Vascular endothelial growth factor encoded by Parapoxviruses can regulate metabolism and survival of triple negative breast cancer cells.

Dysbiotic microbiomes are linked to many pathological outcomes including different metabolic disorders like diabetes, atherosclerosis and even cancer. Breast cancer is the second leading cause of cancer associated death in women, and triple negative breast cancer (TNBC) is the most aggressive type with major challenges for intervention. Previous reports suggested that Parapoxvirus signatures are one of the predominant dysbiotic viral signatures in TNBC. These viruses encode several genes that are homologs of human genes. In this study, we show that the VEGF homolog encoded by Parapoxviruses, can induce cell proliferation, and alter metabolism of breast cancer and normal breast cells, through alteration of MAPK-ERK and PI3K-AKT signaling. In addition, the activity of the transcription factor FoxO1 was altered by viral-encoded VEGF through activation of the PI3K-AKT pathway, leading to reprogramming of cellular metabolic gene expression. Therefore, this study provides new insights into the function of viral-encoded VEGFs, which promoted the growth of the breast cancer cells and imparted proliferative phenotype with altered metabolism in normal breast cells.

Experimental parapoxvirus infection (contagious ecthyma) in semi-domesticated reindeer (Rangifer tarandus tarandus).

Contagious ecthyma (contagious pustular dermatitis, orf) occurs world-wide in sheep and goats and is caused by orf virus (genus Parapoxvirus, family Poxviridae). Contagious ecthyma outbreaks have been described in semi-domesticated reindeer (Rangifer tarandus tarandus) in Sweden, Finland and Norway, occasionally with high mortality. Fourteen one-year-old reindeer were corralled in mid-April. One week after arrival, two animals received a commercial live orf virus vaccine for sheep (Scabivax(®)) on scarified skin of the medial thigh. Four weeks later, the two vaccinated and six additional animals were inoculated in scarified oral mucosa with parapoxvirus obtained from reindeer with clinical contagious ecthyma. The remaining six reindeer were kept as sentinels, sharing feed and water with the inoculated animals. A small whitish lesion appeared on the inoculation site and the labial skin-mucosa junction of three animals five days post inoculation (p.i.). Twelve days p.i., typical ecthyma lesions were visible on the inoculation site in six of eight animals, including both vaccinees. Four inoculated animals (including both vaccinees) and one sentinel seroconverted 12 days p.i., and five animals (including one sentinel) seroconverted 20 days p.i. No contagious ecthyma-like lesions were detected in the sentinels. All animals were euthanized at 26-29 days p.i. Histological examination of lesions showed proliferative dermatitis with epidermal hyperplasia, hyperkeratosis, intra-epithelial pustules and ulcers. Orf virus DNA was detected in mandibular lymph nodes, tonsils and mucosal lesions of four animals, including one sentinel, which showed that virus transmission took place. The commercial orf virus vaccine may be difficult to administer due to the need for close-cropping and its zoonotic nature, and did not indicate significant protection, although the latter has to be verified with a larger number of animals.

Histopatología de las infecciones víricas cutáneas más frecuentes / Histopathology of the More Common Viral Skin Infections

En este trabajo describimos las características histopatológicas de las infecciones víricas cutáneas. El herpes simple y el virus varicela-zóster producen una vesícula intraepidérmica con grados variables de necrosis epitelial. Son característicos los queratinocitos con núcleos balonizados con aspecto de vidrio esmerilado y los queratinocitos gigantes multinucleados. El citomegalovirus produce grandes inclusiones nucleares eosinófilas rodeadas de un halo claro en los endotelios de los vasos dérmicos. El herpes virus tipo 8 se relaciona etiológicamente con el sarcoma de Kaposi, que en sus fases iniciales muestra luces vasculares de endotelios finos disecando los haces de colágeno dérmicos. En las fases en placa y nodular las luces vasculares son más visibles, aumenta progresivamente el número de células fusiformes tumorales con discreto grado de atipia y pleomorfismo y algunas mitosis. El infiltrado se compone de linfocitos y células plasmáticas. El orf y el nódulo de los ordeñadores inducen una epidermis acantósica con queratinocitos balonizados que contienen inclusiones víricas citoplasmáticas eosinófilas. El molusco contagioso muestra lóbulos de epitelio abiertos a la superficie epidérmica con característicos cuerpos de inclusión. En las verrugas vulgares aparece acantosis, papilomatosis e hiperqueratosis, con confluencia de las crestas epidérmicas hacia el centro de la lesión y coilocitos (AU)

We describe the histopathological characteristics of viral skin infections. Herpes simplex virus and varicella-zoster virus produce an intraepidermal vesicle with variable degrees of epithelial necrosis. Typical findings include keratinocytes with ballooned nuclei with a ground-glass appearance and giant multinucleated keratinocytes. In the endothelial cells of the dermal blood vessels, cytomegalovirus produces large eosinophilic nuclear inclusions surrounded by a clear halo. Human herpes virus 8 is etiologically associated with Kaposi sarcoma. In its early stages, this tumor contains blood vessels with a fine endothelium passing through the dermal collagen bundles. In the plaque and nodular stages, the vessel lumens are more clearly visible and there is a progressive increase in the number of neoplastic spindle cells with a low degree of pleomorphism and atypia, and occasional mitoses. The infiltrate is made up of lymphocytes and plasma cells. Contagious ecthyma and milker's nodule give rise to an acanthotic epidermis with ballooned keratinocytes containing eosinophilic cytoplasmic viral inclusions. Molluscum contagiosum shows lobules of epithelium that open onto the epidermal surface and characteristic inclusion bodies. Acanthosis, papillomatosis, and hyperkeratosis are observed in common warts, with confluence of the epidermal ridges in the centre of the lesion and koilocytes (AU)

Atypical parapoxvirus infection in sheep.

This report describes the clinical and laboratory findings for 5 sheep from 3 different flocks with extensive proliferative skin lesions grossly resembling warts on the distal limbs. The lesions affected the front and rear extremities in all sheep, and 2 sheep also had lesions around the head. The sheep exhibited signs of pain when the lesions were touched, and most sheep were reluctant to move. Various empirical treatments, including systemic antibiotics, topical antibiotics, and antifungal ointments, were administered without clinical improvement. Diagnostic tests including skin biopsy and histopathology, examination of skin scrapings, bacteriology, mycology, electron microscopy of lesions, and immunohistochemical analysis demonstrated that the lesions were the result of parapoxvirus infection. All 5 animals were euthanized either because of the lack of resolution of clinical signs or a decision by the owner. These animals illustrate an atypical presentation of parapoxvirus infection in sheep (orf, contagious ecthyma, and scabby mouth). The infection appeared to be minimally contagious; however, the lesions did not spontaneously resolve. This appears to be the 1st report of such lesions in multiple sheep in North America, although similar lesions have been reported in Israel and the United Kingdom.

Infection with parapoxvirus induces CD30-positive cutaneous infiltrates in humans.

Expression of CD30 is a distinct feature of B- or T-cell activation, found in Hodgkin's disease, large cell anaplastic lymphoma, lymphomatoid papulosis, as well as in certain viral infections such as human T-lymphotropic virus type I, HIV, hepatitis B and C virus, and Epstein-Barr virus. Here, we report highly proliferative CD30-positive cutaneous infiltrates in 3 patients with Milkers's nodules, adding parapoxvirus infection to the spectrum of CD30-positive benign lympho-proliferations.

Molecular genetic analyses of parapoxviruses pathogenic for humans.

The current members of the genus parapoxvirus are orf virus (ORFV), bovine papular stomatitis virus (BPSV), pseudocowpoxvirus (PCPV) and parapoxvirus of red deer in New Zealand (PVNZ). BPSV and PCPV are maintained in cattle while ORFV is maintained in sheep and goats, but all three are zoonoses. Only the recently reported PVNZ has yet to be recorded as infecting humans. Tentative members of the genus are camel contagious ecthyma virus, chamois contagious ecthyma virus and sealpoxvirus. The separation of the parapoxviruses into 4 distinct groups has been based on natural host range, pathology and, more recently, on restriction endonuclease and DNA/DNA hybridisation analyses. The latter studies have shown that the parapoxviruses share extensive homology between central regions of their genomes, but much lower levels of relatedness within the genome termini. The high G + C content of parapoxvirus DNA is in contrast to most other poxviruses and suggests that a significant genetic divergence from other genera of this family has occurred. DNA sequencing of portions of the genome of ORFV, the type species of the genus, has allowed a detailed comparison with the fully sequenced genome of the orthopoxvirus, vaccinia virus (VACV). These studies have provided a genetic map of ORFV and revealed a central core of 88 kbp within which the genomic content was strikingly similar to that of VACV. This conservation is not maintained in the genome termini where insertions, deletions and translocations have occurred. The characterisation of specific ORFV genes may lead to the construction of attenuated vaccine strains in which genes such as those with the potential to interfere with the immune response of the host have been deleted. The current ORFV vaccines are living unattenuated virus and vaccination lesions produce virus which contaminates the environment in a manner similar to natural infection. The virus in scab material is relatively resistant to inactivation and this virus both perpetuates the disease in sheep and provides the most likely source of human infections. A vaccine which immunises animals without perpetuating the disease could be the best way of reducing the incidence of ORFV infection of humans. It is likely that protection against infection by ORFV is cell mediated and will require the endogenous production of relevant antigens. We have recently constructed a series of VACV recombinants each of which contains a large multigene fragment of ORFV DNA. Together the recombinants represent essentially all of the ORFV genome in an overlapping manner. Vaccination of sheep with the recombinant library provided protection against challenge with virulent ORFV. Further studies with this library may enable dominant protective antigens of ORFV to be identified and lead to their incorporation into a subunit vaccine.