2-year-old female goat, breed unspecified (Capra circus).Two female goats presented with multifocal to coalescing progressive ulcerative and crusting lesions on the commissures of the lips. Both goats were recently sent to another farm to be bred. The owner reports no change in appetite or behavior.
Portions of the lip were submitted for histopathological evaluation. Gross lesions consisted of multifocal to coalescing proliferative and ulcerative cheilitis.
Haired skin, lip: There was extensive multifocal epidermal hyperplasia with acanthosis up to 10 times normal thickness with elongated, anastomosing rete ridges. Multifocally within the stratum, spinosum, keratinocytes were markedly swollen and often contained clear intracytoplasmic vacuoles (ballooning degeneration) and pyknotic nuclei. Multifocally, rare keratinocytes contained one or more 2-6 μm, round to oval, eosinophilic intracytoplasmic inclusion bodies. Within the superficial stratum spinosum and stratum corneum, there was neutrophilic transmigration and multifocally there were microabscesses composed of aggregates of degenerate neutrophils admixed with eosinophilic cellular and karyorrhectic debris and abundant serum. There was multifocal spongiosis of the epidermis. Overlying the affected epidermis was a thick serocellular crust composed of keratin, proteinaceous fluid, degenerate neutrophils, and rare mixed bacteria. Within the dermis there were numerous dilated small caliber blood vessels separated by increased clear space and fibrin (edema), and moderate numbers of perivascular neutrophils, histiocytes, and lymphocytes.
Haired skin, lip: Cheilitis, proliferative and necrotizing, focally extensive, severe, with epidermal hyperplasia, hyperkeratosis, rare epidermal eosinophilic intracytoplasmic inclusion bodies, and intraepidermal and intracorneal microabscesses, breed unspecified, caprine.
Contagious ecthyma, also called contagious pustular dermatitis, is a zoonotic disease with worldwide distribution that affects sheep, goats, and man.(1-9,13,14,16,17) The causative agent is a dsDNA parapoxvirus (PPV).(1,3,5-9,16) PPV, also known as orf virus, gains entry through abraided skin and replicates in epidermal cells.(1,3,6-9,16,17) Skin lesions progress in an orderly fashion through multiple stages: erythema, macule, papule, vesicle, pustule, scab, and scar.(1-6,8,9,13,16,17) Infection is confined to the squamous epithelium and may involve the oral cavity, eyelids, teats, and coronary band, and predispose affected animals to secondary infections.(1,2,4,13,14,16,18) Very rarely, lesions extend to the squamous epithelium of the esophagus, rumen and omasum, causing ulcerative gastroenteritis.(1,2,4,18) Residual skin lesions are not infective once the scab falls off, but substantial amounts of infective virus are shed within scabs which can remain infective for years.(1,3-8,16) The disease has high morbidity and low mortality but can cause significant debilitation due to the inability of affected animals to suckle or graze.(4,6-9,13) Nursing animals often transfer the virus to adults, typically affecting the teats and udder.(1,3,4,6,7,9,13,14,17) There are several commercial vaccines for orf virus which contain virulent virus.(8,13) These vaccines are valuable because they limit the severity of disease, but they do not prevent infection, induce lesions, and contribute to maintenance of infective virus in the environment, so are only recommended for use in endemically infected herds.(8,13)
Gross lesions are characterized by multifocal to coalescing proliferative and ulcerative dermatitis which is localized to mucocutaneous junctions, particularly around the mouth and nares.(1,3,5,9,14) Histologic lesions are characterized by ballooning degeneration, exuberant epidermal hyperplasia with intracorneal pustules, and eosinophilic intracytoplasmic inclusion bodies within the stratum spinosum that are only briefly detectable at the vesicular stage.(1,3,4,8,9,17) There are frequently superimposed bacterial infections in the affected skin.(13)
Sheep previously exposed to orf virus can be repeatedly infected although the severity of the lesions and time to resolution diminishes with each subsequent infection.(1,6,8,13) This indicates that the host immune response can control the severity of disease but cannot prevent reinfection.(6) The reason is due, at least in part, to the presence of at least five immunomodulatory proteins expressed by orf virus that subvert or suppress elements of the host immune and inflammatory response, including:(2,5-8,11)
(1) Orf virus interferon resistance protein (OVIFNR): Host cells generally attempt to stop viral replication through interferon-induced activation of the double stranded RNA-dependent kinase (PKR) pathway.(5,7,8) In the presence of viral double-stranded RNA, the PKR pathway is induced by interferon and binds to viral dsRNA which inhibits virus (and host cell) protein translation, effectively blocking virus replication.(5-8) The orf virus encodes a protein, OVIFNR, which is a homologue of vaccinia virus E3L gene product, competitively binds to dsRNA and disallows activation of PKR, which ultimately promotes a permissive state for viral replication, leading to sustained protein synthesis and completion of the virus life cycle.(5-8) In other words, the OVIFNR protein prevents activation of PKR and protects the virus from the antiviral effects of interferons, allowing viral replication.(5-8)
(2) Granulocyte/macrophage colony-stimulating factor (GM-CSF) inhibitory factor (GIF): GIF binds to and inhibits the biological activity of the cytokines GMCSF and interleukin2 (IL-2).(2,5-7) In non-hematopoietic tissues, GMCSF is involved in the recruitment and activation of macrophages and neutrophils.(6,8) GMCSF also supports the recruitment and antigen-presenting function of dendritic cells (DC).(6,8) IL2 is required for T cell proliferation and activation, for example, the augmentation of T cell IF gamma production and to expand CTL and NK cell populations.(6) Inhibition of these two important cytokines significantly impedes the development of both innate and acquired immune responses.
(3) Orf viral interleukin 10 (ORFV-IL-10): The initiation of an acquired immune response to a virus requires that antigen be taken up by DC at the periphery, and then processed and transported to lymphoid tissue to be presented to T cells.(7,11) For this to occur, DC must first be activated by signals transmitted through the interaction of viral products with pattern recognition receptors expressed on the surface of the DC.(11) DC therefore form the vital bridge between the innate and acquired arms of the immune response.(11) IL-10 is an immunoregulatory cytokine that inhibits both innate and adaptive immune responses and is produced by macrophages and dendritic cells in response to microbial products.(17) It is produced by multiple T cell subsets, including all three populations of helper T cells (Th1, Th2, and Th17).17 IL10 is able to down regulate MHC class II and co-stimulatory molecule expression on DC and macrophages, thus decreasing antigen presentation.(7,17) Orf virus-encoded interleukin-10 (ORFVIL10), a homologue of IL-10, has specifically been shown to suppress the migration of Langerhans cells (LC) and inhibit DC function in addition to suppressing inflammation and the innate immune response.(11) ORFV-IL-10 has the capacity to impair the initiation of an acquired immune response and hence inhibit the generation of immunological memory necessary for immunity of subsequent exposure.(11) ORFV-IL-10 may be capable of inhibiting the activation of memory cells recruited to infected skin following reinfection, as well as having the potential to inhibit the activation of na+â-»ve T cells that would otherwise be brought about by activated LC trafficking to the draining lymphoid tissue.(11) The implications of this are that on repeated cycles of infection, the virus can replicate, shed, and be transmitted to other hosts before elimination by the acquired immune response.(11)
(4) Orf virus chemokine-binding protein (CBP): Orf virus produces a novel CBP that binds CC chemokines such as monocyte chemotactic protein-1, macrophage inflammatory protein-1-alpha and RANTES (regulated upon activation normal T cell expressed and secreted) that control monocyte/macrophage and T cell recruitment to sites of infection.(5) Orf virus CBP also binds lymphotactin, a C chemokine that recruits T cells, B cells and neutrophils through the XCR1 receptor.(5) This provides further evidence that orf virus has evolved to inhibit important cellular elements of an anti-viral immune response.(5)
(5) Orf virus vascular endothelial growth factor (VEGF): Orf virus VEGF functions in the same way as cellular VEGFs, causing vascular proliferation and angiogenesis.(5,6,8,16) Orf virus lesions in sheep are characterized by vascular proliferation and dilation as well as epidermal proliferation.(5,8,16) The induction of epidermal proliferation by orf virus is probably important in supplying an abundance of target epidermal cells for virus replication.(5,8,16) Additionally, host cell VEGF has the ability to inhibit the development and maturation of dendritic cells.(5,8) If viral VEGF also has this ability, it would benefit the virus because of the important role that dendritic cells play in the generation and maintenance of immune responses.(5)
Mucocutaneous junction: Epithelial hyperplasia, diffuse, severe, with marked acanthosis, focally extensive necrosis, ballooning degeneration and rare intracytoplasmic viral inclusions.
The contributor provides an excellent, comprehensive review of parapoxviruses. This genus causes epitheliotropic disease in a number of species of veterinary importance, in addition to sheep and goats. Papular stomatitis virus causes proliferative to ulcerative lesions on the lips and oral mucosa of cattle, while pseudocowpox virus causes similar lesions on the teats of dairy cattle and on the muzzles and mouths of nursing calves.(13) A parapoxvirus has been blamed for the sporadic occurrence of pustular facial dermatitis in camels(13) as well as New Zealand farmed red deer.(10) Additionally, outbreaks of contagious ecthyma have resulted in serious economical loss in Norwegian reindeer.(10) Sealpox virus, which produces self-limiting ulcerative dermal nodules in some pinniped species, has also been tentatively classified as a parapoxvirus.(15) The red squirrel population in the United Kingdom has been devastated by what was initially classified as a parapoxvirus, but is more likely a closely related poxvirus from the subfamily Chordopoxvirinae. American grey squirrels, which are relatively resistant to this virulent squirrelpox virus, likely serve as a reservoir for disease in the more susceptible red squirrel population.(12)
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