A parapoxviral virion protein targets the retinoblastoma protein to inhibit NF-κB signaling.

Poxviruses have evolved multiple strategies to subvert signaling by Nuclear Factor κB (NF-κB), a crucial regulator of host innate immune responses. Here, we describe an orf virus (ORFV) virion-associated protein, ORFV119, which inhibits NF-κB signaling very early in infection (≤ 30 min post infection). ORFV119 NF-κB inhibitory activity was found unimpaired upon translation inhibition, suggesting that virion ORFV119 alone is responsible for early interference in signaling. A C-terminal LxCxE motif in ORFV119 enabled the protein to interact with the retinoblastoma protein (pRb) a multifunctional protein best known for its tumor suppressor activity. Notably, experiments using a recombinant virus containing an ORFV119 mutation which abrogates its interaction with pRb together with experiments performed in cells lacking or with reduced pRb levels indicate that ORFV119 mediated inhibition of NF-κB signaling is largely pRb dependent. ORFV119 was shown to inhibit IKK complex activation early in infection. Consistent with IKK inhibition, ORFV119 also interacted with TNF receptor associated factor 2 (TRAF2), an adaptor protein recruited to signaling complexes upstream of IKK in infected cells. ORFV119-TRAF2 interaction was enhanced in the presence of pRb, suggesting that ORFV119-pRb complex is required for efficient interaction with TRAF2. Additionally, transient expression of ORFV119 in uninfected cells was sufficient to inhibit TNFα-induced IKK activation and NF-κB signaling, indicating that no other viral proteins are required for the effect. Infection of sheep with ORFV lacking the ORFV119 gene led to attenuated disease phenotype, indicating that ORFV119 contributes to virulence in the natural host. ORFV119 represents the first poxviral protein to interfere with NF-κB signaling through interaction with pRb.

Giant Orf on the Nose.

Orf is a zoonotic infectious disease caused by parapoxvirus. Orf lesions are typically seen on the hand, but they have rarely been reported on the nose. Herein, the authors report a rare patient of an orf lesion on the nose of a 52-year-old man after the Muslim celebration of the feast of the sacrifice. The lesion spontaneously recovered 8 weeks after the initial appearance and showed no evidence of recurrence after 1 year of follow-up. Orf virus infections may occur more often after the celebration of the feast of the sacrifice in Muslim countries.

Orf Infection in a Patient with Stat1 Gain-of-Function.

PURPOSE: Chronic Mucocutaneous Candidiasis (CMC) refers to a group of immunodeficiencies, characterized by persistent or recurrent infections of the skin, nails, and mucosae caused by Candida. It is typically caused by inborn errors of IL-17 immunity. Orf, also known as contagious ecthyma, is a zoonotic infection caused by a dermatotropic parapoxvirus that commonly infects sheep and goats; it is transmitted to humans through contact with an infected animal or fomites. While orf is usually a benign self-limiting illness, it can be progressive and even life-threatening in immune-compromised hosts. METHODS AND RESULTS: A 34-year-old man with autosomal dominant CMC due to a heterozygous STAT1 gain-of-function (GOF) mutation cut his hand with a knife during slaughter. Giant orf infection developed in 2 weeks. He was successfully treated by cidofovir injections every other week for 4 months. CONCLUSIONS: This is the first patient with severe orf in the context of a well-defined genetically identified PID: CMC and inborn error of IL-17 immunity due to a GOF STAT1 mutation.

[A woman with skin lesions on her hand]. / Een vrouw met huidafwijkingen op haar hand.

A Moroccan woman was seen with a blister on her left thumb and a rash on the palm of the left hand. She did not recall burning herself, but prepared sheep meat regularly. It appeared the skin lesions were caused by orf (ecthyma contagiosum).

Isolation and characterization of an Indian ORF virus from goats.

Isolation and characterization of an orf virus has been described here. The virus was isolated from an outbreak of 'scabby mouth' in goats in Northern India. Viral morphology from the scab biopsy revealed typical ovoid-shaped particles characteristic of Parapoxvirus. Virus was isolated from sonicated scab suspension and characterized by restriction enzyme (RE) analysis and sequencing of full-length GM-CSF- and interleukin-2 inhibitory factor (GIF) gene. RE pattern of the virus did not show close resemblance to most of the orf viruses published earlier. However, it showed high sequence identity and closer phylogenetic relationship with previously published ORFV-SA00 strain, as evident from the nucleotide and deduced amino acid sequence of GIF gene.

A viral infection of the hand commonly seen after the feast of sacrifice: human orf (orf of the hand).

Orf of the hand is an uncommon zoonotic infection caused by a dermotropic DNA virus that belongs to the Parapoxvirus genus of the family Poxviridae. It is transmitted to humans through contact with infected sheep and goats and is reported as an occupational disease. We report nine cases of human orf seen in the hands of individuals, who were not occupationally exposed, after the feast of sacrifice in Turkey. Three cases were teachers and six out of the nine were housewives. We observed musculoskeletal complications and misdiagnoses. It is important to consider human orf in the differential diagnosis of hand lesions to prevent overtreatment and complications.

Contagious mucocutaneous dermatitis of the mountain hare (Lepus timidus): pathology and cause.

Contagious mucocutaneous dermatitis is a frequently encountered disease of mountain hares (Lepidus timidus) in Finland. We describe the histopathologic changes and propose an etiologic cause for this disorder. Fifty-three cases collected during 1982-2000 were examined histologically. Transmission electron microscopy was performed in one case. In fully developed lesions, keratinocytes in epidermis and follicular infundibula were swollen and contained large eosinophilic intracytoplasmic inclusion bodies with marked reticular and ballooning degeneration. In later stages, there was marked necrosis and ulceration with severe pyogranulomatous and suppurative inflammation. At this stage, no viral inclusions were detectable, but secondary Staphylococcus warnerii infection was present in most cases. In late lesions, there was dermal fibrosis with epidermal hyperplasia. No spiral-shaped bacteria suggesting treponematosis were detected at any stage. Ultrastructurally, swollen epidermal and follicle infundibular cells contained round intracytoplasmic inclusion bodies with a myriad of virions typical of poxvirus with a biconcave nucleocapsid core, two lateral bodies, and a clearly discernible outer lipoprotein capsule. The findings suggest that contagious mucocutaneous dermatitis in mountain hares is a viral disease caused by a poxvirus. The disease is often complicated by secondary bacterial infection, most commonly S. warneri.

The immune and inflammatory response to orf virus.

Orf virus is a zoonotic, epitheliotropic DNA parapox virus that principally infects sheep and goats. The fact that the virus can repeatedly reinfect sheep has provoked an interest in the underlying cellular, virological and molecular mechanisms for its apparent escape from the host protective immune response. The local immune and inflammatory response in skin and the cell phenotype and cytokine response in lymph analysed around a single lymph node are characteristic of an anti-viral response. An unusual feature is the dense accumulation of MHC Class II+ dendritic cells in the skin lesion. The function of these cells is not known. Orf virus virulence genes and activities have been identified that may interfere with the development of the host protective immune and inflammatory response.