S bond formation pathway; thioredoxin-like0.146988
HYPV-062HYPV-5051,803-53,140445EPTV-05876.71Fen-1-like nuclease, DNA repair and recombination0.03789
HYPV-063HYPV-5153,142-53,33363EPTV-05988.89RNA polymerase subunit (RPO7)0.047390
HYPV-064HYPV-5253,337-53,870177EPTV-06079.1NLPc/P60 superfamily protein, predicted hydrolase0.027791
HYPV-065HYPV-5354,933-53,836365EPTV-06179.06Virion phosphoprotein, early morphogenesis0.0392
HYPV-066HYPV-5454,962-55,744260EPTV-06296.54Viral late transcription factor 1 (VLTF-1), PCNA homolog0.006293
HYPV-067HYPV-5555,760-56,782340EPTV-06383.24MV membrane, myristylated entry/fusion complex component0.030594
HYPV-068HYPV-5656,783-57,532249EPTV-06489.16MV membrane, myristylated entry/fusion complex component0.015295
HYPV-069HYPV-5757,558-57,83391EPTV-06568.54crescent membrane, viral membrane assembly proteins0.08196
HYPV-070HYPV-5858,790-57,825321EPTV-06684.69Internal virion protein, required for early transcription by cores0.028397
HYPV-071HYPV-5958,815-59,573252EPTV-06793.25DNA-binding core transcription protein (VP8), early mRNA regulation0.018698
HYPV-072HYPV-6059,588-59,992134EPTV-06882.84MV membrane, entry/fusion complex component0.135899
HYPV-073HYPV-6159,934-60,380148EPTV-06986.49Virion membrane protein, early stage morphogenesis0.0918100
HYPV-074HYPV-6260,402-60,932176EPTV-07080.68Thymidine kinase0.0306101
HYPV-075HYPV-6361,026-61,625199EPTV-07160.41Type I IFN inhibitor (host range), antagonist of SAMD9, and SAMD9L0.002627
HYPV-076HYPV-6461,692-62,693333EPTV-07287.39Poly (A) polymerase small subunit (VP39), cap methyltransferase0.0554102
HYPV-077HYPV-6562,608-63,165185EPTV-07386.49RNA polymerase subunit (RPO22) 0.0306103
HYPV-078HYPV-6663,580-63,170136EPTV-07481.48MV membrane, entry/fusion complex component0.0332104
HYPV-079HYPV-6763,688-67,5451285EPTV-07594.32RNA polymerase subunit (RPO147) 0.0063105
HYPV-080HYPV-6868,060-67,542172EPTV-07690.7Tyr/Ser phosphatase, IFN-γ inhibitor, dephosphorylates STAT10.0174106
HYPV-081HYPV-6968,074-68,646190EPTV-07792.63MV membrane, entry/fusion complex component0.023107
HYPV-082HYPV-7069,667-68,654337EPTV-07879.46MV heparin bind surface protein0.0197108
HYPV-083HYPV-7172,058-69,671795EPTV-07992.45RNA polymerase-associated protein (RAP94), early transcription0.0173109
HYPV-084HYPV-7272,228-72,872214EPTV-08061.95Late transcription factor 4 (VTLF-4), multifunctional protein0.0792110
HYPV-085HYPV-7372,894-73,829311EPTV-08183.6DNA topoisomerase type I0.0538111
HYPV-086HYPV-7473,868-74,314148EPTV-08277.03Crescent membrane and IV formation0.0701112
HYPV-087HYPV-7574,355-76,889844EPTV-08387.91mRNA capping enzyme large subunit, transcription termination factor0.0146113
HYPV-088HYPV-7677,288-76,851145EPTV-08477.93Virion core protein, early stage morphogenesis0.0974114
HYPV-089HYPV-7777,287-78,030247EPTV-08568.02Virion core protein, early stage morphogenesis0.1698115
HYPV-090HYPV-7878,027-78,683218EPTV-08691.28Uracil DNA glycosylase, DNA pol processivity factor0.0222116
HYPV-091HYPV-7978,717-81,080787EPTV-08791.11NTPase, DNA primase, and nucleic acid-independent nucleoside triphosphatase0.0115117
HYPV-092HYPV-8081,077-82,984635EPTV-08896.69Early transcription factor small subunit (VETF-s), ATPase, predicted helicase0.0046118
HYPV-093HYPV-8183,017-83,532171EPTV-08978.82RNA polymerase subunit (RPO18)0.0384119
HYPV-094HYPV-8284,339-83,464291EPTV-09068.86Carbonic anhydrase, GAG-binding MV membrane protein0.0928120
HYPV-095HYPV-8384,397-85,068223EPTV-09176.02mRNA decapping enzyme0.0428121
HYPV-096HYPV-8485,043-85,822259EPTV-09284.5mRNA decapping enzyme, mitochondrial0.0291122
HYPV-097HYPV-8587,703-85,796635EPTV-09394.17DNA-dependent ATPase (NPH-I), transcription termination0.008123
HYPV-098HYPV-8688,609-87,746287EPTV-09489.55mRNA capping enzyme small subunit, transcription initiation factor0.0154124
HYPV-099HYPV-8790,295-88,643550EPTV-09590.91Trimeric virion coat protein (rifampicin resistance)0.0114125
HYPV-100HYPV-8890,776-90,321151EPTV-09682.78Late transcription factor (VLTF-2)0.0282126
HYPV-101HYPV-8991,479-90,805224EPTV-09795.98Late transcription factor (VLTF-3)0.0058127
HYPV-102HYPV-9091,706-91,47676EPTV-09889.47Virion protein, S-S bond formation pathway0.067128
HYPV-103HYPV-9193,726-91,726666EPTV-09983.81Precursor of major core protein 4b (p4b), morphogenesis0.0228129
HYPV-104-94,424-93,780214EPTV-10042.62Membrane-associated virion core protein (p39), morphogenesis0.1317130
HYPV-105HYPV-9294,462-94,992176EPTV-10179.88RNA polymerase subunit (RPO19)0.0299131
HYPV-106HYPV-9396,107-94,989372EPTV-10285.75Crescent membrane and IV formation, VMAP0.0217132
HYPV-107HYPV-9498,275-96,131714EPTV-10391.88Early transcription factor large subunit (VETF-L)0.0135133
HYPV-108HYPV-9598,338-99,213291EPTV-10486.6Intermediate transcription factor small subunit (VITF-3s)0.0205134
HYPV-109HYPV-9699,459-99,22378EPTV-10587.18MV membrane, early morphogenesis 0.0461135
HYPV-110HYPV-97102,192-99,460910EPTV-10676.87Precursor of major core protein 4a (p4a), morphogenesis0.0297136
HYPV-111HYPV-98102,207-103,142311EPTV-10791Crescent membrane and IV formation, VMAP0.0136137
HYPV-112HYPV-99103,705-103,139188EPTV-10869.82Virion core protein, morphogenesis0.0651138
HYPV-113HYPV-100104,002-103,139287EPTV-10962.12MV membrane phosphoprotein, morphogenesis0.05139
HYPV-114HYPV-101104,348-104,06793EPTV-11090.32MV membrane phosphoprotein, morphogenesis, essential0.0206140
HYPV-115HYPV-102104,526-104,36553EPTV-11194.34MV membrane, virulence factor, non-essential0.0521141
HYPV-116HYPV-103104,809-104,51697EPTV-11285.57Virion core protein, early stage morphogenesis0.1194142
HYPV-117HYPV-104105,935-104,793380EPTV-11381.05MV membrane, myristylated entry/fusion complex component0.0283143
HYPV-118HYPV-105106,526-105,936196EPTV-11489.74MV membrane phosphoprotein, required for morphogenesis0.01144
HYPV-119HYPV-106106,541-107,995484EPTV-11582.22DNA-dependent ATPase, DNA helicase0.0531145
HYPV-120HYPV-107108,188-107,96773EPTV-11680.56Zinc finger-like protein, involved in IV maturation to MV0.0009146
HYPV-121HYPV-108108,533-108,189114EPTV-11790.35MV membrane, entry/fusion complex component0.0234147
HYPV-122HYPV-109108,532-109,809425EPTV-11876.71DNA polymerase processivity factor, DNA replication0.0625148
HYPV-123HYPV-110109,793-110,338181EPTV-11985.64Holliday junction resolvase0.0337149
HYPV-124HYPV-111110,335-111,495386EPTV-12081.35Intermediate transcription factor large subunit (VITF-3L)0.052150
HYPV-125HYPV-112111,492-115,0101172EPTV-12195.11RNA polymerase subunit (RPO132)0.0062151
HYPV-126 #HYPV-113117,881-114,996961EPTV-12268.34A-type inclusion body protein0.0461152
HYPV-127HYPV-114119,800-117,926624EPTV-12371.45A-type inclusion protein, p4c precursor0.0434153
HYPV-128HYPV-115120,206-119,856116EPTV-12474.56MV membrane fusion protein, required for MV wrapping0.0523154
HYPV-129HYPV-116120,623-120,207138EPTV-12587.68MV membrane, entry/fusion complex component0.0243155
HYPV-130HYPV-117121,539-120,637300EPTV-12685.33RNA polymerase subunit (RPO35)0.0334156
HYPV-131HYPV-118121,750-121,52375EPTV-12784MV phosphoprotein, early stage morphogenesis0.1467157
HYPV-132HYPV-119121,953-122,435160EPTV-12869.81Hypothetical protein0.0562159
HYPV-133HYPV-120123,235-122,465256EPTV-12989.37ATPase/DNA packaging protein0.0274160
HYPV-134HYPV-121123,371-123,922183EPTV-13065.57EV membrane phosphoglycoprotein, actin tail formation, C-type lectin-like domain0.0715161
HYPV-135HYPV-122123,970-124,470166EPTV-13181.93EV membrane glycoprotein, actin tail formation, C-type lectin-like domain0.0516162
HYPV-136HYPV-123124,509-125,033174EPTV-13268.6MHC class II antigen presentation inhibitor, actin tail formation0.1094163
HYPV-137HYPV-124125,073-125,918281EPTV-13361.07Concanavalin-like precursor0.0697
HYPV-138HYPV-125125,953-126,681242EPTV-13454.08EEV glycoprotein0.0937
HYPV-139HYPV-126126,724-127,554 276EPTV-13558.91Hypothetical protein0.0978165
HYPV-140HYPV-127127,578-127,81779EPTV-13660.26Hypothetical protein0.0026
HYPV-141HYPV-128128,404-127,814196EPTV-13763.92CD47-like, integral membrane protein, regulation of Ca2+ influx (partial)0.2027167
HYPV-142HYPV-129128,422-128,829135EPTV-13856.06Myristoylated protein0.26669
HYPV-143HYPV-130128,826-129,587253EPTV-13962.4Hypothetical protein0.1396
HYPV-144HYPV-131130,438-129,575287EPTV-14051.06Chemokine-binding protein, interferes with chemokine-GAG interaction0.1061170
HYPV-145HYPV-132130,558-130,959133EPTV-14193.98Profilin-like protein, ATI-localized0.0109171
HYPV-146HYPV-133131,339-130,956127EPTV-14263.2Hypothetical protein0.0876
EPTV-143 Hypothetical protein
HYPV-147-131,608-131,89595 Hypothetical protein
HYPV-148HYPV-134131,948-133,015355EPTV-14470.373 β-hydroxysteroid dehydrogenase/δ 5 → 4 isomerase0.0537174
EPTV-145 Hypothetical protein
HYPV-149-133,582-133,37369EPTV-146 Gasdermin homolog, pyroptosis inhibitor, immunoprevalent (partial) 177
HYPV-150HYPV-135133,646-134,233195EPTV-14772.68Thymidylate kinase0.0498178
HYPV-151HYPV-136134,265-135,944559EPTV-14875.85ATP-dependent DNA ligase0.0328180
HYPV-152-135,990-136,703237EPTV-149 BTB kelch-domain protein, NF-κB activation inhibitor (partial) 184
HYPV-153HYPV-137137,441-138,046201EPTV-15066.67Bcl-2 domain, blocks IFN-β promoter induction, interact with DDX30.068144
HYPV-154-138,094-138,441115EPTV-15153.91Hypothetical protein0.2055
HYPV-155HYPV-138138,641-139,717358EPTV-15245.48Stabilizing microtubules, negatively regulating microtubule-dependent transport0.1061181
HYPV-156HYPV-139139,781-140,428215EPTV-15376.28TLR-induced NF-κB pathway inhibitor0.0396182
HYPV-157HYPV-140140,954-140,538138EPTV-15456.2Hypothetical protein0.141
HYPV-158HYPV-141141,056-142,690544EPTV-15560.45BTB kelch-domain protein, NF-κB activation inhibitor0.0623184
HYPV-159HYPV-142142,737-143,477246EPTV-15655.28EV membrane, hemagglutinin0.1577185
HYPV-160HYPV-143143,532-144,467311EPTV-15783.92Ser/Thr protein kinase, essential for viral DNA replication0.0248187
HYPV-161HYPV-144144,505-145,470321EPTV-15857.5IL-1 receptor antagonist, virulence factor0.195720
HYPV-162HYPV-145145,503-146,378291EPTV-15953.36KilA-N/RING finger protein (host range), E3 ubiquitin ligase, apoptosis inhibition0.204121
HYPV-163HYPV-146146,424-147,011195EPTV-16066.15Poxin, 2′-3′-cGAMP nuclease, blocks DNA sensing and IFN induction0.0626188a
HYPV-164HYPV-147147,108-147,815235EPTV-16162.39EV type-1 membrane glycoprotein (host range), WV formation0.0707190
HYPV-165HYPV-148147,851-148,294 147EPTV-16259.44Anti-apoptotic Bcl-2-like protein, inhibits NF-κB and IRF3 activation0.095235
HYPV-166-148,323-148,751142MYXV-m135R26.09transmembrane virulence factor
HYPV-167-148,753-149,505250EPTV-16344.58Z-DNA binding domain, dsRNA-binding, PKR inhibitor (host range)0.134565
HYPV-168HYPV-149149,551-150,555334EPTV-16458.68Serpin (SPI1) (host range), apoptosis inhibitor0.0753208
HYPV-169HYPV-150150,662-151,132156EPTV-16557.62Soluble IL-1β receptor, NF-kB signal inhibitor0.0978200
HYPV-170HYPV-151151,173-152,036287EPTV-16659.79Tyrosine protein kinase-like protein0.0752
HYPV-171HYPV-152152,065-153,093342EPTV-16755.82IL-1 receptor-like protein0.0827201
HYPV-172HYPV-153153,125-155,104659EPTV-16850.62Ankyrin repeat-containing protein0.083
HYPV-173-155,154-157,172672EPTV-18225.69Ankyrin repeat-containing protein 23
HYPV-174 #HYPV-154157,231-157,827198EPTV-16947.98Ankyrin repeat-containing protein0.2267
HYPV-175-157,902-158,273123 Hypothetical protein
HYPV-176HYPV-155158,306-159,013235EPTV-17068.24Bcl-2 domain, α-amanitin target protein, nuclear IRF3 inhibitor0.100236
HYPV-177HYPV-156159,072-159,752226EPTV-17165.33NF-κB inhibitor, blocks CD28-mediated T cell activation0.070938
HYPV-178HYPV-157159,796-160,02074EPTV-17251.35Endothelin precursor0.0035
HYPV-179HYPV-158160,059-160,712217EPTV-17352.83NF-κB inhibitor, blocks CD28-mediated T cell activation0.003338
HYPV-180HYPV-159160,747-161,529260EPTV-17459.46Secreted complement-binding protein (host range)0.080932
HYPV-181-161,564-162,049161SWPV-00931.08LAP/PHD finger-like protein
HYPV-182HYPV-160162,096-162,521141EPTV-17566.43IL-18 binding protein 0.1212
EPTV-176 Hypothetical protein
HYPV-183-162,582-162,977131EPTV-17739.84TNF receptor homolog (host range), CrmB (partial)0.17732
EPTV-178 MHC class I-like protein
HYPV-184-163,038-163,24167EPTV-182 Ankyrin repeat-containing protein, CP77 protein (host range) (partial) 23
HYPV-185HYPV-161164,706-166,571621EPTV-17941.2Ankyrin repeat-containing protein0.112
EPTV-180 eIF2a-like PKR inhibitor (host range) 41
EPTV-181 Ankyrin repeat-containing protein
EPTV181.5 * STAT1 binding, type I IFN inhibitor 24
EPTV-182 Ankyrin repeat-containing protein 23
EPTV-183 Soluble IL-1β receptor, NF-kB signal inhibitor 200
EPTV-184 Hypothetical protein
EPTV-185 ER-localized apoptosis regulator, retains MHC I in ER 195
EPTV-186 Tyrosine protein kinase-like protein
EPTV-187 TLR-induced NF-κB pathway inhibitor
EPTV-188 IL-1 receptor-like protein
EPTV-189 Bcl-2 domain, α-amanitin target protein, nuclear IRF3 inhibitor 36
EPTV-190 Serpin (SPI2), CrmA, anti-apoptosis 199
EPTV-191 Soluble IL-1β receptor, NF-kB signal inhibitor 200
Empty cells: no orthologs at the position. EPTV genes in the ITR regions are bolded. 1 If no homologous genes are found in EPTV, their closest homologs from other poxviruses are indicated. 2 OPG numbers according to reference [17]. # Gene starting/ending position different from original annotation. * newly identified genes in EPTV.
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Zhang, C.; Heye, K.; Lelli, D.; Tazi, L.; Rothenburg, S. Comparative Genomic Analysis of Two Bat Poxviruses in the Genus Vespertilionpoxvirus. Viruses 2026, 18, 706. https://doi.org/10.3390/v18070706

AMA Style

Zhang C, Heye K, Lelli D, Tazi L, Rothenburg S. Comparative Genomic Analysis of Two Bat Poxviruses in the Genus Vespertilionpoxvirus. Viruses. 2026; 18(7):706. https://doi.org/10.3390/v18070706

Chicago/Turabian Style

Zhang, Chi, Kyle Heye, Davide Lelli, Loubna Tazi, and Stefan Rothenburg. 2026. "Comparative Genomic Analysis of Two Bat Poxviruses in the Genus Vespertilionpoxvirus" Viruses 18, no. 7: 706. https://doi.org/10.3390/v18070706

APA Style

Zhang, C., Heye, K., Lelli, D., Tazi, L., & Rothenburg, S. (2026). Comparative Genomic Analysis of Two Bat Poxviruses in the Genus Vespertilionpoxvirus. Viruses, 18(7), 706. https://doi.org/10.3390/v18070706

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