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Nature Communications Jan 2023The advantage of oncolytic viruses (OV) in cancer therapy is their dual effect of directly killing tumours while prompting anti-tumour immune response. Oncolytic...
The advantage of oncolytic viruses (OV) in cancer therapy is their dual effect of directly killing tumours while prompting anti-tumour immune response. Oncolytic parapoxvirus ovis (ORFV) and other OVs are thought to induce apoptosis, but apoptosis, being the immunogenically inert compared to other types of cell death, does not explain the highly inflamed microenvironment in OV-challenged tumors. Here we show that ORFV and its recombinant therapeutic derivatives are able to trigger tumor cell pyroptosis via Gasdermin E (GSDME). This effect is especially prominent in GSDME-low tumor cells, in which ORFV-challenge pre-stabilizes GSDME by decreasing its ubiquitination and subsequently initiates pyroptosis. Consistently, GSDME depletion reduces the proportion of intratumoral cytotoxic T lymphocytes, pyroptotic cell death and the success of tumor ORFV virotherapy. In vivo, the OV preferentially accumulates in the tumour upon systemic delivery and elicits pyroptotic tumor killing. Consequentially, ORFV sensitizes immunologically 'cold' tumors to checkpoint blockade. This study thus highlights the critical role of GSDME-mediated pyroptosis in oncolytic ORFV-based antitumor immunity and identifies combinatorial cancer therapy strategies.
Topics: Humans; Gasdermins; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Parapoxvirus; Pyroptosis; Tumor Microenvironment
PubMed: 36641456
DOI: 10.1038/s41467-023-35917-2 -
Annales de Dermatologie Et de... May 2019Poxvirus (PXV) infections are a common cause of cutaneous signs. In France, certain forms of poxvirus are frequent and benign (molluscum contagiosum), while others are... (Review)
Review
Poxvirus (PXV) infections are a common cause of cutaneous signs. In France, certain forms of poxvirus are frequent and benign (molluscum contagiosum), while others are rare but potentially serious (cowpox virus [CPXV]). Whereas only smallpox and molluscum contagiosum viruses have a human reservoir and are transmitted between humans, most poxvirus infections are zoonoses having only animal reservoirs. Only a small number of poxviruses are responsible for infection in humans, but the increasing number of new pets, some of which are exotic, coupled with the rapid rise in international travel are creating a greater risk of transmission of zoonotic PXV to new vectors and of spread of these diseases to new regions throughout the world. In France, molluscum contagiosum, orf and milkers' nodule give rise to numerous consultations and are well known to dermatologists. However, dermatologists must also be able to identify other parapoxviruses of similar presentation to orf; thus, CPXV and monkeypox are considered potentially emergent viruses with a high risk of epidemic and spread due to increasing international transport and the loss of the maximum protection against smallpox. Finally, despite its declared eradication, smallpox is currently being monitored because of the potential risk of reintroduction, whether accidentally or deliberately through bioterrorism.
Topics: Animals; Communicable Diseases, Emerging; Cowpox; Diagnosis, Differential; Disease Reservoirs; France; Humans; Molluscum Contagiosum; Pets; Poxviridae Infections; Skin Diseases, Viral; Smallpox; Zoonoses
PubMed: 31079914
DOI: 10.1016/j.annder.2019.03.001 -
Veterinary Medicine and Science Mar 2022Several viruses belonging to the family Poxviridae can cause infections in humans and animals. In Corsica, livestock farming (sheep, goats, pigs, and cattle) is mainly...
BACKGROUND
Several viruses belonging to the family Poxviridae can cause infections in humans and animals. In Corsica, livestock farming (sheep, goats, pigs, and cattle) is mainly mixed, leading to important interactions between livestock, wildlife, and human populations. This could facilitate the circulation of zoonotic diseases, and makes Corsica a good example for studies of tick-borne diseases.
OBJECTIVES
To gain understanding on the circulation of poxviruses in Corsica, we investigated their presence in tick species collected from cattle, sheep, horses, and wild boar, and characterized them through molecular techniques.
METHODS
Ticks were tested using specific primers targeting conserved regions of sequences corresponding to two genera: parapoxvirus and orthopoxvirus.
RESULTS
A total of 3555 ticks were collected from 1549 different animals (687 cattle, 538 horses, 106 sheep, and 218 wild boars). They were tested for the presence of parapoxvirus DNA on one hand and orthopoxvirus DNA on the other hand using Pangeneric real-time TaqMan assays. Orthopoxvirus DNA was detected in none of the 3555 ticks. Parapoxvirus DNA was detected in 6.6% (36/544) of ticks collected from 23 cows from 20 farms. The remaining 3011 ticks collected from horses, wild boars, and sheep were negative. The infection rate in cow ticks was 8.0% (12/148) in 2018 and 6.0% (24/396) in 2019 (p = 0.57). Parapoxvirus DNA was detected in 8.5% (5/59) of Hyalomma scupense pools, 8.2% (15/183) of Hyalomma marginatum pools, and 6.7% (16/240) of Rhipicephalus bursa pools (p = 0.73). We successfully amplified and sequenced 19.4% (7/36) of the positive samples which all corresponded to pseudocowpox virus.
CONCLUSIONS
Obviously, further studies are needed to investigate the zoonotic potential of pseudocowpox virus and its importance for animals and public health.
Topics: Animals; Cattle; Female; Goat Diseases; Horse Diseases; Horses; Ixodidae; Parapoxvirus; Sheep; Sheep Diseases; Swine; Swine Diseases; Tick Infestations; Tick-Borne Diseases; Ticks
PubMed: 35092189
DOI: 10.1002/vms3.700 -
Infection, Genetics and Evolution :... Mar 2022Poxviruses are a family of specialized cytoplasm-parasitic DNA viruses that replicate and assembly in virus factory. In Parapoxvirus (PPV) genus, with the orf virus... (Review)
Review
Poxviruses are a family of specialized cytoplasm-parasitic DNA viruses that replicate and assembly in virus factory. In Parapoxvirus (PPV) genus, with the orf virus (ORFV) as a representative species of this genus, their behaviors are significantly different from that of Orthopoxvirus, and the plots of viral practical solutions for evading host immunity are intricate and fascinating, particularly to anti-host and host's antiviral mechanisms. In order to protect the virus factory from immune elimination caused by infection, PPVs attempt to interfere with multiple stress levels of host, mainly by modulating innate immunity response (IIR) and adaptive immunity response (AIR). Given that temporarily constructed by virus infection, ORFV-HOST (OH) system accompanied by viral strategies is carefully managed in the virus factory, thus directing many life-critical events once undergoing the IIR and AIR. Evolutionarily, to reduce the risk of system destruction, ORFV have evolved into a mild-looking mode to avoid overstimulation. Moreover, the current version of development also focus on recognizing and hijacking more than eight antiviral security mechanisms of host cells, such as the 2',5'-oligoadenylate synthetase (OAS)/RNase L and PKR systems, the ubiquitin protease system (UPS), and so on. In summary, this review assessed inescapable pathways as mentioned above, through which viruses compete with their hosts strategically. The OH system provides a panoramic view and a powerful platform for us to study the PPV-Host interaction, as well as the corresponding implications on a great application potential in anti-virus design.
Topics: Adaptive Immunity; Animals; Cattle; Ecthyma, Contagious; Host-Pathogen Interactions; Humans; Immunity, Innate; Orf virus; Sheep
PubMed: 35066165
DOI: 10.1016/j.meegid.2022.105220 -
Pathogens (Basel, Switzerland) Apr 2022Homologues of interleukin (IL)-10, a pleiotropic immunomodulatory cytokine, have been identified in the genus. The first identified, (ORFV) IL-10, greatly enhanced...
Homologues of interleukin (IL)-10, a pleiotropic immunomodulatory cytokine, have been identified in the genus. The first identified, (ORFV) IL-10, greatly enhanced infection of its host, exhibiting immune modulatory effects equivalent to human IL-10. IL-10-like genes were then identified in (BPSV), (PCPV), (RDPV) and (GSPV). This study aimed to produce and characterise recombinant parapoxvirus IL-10s, then quantitatively compare their receptor binding and immunomodulatory activities. Recombinant IL-10s were expressed, purified, then characterised using bioinformatic, biochemical and enzymatic analyses. Anti-inflammatory effects were assessed in lipoteichoic acid-activated THP-1 monocytes, and stimulatory effects in MC/9 mast cells. IL-10 receptor (IL-10R)1 binding was detected in a competitive displacement assay. BPSV IL-10 inhibited production of monocyte chemoattractant protein (MCP)-1, IL-8 and IL-1β, induced mast cell proliferation, and bound IL-10R1 similarly to ORFV IL-10. PCPV IL-10 showed reduced MCP-1 inhibition, mast cell proliferation, and IL-10R1 binding. RDPV IL-10 displayed reduced inhibition of IL-8 and MCP-1 production. GSPV IL-10 showed limited inhibition of IL-1β production and stimulation of mast cell proliferation. These findings provide valuable insight into IL-10 receptor interactions, and suggest that the parapoxvirus IL-10s play similar pathogenic roles during infection of their hosts.
PubMed: 35631028
DOI: 10.3390/pathogens11050507 -
Vaccines Nov 2021Orf virus (ORFV), the prototype species of the parapoxvirus genus, is the causative agent of contagious ecthyma, an extremely devastating skin disease of sheep, goats,... (Review)
Review
Orf virus (ORFV), the prototype species of the parapoxvirus genus, is the causative agent of contagious ecthyma, an extremely devastating skin disease of sheep, goats, and humans that causes enormous economic losses in livestock production. ORFV is known for its ability to repeatedly infect both previously infected and vaccinated sheep due to several immunomodulatory genes encoded by the virus that temporarily suppress host immunity. Therefore, the development of novel, safe and effective vaccines against ORFV infection is an important priority. Although, the commercially licensed live-attenuated vaccines have provided partial protection against ORFV infections, the attenuated viruses have been associated with major safety concerns. In addition to safety issues, the persistent reinfection of vaccinated animals warrants the need to investigate several factors that may affect vaccine efficacy. Perhaps, the reason for the failure of the vaccine is due to the long-term adaptation of the virus in tissue culture. In recent years, the development of vaccines against ORFV infection has achieved great success due to technological advances in recombinant DNA technologies, which have opened a pathway for the development of vaccine candidates that elicit robust immunity. In this review, we present current knowledge on immune responses elicited by ORFV, with particular attention to the effects of the viral immunomodulators on the host immune system. We also discuss the implications of strain variation for the development of rational vaccines. Finally, the review will also aim to demonstrate future strategies for the development of safe and efficient vaccines against ORFV infections.
PubMed: 34835272
DOI: 10.3390/vaccines9111341 -
Journal of Veterinary Diagnostic... May 2018A group of Holstein first-calved heifers developed small pustules and ulcers on the vulva and in the vagina during the first 1-4 wk postpartum. The lesions varied from...
A group of Holstein first-calved heifers developed small pustules and ulcers on the vulva and in the vagina during the first 1-4 wk postpartum. The lesions varied from small red pinpoint foci to pustules and ulcers, 3-5 mm diameter. Some ulcers coalesced to form large ulcerated areas up to 15 mm diameter. In some animals, these ulcers progressed to become deep ulceration of the vaginal and vulvar mucosa with >50% of the mucosa involved. Vaginal biopsies from 4 heifers and vaginal individual swabs from 8 heifers for a combined sampling of 9 heifers were taken for clinical assessment. Six of the 9 heifers had parapoxvirus based on histopathology and/or PCR. Histologic examination of the biopsies of the pustules identified ballooning degeneration of the epithelium with degenerate epithelium containing eosinophilic intracytoplasmic inclusions consistent with a parapoxvirus in 3 of 4 biopsies. Testing for bovine herpesvirus 1, 2, and 4, bovine viral diarrhea virus, bovine papular stomatitis virus, and orf virus remained negative.
Topics: Animals; Animals, Newborn; California; Cattle; Cattle Diseases; Dairying; Disease Outbreaks; Female; Parapoxvirus; Polymerase Chain Reaction; Poxviridae Infections; Vulvovaginitis
PubMed: 29429402
DOI: 10.1177/1040638718758829 -
Virology Journal Jan 2021Orf virus (ORFV) is a member of the genus Parapoxvirus and family Poxviridae. The virus has a worldwide distribution and infects sheep, goats, humans, and wild animals....
BACKGROUND
Orf virus (ORFV) is a member of the genus Parapoxvirus and family Poxviridae. The virus has a worldwide distribution and infects sheep, goats, humans, and wild animals. However, due to the complex structure of the poxvirus, the underlying mechanism of the entry and infection by ORFV remains largely unknown. ORFV ORF047 encodes a protein named L1R. Poxviral L1R serves as the receptor-binding protein and blocks virus binding and entry independently of glycosaminoglycans (GAGs). The study aimed to identify the host interaction partners of ORFV ORF047.
METHODS
Yeast two-hybrid cDNA library of sheep testicular cells was applied to screen the host targets with ORF047 as the bait. ORF047 was cloned into a pBT3-N vector and expressed in the NMY51 yeast strain. Then, the expression of bait proteins was validated by Western blot analysis.
RESULTS
Sheep SERP1and PABPC4 were identified as host target proteins of ORFV ORF047, and a Co-IP assay further verified their interaction.
CONCLUSIONS
New host cell proteins SERP1and PABPC4 were found to interact with ORFV ORF047 and might involve viral mRNA translation and replication.
Topics: Animals; Cells, Cultured; Host Microbial Interactions; Male; Membrane Proteins; Orf virus; Protein Binding; Sheep; Testis; Viral Envelope Proteins
PubMed: 33499896
DOI: 10.1186/s12985-021-01499-y -
Research and Reports in Tropical... 2021Orf virus (ORFV) is the etiologic agent of Orf or ecthyma contagiosum in humans but primarily affects different domestic and wild animals. The disease mostly affects... (Review)
Review
Orf virus (ORFV) is the etiologic agent of Orf or ecthyma contagiosum in humans but primarily affects different domestic and wild animals. The disease mostly affects sheep, goats and other small wild ruminants and spreads to humans through direct contact with infected animals or by way of contaminated fomites worldwide. ORFV is taxonomically classified as a member of the genus Parapoxvirus. It is known to have tolerance to inactivation in a drier environment, and it has been recovered from crusts after several months to years. Among immunocompetent people, the lesions usually resolve by its natural course within a maximum of 8 weeks. In immunosuppressed patients, however, it needs the use of various approaches including antiviral, immune modifier or minor surgical excisions. The virus through its association with divergent host ranges helps to develop a mechanism to evade the immune system. The relative emergence of Orf, diagnosed on clinical ground among human cases, in unusual frequencies in southwest Ethiopia between October 2019 and May 2020, was the driver to write this review. The objective was to increase health care providers' diagnostic curiosity and to bring the attentiveness of public health advisors for prevention, control and the development of schemes for surveillance of Orf zoonosis in a similar setting like Ethiopia.
PubMed: 34267574
DOI: 10.2147/RRTM.S306446