Biology subjects

Enow, J. A.

Publications and source records attributed to Enow, J. A..

4 recordsLinked to original sources

bioRxiv2026

Atypical myxomatosis in European rabbits is caused by the recombinant myxoma virus involved in species jumping into hares

Myxoma virus (MYXV), a member of the Leporipoxvirus genus (species Leporipoxvirus myxoma; family Poxviridae), causes a highly lethal disease known as myxomatosis in European rabbits. In late 2018, a new natural MYXV isolate, MYXV-Tol (a.k.a. hare MYXV; ha-MYXV), emerged and caused myxomatosis-like disease with high mortality in Iberian hares, European brown hares, and European rabbits. This variant contains an approximately 2.8-kb insertion of a recombination cassette within the M009L gene encoding four additional genes, including the C7-like host range gene, M159L. M159 is essential for replication of MYXV-Tol in hare cells and is likely a key determinant of its pathogenicity in both hares and rabbits. Here, we compared the pathogenicity of wild-type MYXV-Tol (vMyx-Tol), an M159 deletion strain (vMyx-Tol-M159KO), and the classical MYXV-Lau strain (vMyx-Lau) in European rabbits. All three viruses caused systemic disease; however, vMyx-Tol and vMyx-Tol-M159KO produced clinical signs distinct from classical myxomatosis. Infection with vMyx-Tol and vMyx-Tol-M159KO was characterized by the absence of the typical primary and secondary nodular lesions, and caused severe edema, marked fluid accumulation, lymphocyte infection, and significantly reduced or no virus-neutralizing antibody responses. The disease caused by both vMyx-Tol and vMyx-Tol-M159KO progressed rapidly within 9-11 days, resulting in animals reaching humane euthanasia endpoints like vMyx-Lau. Deletion of M159 did not significantly alter MYXV-Tol pathogenicity in rabbits. Collectively, these findings demonstrate that MYXV-Tol has evolved to cause an atypical, amyxomatous-like acute to hyperacute disease in European rabbits and likely in hares. SignificanceNatural evolution enables viruses to cross species barriers and adapt to new hosts. Myxoma virus (MYXV), released in the 1950s in Australia and Europe as a biocontrol agent against European rabbits, became a classic model for real-time monitoring of virus evolution, virulence, and host adaptation. Although MYXV is typically host-restricted, a newly emerged natural isolate, MYXV-Tol, causes lethal disease in both hares and rabbits. Here, we show that MYXV-Tol induces an atypical, amyxomatous-like disease characterized by the absence of nodular lesions, severe edema, lymphocyte infection, and markedly reduced virus-neutralizing antibody responses. These findings reveal previously unrecognized virus-host interactions that shape disease outcome and provide new insight into the mechanisms driving viral adaptation and evolution.

microbiology↗

bioRxiv2025

Evolutionary Variation of Poxvirus Genome Architecture

Poxviruses (PXV) are large double-stranded DNA viruses (dsDNA) that infect and cause disease in a wide variety of hosts, including humans.. They are studied as models to understand host-specific disease and they have a wide variety of applications in biotechnology, including vaccines, oncolytic virotherapy, and immunotherapy. Despite a nearly fourfold variation in genome sizes across the Poxviridae family, the basic genome architectural features driving their evolution remain poorly understood. In this study of the summated poxvirus genome sequence database, we report that while only a weak negative correlation exist between viral coding densities and genome sizes, we detected a strong positive correlation between the number of assigned open reading frames (ORF) and genome sizes. We observe an inflection point at a genome size of 229 kb, above or below with the percentage of genes encoding secreted proteins increasing with genome size, and the percentage of predicted cytoplasmic proteins decreasing with genome size. Additionally, we observed a weak positive correlation between the potential of transcript overlap that would be expected to generate dsRNA and genome size. Unexpectedly, we observed a significant positive correlation between coding density and GC-content in mpox virus isolates (R2 = 0.799). Further analysis illustrated a rise in both GC-content and coding density of mpox isolates between 2022 and 2024. Codon usage bias was observed to be clustered by virus families, with tryptophan being the least utilized amino acid across all poxviruses. Protein distribution analysis revealed a right-skewed distribution of poxviral predicted ORFs, with the 150 - 250 amino acid cohort containing the highest number of viral proteins. Finally, we observe a significant positive correlation between ITR sizes and duplicate gene clusters (R2 = 0.679). Together, these architectural findings outline the constraints and adaptive pathways governing poxviral evolution and biology. ImportanceThis study establishes a family genome design rulebook for poxviruses and illustrates how these rules might be linked with their biology and evolution. We demonstrate that genome growth is accompanied by a modest increase in noncoding DNA and an increase in extracellular proteome investment. We further demonstrate that ITR expansions correlate with duplicate gene clusters, rather than genome size, indicating that ITRs serve as hubs of innovation. Our results provide a standard for generating hypotheses and experiments with poxviruses. This work also introduces matrices for within-family viral comparisons.

microbiology↗

bioRxiv2024

Divergence in poxvirus-encoded E3-like proteins can dictate poxvirus activation of cellular necroptosis

Poxviruses encode a plethora of proteins to modulate diverse cellular responses against viruses. Poxvirus-encoded E3-like proteins are multifunctional, regulating diverse cellular antiviral responses. The canonical Vaccinia E3-like proteins have two domains: an N-terminal Z-form nucleic acid binding domain (Z-BD) and a C-terminal double-stranded RNA binding domain (dsRNA-BD)-.Using protein sequence and structural homology modeling, we identified the presence of dsRNA- BD-containing proteins in all the poxviruses except Avipoxviruses, Salmon poxvirus and Entemopoxviruses. However, the acquisition of these proteins likely happened under three distinct events. Using structural homology modeling and FATCAT score, we can classify E3-like proteins in three distinct categories: i) the E3-like proteins with highly conserved dsRNA-BD but with or without the N-terminal domain, present in most poxviruses; ii) unconventional E3-like proteins with highly diverged dsRNA-BD, present in Macropoxvirus and Molluscipoxvirus and iii) E3-like protein with dsRNA-BD that may have different origin present in Crocodilepoxvirus.12-52-6 Members of Leporipoxvirus, Waddenpoxvirus, Cetaceanpoxvirus, and selected members of Orthopoxvirus contain E3-like proteins missing the N-terminal Z-BD required for necroptosis inhibition. Additionally, using Alphafold, we show that the Z-BD of Chordopoxviruses E3-like proteins is structurally more variable than the ds-RNA binding domain. Compared to members of Orthopoxviruses-Vaccinia virus (VACV) and Cowpox virus (CPXV) that have been shown to inhibit necroptosis and contain an N-terminus Z-BD of the canonical E3 protein, our results show that members of leporipoxviruses induce necroptosis in human and mouse necroptosis competent cell lines. Furthermore, myxoma virus (MYXV) infection activates RIP1 and RIP3-mediated necroptosis in both human and mouse necroptosis-competent cells. These data suggest that Leporipoxviruses lack countermeasures to necroptosis compared to Orthopoxviruses that encode multiple key regulators of necroptosis, possibly due to a lack of selective pressure within the viral host species (Lagomorphs). Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/627069v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@132ce9borg.highwire.dtl.DTLVardef@9a459borg.highwire.dtl.DTLVardef@4fc88dorg.highwire.dtl.DTLVardef@1f7ac6c_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

A novel anti-cancer therapy with nuclear export inhibitor Selinexor in combination with oncolytic myxoma virus

Oncolytic viruses exploited for cancer therapy are developed to selectively infect, replicate, and kill cancer cells to stop tumor growth. However, in some cancer cells, oncolytic viruses are often limited in completing their full replication cycle, making progeny virions, and/or spread in the tumor bed due to the heterogeneous cell types within the tumor bed. Here we report that nuclear export pathway regulates oncolytic myxoma virus (MYXV) infection and cytoplasmic viral replication in a subclass of human cancer cell types where virus replication is restricted. Inhibition of CRM1/XPO-1 nuclear export pathway with nuclear export inhibitors can overcome this restriction by trapping restriction factors in the nucleus and allow significantly enhanced virus replication and killing of human cancer cells. Furthermore, knockdown of CRM1/XPO-1 significantly enhanced MYXV replication in restrictive human cancer cells and reduced the formation of anti-viral granules associated with RNA helicase DHX9. Both in vitro and in vivo, we demonstrate that the approved CRM1 inhibitor drug Selinexor enhances the replication of MYXV and cell killing of diverse human cancer cells. In the xenograft tumor model in NSG mice, combination therapy with Selinexor plus MYXV significantly reduced tumor burden and enhanced the survival of animals. Additionally, we performed global scale proteomic analysis of nuclear and cytosolic proteins in human cancer cells to identify the host and viral proteins that are upregulated or downregulated by different treatments. These results for the first time indicate that Selinexor in combination with oncolytic MYXV can be used as potential new anti-cancer therapy

microbiology↗