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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 -
Advances in Experimental Medicine and... 2024Despite being common worldwide, parapoxvirus infections are regarded as neglected zoonoses because their incidence is either unknown or grossly overestimated. In... (Review)
Review
Despite being common worldwide, parapoxvirus infections are regarded as neglected zoonoses because their incidence is either unknown or grossly overestimated. In ruminants all throughout the world, parapoxvirus produces oral lesions and infectious pustular dermatitis. The pathogen is typically spread directly via items contaminated with parapoxvirus and indirectly via a near contact with dermatological lesions that contain the virus on affected animals. Animals infected with the parapoxvirus typically exhibit no clinical symptoms, and the mode of parapoxvirus transmission is occasionally unclear. For accurate etiological diagnosis and appropriate therapy of patients affected by zoonotic infections, the significance of adopting a "One Health" approach and cross-sector collaboration between human and veterinary medicine should be emphasized. The causative pathogen of ecthyma contagiosum in general people is the orf virus, which mostly infects various animals, either pets or wildlife species. The illness primarily affects minute wild ruminants, sheep, cattle, deer, and goats, and it can spread to people through contact with infected animals or contaminated meats anywhere in the world. Taxonomically speaking, the virus belongs to the parapoxvirus genus. Thus pathogen can be detected from crusts for a very long period (several months to several years), and the virus is found to be resistant to inactivation with a hot or dry atmosphere. In immunocompetent individuals, the lesions often go away on their own with a period as long 2 months. Nevertheless, it necessitates the applying of diverse strategies, such as antiviral, immunological modulator, or modest surgical excisions in immunosuppressed patients. The interaction of the virus with various host populations aids in the development of a defense mechanism against the immune system. The parapoxvirus illness in humans is covered in this chapter. The orf illness, a significant known human parapoxvirus infection, is given specific attention.
Topics: Ecthyma, Contagious; Animals; Humans; Orf virus; Zoonoses; Parapoxvirus
PubMed: 38801578
DOI: 10.1007/978-3-031-57165-7_11 -
The New Microbiologica Dec 2022Parapoxvirus (PPV) infections are considered neglected zoonoses because their incidence is often unknown or greatly underestimated despite being endemic globally. Here,...
Parapoxvirus (PPV) infections are considered neglected zoonoses because their incidence is often unknown or greatly underestimated despite being endemic globally. Here, we report the comprehensive diagnostic workflow that led to the identification of two cases of persistent PPV infections. The results obtained underline the importance of adopting a "One Health" approach and cross-sectoral collaboration between human and veterinary medicine for precise aetiological diagnosis and correct management of patients affected by zoonotic diseases.
Topics: Animals; Humans; Parapoxvirus; Zoonoses; Poxviridae Infections
PubMed: 36066214
DOI: No ID Found -
The Journal of General Virology Dec 2023Parapoxviruses (PPV) cause skin and mucous membrane lesions in several animal species, and of the five recognized PPVs, at least three are zoonotic. Equine PPV (EqPPV)...
Parapoxviruses (PPV) cause skin and mucous membrane lesions in several animal species, and of the five recognized PPVs, at least three are zoonotic. Equine PPV (EqPPV) is the sixth one initially described in humans in the United States and later in a severely sick horse in Finland in 2013-2015. In 2021-2022, a large-scale pustulo-vesicular pastern dermatitis outbreak occurred in horses all over Finland. This study aimed at analysing the outbreak, identifying and describing the causative agent, describing clinical signs, and searching for risk factors. EqPPV was identified as a probable causative agent and co-infections with several potentially pathogenic and zoonotic bacteria were observed. Histopathologically, suppurative and ulcerative dermatitis was diagnosed. Due to the lack of specific tests for this virus, we developed a novel diagnostic EqPPV-PCR with sensitivity of 10 copies/reaction. Based on a large proportion of the genome sequenced directly from clinical samples, very little variation was detected between the sequences of the case from 2013 and the cases from 2021 to 2022. Based on an epidemiological survey, the main risk factor for pastern dermatitis was having racehorses. Approximately one third of the horses at each affected stable got clinical dermatitis, manifesting as severe skin lesions. Skin lesions were also occasionally reported in humans, indicating potential zoonotic transmission. Case stables commonly reported attendance at race events before acquiring the disease. Survey also identified differences in practises between case and control stables. Taken together, these results enable a better preparedness, diagnostics, and guidelines for future outbreaks.
Topics: Humans; Animals; Horses; Disease Outbreaks; Skin; Coinfection; Dermatitis; Parapoxvirus
PubMed: 38117290
DOI: 10.1099/jgv.0.001940 -
Virus Research Jan 2022Orf virus (ORFV) is the type species of the Parapoxvirus genus that belongs to the Poxviridae family. Type I interferons (IFN) are critical in the host defence against...
Orf virus (ORFV) is the type species of the Parapoxvirus genus that belongs to the Poxviridae family. Type I interferons (IFN) are critical in the host defence against viruses. They induce hundreds of interferon stimulated genes (ISGs) many of which have an antiviral role. The ability of ORFV to modulate type I IFN production was undertaken to investigate whether ORFV could inhibit IFN-β expression via dsRNA dependant signalling pathways. HEK293 cells are known to lack DNA pattern-recognition receptors and Toll-like receptors however, they do express the cytosolic dsRNA receptors RIG-I and MDA5. HEK293 cells were shown to produce high levels of IFN-β when cells were stimulated with poly(I:C) and this was shown to be predominantly via RIG-I-dependant signalling as confirmed by siRNA knock-down of RIG-I. Further we showed that HEK293 cells are permissive for ORFV and caused potent inhibition of IFN-β transcription when cells were stimulated with poly(I:C) post-viral infection. Studies using heat inactivated ORFV suggested that de novo synthesis of early genes was required. In addition our findings showed that the ORFV encoded factor ORF020, that is known to bind dsRNA, is involved in antagonising IFN expression. Overall, this study has shown for first time the ability of ORFV to counteract type I IFN expression by antagonising dsRNA-activated RIG-I signalling.
Topics: Antiviral Agents; HEK293 Cells; Humans; Interferon Type I; Interferon-beta; Orf virus; RNA, Double-Stranded
PubMed: 34742812
DOI: 10.1016/j.virusres.2021.198619 -
Emerging Infectious Diseases Sep 2023We report a sequencing protocol and 121-kb poxvirus sequence from a clinical sample from a horse in Finland with dermatitis. Based on phylogenetic analyses, the virus is...
We report a sequencing protocol and 121-kb poxvirus sequence from a clinical sample from a horse in Finland with dermatitis. Based on phylogenetic analyses, the virus is a novel parapoxvirus associated with a recent epidemic; previous data suggest zoonotic potential. Increased awareness of this virus and specific diagnostic protocols are needed.
Topics: Horses; Animals; Parapoxvirus; Finland; Phylogeny; Poxviridae; Communicable Diseases
PubMed: 37610155
DOI: 10.3201/eid2909.230049 -
Virus Research Sep 2002Orf virus is a DNA parapoxvirus that causes orf, an acute debilitating skin disease of sheep, goats and humans. In sheep, a vigorous immune response involving... (Review)
Review
Orf virus is a DNA parapoxvirus that causes orf, an acute debilitating skin disease of sheep, goats and humans. In sheep, a vigorous immune response involving neutrophils, dermal dendritic cells, T cells, B cells and antibody is generated after infection. CD4(+) T cells, IFN-gamma and to a lesser extent CD8(+) T cells are involved in partial protection against infection. In spite of this, orf virus can repeatedly infect sheep albeit with reduced lesion size and time to resolution compared to primary infection. This is due at least in part to the action of virus immuno-modulator proteins that interfere with host immune and inflammatory responses. These include: an interferon resistance protein; a viral orthologue of mammalian IL-10 (vIL-10) that is an anti-inflammatory cytokine; and a novel inhibitor of the cytokines GM-CSF and IL-2 (GIF). The virus also encodes a virulence protein that is an orthologue of mammalian vascular endothelial growth factor. The study of the immuno-modulator proteins provides an insight into disease pathogenesis and important elements of a host protective response. This information will be used to devise a rational disease control strategy.
Topics: Adjuvants, Immunologic; Animals; Ecthyma, Contagious; Immunity; Orf virus; Sheep; Viral Proteins; Virulence
PubMed: 12297324
DOI: 10.1016/s0168-1702(02)00117-x -
The New England Journal of Medicine Apr 2021
Topics: Animals; Ecthyma, Contagious; Humans; Male; Middle Aged; Orf virus; Sheep; Thumb; Viral Zoonoses
PubMed: 33882630
DOI: 10.1056/NEJMicm2029641 -
Veterinary Immunology and... Dec 1999Three orf virus putative virulence proteins are described that exhibit immunomodulatory functions. The OVIFNR gene at the left terminus of the viral genome encodes an... (Review)
Review
Three orf virus putative virulence proteins are described that exhibit immunomodulatory functions. The OVIFNR gene at the left terminus of the viral genome encodes an interferon resistance protein with homology to the E3L gene of vaccinia virus. OVIFNR functions by preventing a dsRNA-dependent kinase from inhibiting virus and cell protein synthesis as part of the interferon-induced anti-viral state within infected cells. The orf virus orthologue of the ovine interleukin-10 (vIL-10) gene is located at the right terminus of the viral genome. Both vIL-10 and host (ovine) IL-10 function in vitro as inhibitors of pro-inflammatory cytokine production by keratinocytes and macrophages, and both inhibit IFN-gamma production from activated peripheral blood lymphocytes. Both the orf virus vIL-10 and ovine IL-10 stimulate mast cell and thymocyte proliferation. In this respect the orf virus IL-10 differs from Epstein Barr virus IL-10 which does not exhibit cell proliferative activity. Finally, the orf virus GM-CSF inhibitory factor gene (GIF) at the right terminus of the viral genome encodes an inhibitor of GM-CSF that also binds IL-2. Together, these viral proteins are capable of inhibiting key components of the ovine anti-virus immune and inflammatory response.
Topics: Animals; Ecthyma, Contagious; Orf virus; Sheep; Viral Proteins; Virulence
PubMed: 10614496
DOI: 10.1016/s0165-2427(99)00119-1 -
Veterinary Immunology and... May 2013Inactivated Parapoxvirus ovis (iPPVO) and Propionibacterium acnes (P. acnes) are currently used in equine medicine as immune-modulators for prophylactic treatment or... (Review)
Review
Inactivated Parapoxvirus ovis (iPPVO) and Propionibacterium acnes (P. acnes) are currently used in equine medicine as immune-modulators for prophylactic treatment or adjunct to conventional therapy in order to improve immune defences, to prevent or treat infectious diseases. Their mode of action relies on a non-antigen specific interaction with the innate and/or adaptive immune responses. iPPVO stimulates and regulates cytokine secretion by leucocytes, while P. acnes acts primarily through the activation of macrophages. This report aims to describe their activity as immune-modulators and to summarise the scientific literature and reports available about their use in horses, particularly in the prevention or treatment of equine respiratory diseases. This systematic review regroups articles published in peer-review journals, clinical trials reports, conference proceedings and other information made available in the last 2 decades.
Topics: Animals; Horse Diseases; Horses; Immunity, Innate; Immunologic Factors; Parapoxvirus; Propionibacterium acnes; Respiratory Tract Infections
PubMed: 23481655
DOI: 10.1016/j.vetimm.2013.01.010