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There are no FDA-approved antiviral agents to treat infection with variola virus, the cause of smallpox. In this report, the efficacy of tecovirimat, a new antiviral agent, is shown in monkey and rabbit models, with supporting human pharmacokinetic data.

Host restriction factors constitute a formidable barrier for viral replication to which many viruses have evolved counter-measures. Human SAMD9, a tumor suppressor and a restriction factor for poxviruses in cell lines, is antagonized by two classes of poxvirus proteins, represented by vaccinia virus (VACV) K1 and C7. A paralog of SAMD9, SAMD9L, is also encoded by some mammals, while only one of two paralogs is retained by others. Here, we show that SAMD9L functions similarly to SAMD9 as a restriction factor and that the two paralogs form a critical host barrier that poxviruses must overcome to establish infection. In mice, which naturally lack SAMD9, overcoming SAMD9L restriction with viral inhibitors is essential for poxvirus replication and pathogenesis. While a VACV deleted of both K1 and C7 (vK1L-C7L-) was restricted by mouse cells and highly attenuated in mice, its replication and virulence were completely restored in SAMD9L-/- mice. In humans, both SAMD9 and SAMD9L are poxvirus restriction factors, although the latter requires interferon induction in many cell types. While knockout of SAMD9 with Crispr-Cas9 was sufficient for abolishing the restriction for vK1L-C7L- in many human cells, knockout of both paralogs was required for abolishing the restriction in interferon-treated cells. Both paralogs are antagonized by VACV K1, C7 and C7 homologs from diverse mammalian poxviruses, but mouse SAMD9L is resistant to the C7 homolog encoded by a group of poxviruses with a narrow host range in ruminants, indicating that host species-specific difference in SAMD9/SAMD9L genes serves as a barrier for cross-species poxvirus transmission.

Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during infection antagonize cellular apoptotic pathways. Poxvirus products target multiple points in both the extrinsic and intrinsic apoptotic pathways, thereby mitigating apoptosis during infection. Interestingly, recent evidence indicates that poxviruses also hijack cellular means of eliminating apoptotic bodies as a means to spread cell to cell through a process called apoptotic mimicry. Poxviruses are the causative agent of many human and veterinary diseases. Further, there is substantial interest in developing these viruses as vectors for a variety of uses including vaccine delivery and as oncolytic viruses to treat certain human cancers. Therefore, an understanding of the molecular mechanisms through which poxviruses regulate the cellular apoptotic pathways remains a top research priority. In this review, we consider anti-apoptotic strategies of poxviruses focusing on three relevant poxvirus genera: Orthopoxvirus, Molluscipoxvirus, and Leporipoxvirus. All three genera express multiple products to inhibit both extrinsic and intrinsic apoptotic pathways with many of these products required for virulence.

Background Poxviruses are a diverse group of pathogens with significant implications for both human and animal health. Ticks, as hematophagous arthropods, are capable of switching hosts during their life cycle. Although previous research has suggested the potential for parapoxviral transmission via ticks, the poxviral transmission dynamics remain poorly understood, particularly regarding the role of ticks as vectors. Methods Tick samples were collected from western China, followed by metagenomic sequencing. The diversity of potential blood-feeding hosts and the prevalence of poxviruses were assessed using BWA. Poxviral sequences were assembled using MetaSPAdes and TGICL, and phylogenetic analysis was conducted to examine the origin of prevalent poxviruses and the unblasted poxviral fragments in ticks. Results A total of 61 poxvirus species across 22 genera were identified, with 387 distinct poxviral sequences assembled. Of these, viral and host abundance were relatively higher in Tibet than in samples from Shaanxi and Gansu. Notably, unblasted gene fragments were identified within the assembled poxviral genomes, originating from a broad range of hosts, including mammals (e.g., rodents), fish, and arthropods. Phylogenetic analysis of the parapoxviruses revealed ongoing mutations, particularly in the Parapoxvirus orf , suggesting an increase in adaptability and potential pathogenicity. The results indicate that environmental factors such as altitude, host availability and host sensitivity may significantly shape viral diversity and transmission dynamics. Conclusions Ticks may contribute to the ecological circulation of poxviruses by switching hosts during their life cycle, potentially influencing viral genetic diversity. It underscores the risks of zoonotic spillover, particularly in regions with frequent human-animal interactions.

Excessive tumor necrosis factor (TNF) is known to cause significant pathology. Paradoxically, deficiency in TNF (TNF−/−) also caused substantial pathology during respiratory ectromelia virus (ECTV) infection, a surrogate model for smallpox. TNF−/− mice succumbed to fulminant disease whereas wild-type mice, and those engineered to express only transmembrane TNF (mTNF), fully recovered. TNF deficiency did not affect viral load or leukocyte recruitment but caused severe lung pathology and excessive production of the cytokines interleukin (IL)-6, IL-10, transforming growth factor beta (TGF-β), and interferon gamma (IFN-γ). Short-term blockade of these cytokines significantly reduced lung pathology in TNF−/− mice concomitant with induction of protein inhibitor of activated STAT3 (PIAS3) and/or suppressor of cytokine signaling 3 (SOCS3), factors that inhibit STAT3 activation. Consequently, inhibition of STAT3 activation with an inhibitor reduced lung pathology. Long-term neutralization of IL-6 or TGF-β protected TNF−/− mice from an otherwise lethal infection. Thus, mTNF alone is necessary and sufficient to regulate lung inflammation but it has no direct antiviral activity against ECTV. The data indicate that targeting specific cytokines or cytokine-signaling pathways to reduce or ameliorate lung inflammation during respiratory viral infections is possible but that the timing and duration of the interventive measure are critical.

Carp edema virus (CEV), a member of the Poxviridae family, has been a significant pathogen in koi and common carp since its initial identification in Japan during the 1970s. CEV, the causative agent of Koi Sleepy Disease (KSD), can cause high mortality rates and has been reported in many countries and is often linked to the fish trade. The virus is typically detected through DNA analysis of gill tissues, where the highest viral loads are found. However, traditional sampling methods, such as gill sampling, are lethal, complicating routine surveillance, particularly in asymptomatic or high-value koi. This study aimed to evaluate nonlethal sampling methods for CEV surveillance in the koi trade. We analysed various shipping environment samples, such as shipping water and fish bag swabs, alongside gill swabs from anaesthetised fish and gills from naturally deceased fish. Using qPCR, we found that the sensitivity of environmental samples, particularly shipping water, was greater than that of direct fish samples. Latent class modelling estimated that the sensitivity associated with 1.5 mL shipping water samples was greater than 89%, making them a reliable alternative for early detection. All detected variants belonged to genogroup II. Some post-import outbreaks shared variants with earlier outbreaks or shipping environment samples, suggesting that the detected DNA generally reflected infectious particles rather than just free environmental DNA and indicating that CEV can go unnoticed for several months after importation. These findings highlight the utility of environmental samples for effective, non-invasive surveillance and improved biosecurity management in the koi trade.

During 2012, 2013 and 2015, we collected small mammals within 25 km of the town of Boende in Tshuapa Province, the Democratic Republic of the Congo. The prevalence of monkeypox virus (MPXV) in this area is unknown; however, cases of human infection were previously confirmed near these collection sites. Samples were collected from 353 mammals (rodents, shrews, pangolins, elephant shrews, a potamogale, and a hyrax). Some rodents and shrews were captured from houses where human monkeypox cases have recently been identified, but most were trapped in forests and agricultural areas near villages. Real-time PCR and ELISA were used to assess evidence of MPXV infection and other Orthopoxvirus (OPXV) infections in these small mammals. Seven (2.0%) of these animal samples were found to be anti-orthopoxvirus immunoglobulin G (IgG) antibody positive (six rodents: two Funisciurus spp.; one Graphiurus lorraineus; one Cricetomys emini; one Heliosciurus sp.; one Oenomys hypoxanthus, and one elephant shrew Petrodromus tetradactylus); no individuals were found positive in PCR-based assays. These results suggest that a variety of animals can be infected with OPXVs, and that epidemiology studies and educational campaigns should focus on animals that people are regularly contacting, including larger rodents used as protein sources.

Mpox clade Ib is significant as it is associated with human cases and plays a key role in understanding the transmission and public health implications of mpox outbreaks. Here we present a case report of the first confirmed human infection of clade Ib in China, which occurred in December 2024 in Zhejiang Province. The case was a 28-year-old woman from South Africa who had sexual contact with an asymptomatic man from the Democratic Republic of the Congo. She presented with disseminated vesicular lesions on the extremities, face, buttocks, trunk, palms, and dorsum of the hands, but lesions were absent from the oral cavity, perineum, and anus. By the 18th day post-onset (DPO), only vesicles remained on the dorsum of the right foot and in the finger web spaces, with complete resolution by the 24th DPO. Among 59 consecutive samples collected, 55 tested positive for mpox virus. Oropharyngeal swabs turned negative by the 16th DPO, while skin lesion samples, urine samples, and scab specimens remained positive through the 20th DPO. Consecutive scab samples consistently exhibited high viral loads. In total, 211 contacts of the symptomatic patient were identified, and no secondary cases occurred. This study underscores the importance of multisite sampling for diagnostic sensitivity, highlights the transmission risk associated with asymptomatic sexual contact, and emphasizes the need for refined contact definitions and management strategies. Further research is needed to explore infection risks across different types of exposure. The first outbreaks of mpox outside Africa in 2022 were caused by clade II but cases of a new clade Ib have been increasing in the Democratic Republic of Congo and neighbouring countries since 2024. Here, the authors describe a case report and public health investigation of the first detected case of mpox clade Ib in China.

A novel poxvirus was discovered in Crocodilurus amazonicus (Teiidae) presenting with a debilitating skin disease. The generated first genome sequence of a reptilian poxvirus revealed the closest phylogenetic relationship to avipoxviruses, highlighting potential virus exchanges between avian and reptilian species.

Evasion of host antiviral mechanisms Many cellular messenger RNAs and viral RNAs are methylated at the 2′- O position of the 5′ guanosine cap. The role of this modification in virus infection has been unclear. Michael Diamond and colleagues now show that this form of methylation enables several unrelated viruses to evade innate host antiviral responses through escape from suppression by interferon-stimulated genes. This suggests an evolutionary explanation for 2′- O methylation of cellular mRNA: it may distinguish self from non-self RNA under conditions of infection. Novel classes of pharmacological agents that specifically inhibit cytoplasmic viral 2′- O methyltransferases may be expected to have broad-spectrum antiviral activity. Many cellular and virus messenger RNAs are methylated at the 2′- O positions of the 5′ guanosine cap. The role of 2′- O methylation in virus infection has been unclear. These authors show that this form of methylation enables several unrelated viruses to evade the antiviral effects of genes stimulated by type I interferon. Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2′- O positions of the 5′ guanosine cap by specific nuclear and cytoplasmic methyltransferases (MTases), respectively. Whereas N-7 methylation is essential for RNA translation and stability 1 , the function of 2′- O methylation has remained uncertain since its discovery 35 years ago 2 , 3 , 4 . Here we show that a West Nile virus (WNV) mutant (E218A) that lacks 2′- O MTase activity was attenuated in wild-type primary cells and mice but was pathogenic in the absence of type I interferon (IFN) signalling. 2′- O methylation of viral RNA did not affect IFN induction in WNV-infected fibroblasts but instead modulated the antiviral effects of IFN-induced proteins with tetratricopeptide repeats (IFIT), which are interferon-stimulated genes (ISGs) implicated in regulation of protein translation. Poxvirus and coronavirus mutants that lacked 2′- O MTase activity similarly showed enhanced sensitivity to the antiviral actions of IFN and, specifically, IFIT proteins. Our results demonstrate that the 2′- O methylation of the 5′ cap of viral RNA functions to subvert innate host antiviral responses through escape of IFIT-mediated suppression, and suggest an evolutionary explanation for 2′- O methylation of cellular mRNA: to distinguish self from non-self RNA. Differential methylation of cytoplasmic RNA probably serves as an example for pattern recognition and restriction of propagation of foreign viral RNA in host cells.