Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis.

Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during infection antagonize cellular apoptotic pathways. Poxvirus products target multiple points in both the extrinsic and intrinsic apoptotic pathways, thereby mitigating apoptosis during infection. Interestingly, recent evidence indicates that poxviruses also hijack cellular means of eliminating apoptotic bodies as a means to spread cell to cell through a process called apoptotic mimicry. Poxviruses are the causative agent of many human and veterinary diseases. Further, there is substantial interest in developing these viruses as vectors for a variety of uses including vaccine delivery and as oncolytic viruses to treat certain human cancers. Therefore, an understanding of the molecular mechanisms through which poxviruses regulate the cellular apoptotic pathways remains a top research priority. In this review, we consider anti-apoptotic strategies of poxviruses focusing on three relevant poxvirus genera: Orthopoxvirus, Molluscipoxvirus, and Leporipoxvirus. All three genera express multiple products to inhibit both extrinsic and intrinsic apoptotic pathways with many of these products required for virulence.

Infecção por pox vírus e Aspergillus fumigatus em Bubo virginianus (Coruja jacurutu) / Avipoxvirus infecction in Bubo virginianus (great horned owl)

Este trabalho descreve um caso de infecção mista por pox vírus e Aspergillus fumigatus em Bubo virginianus (coruja jacurutu). A ave, um macho adulto, foi encaminhada ao Núcleo de Reabilitação da Fauna Silvestre do Instituto de Biologia da Universidade Federal de Pelotas (NURFS/CETAS/UFPEL). Apresentava bom estado corporal, estava ativa, porém com incapacidade de voo. Após três dias apresentou lesões crostosas e de aspecto verrucoso na superfície dorsal das patas. Havia, também, nódulos de mesmo aspecto na pálpebra esquerda e na cera. A ave morreu após 15 dias de sua chegada ao NURFS e foi necropsiada no Laboratório Regional de Diagnóstico da Faculdade de Veterinária da Universidade Federal de Pelotas (LRD/UFPel). Histologicamente, as lesões verrucosas caracterizavam-se por hiperplasia do epitélio e nas células das camadas basal, espinhosa, granular e córnea havia corpúsculos de inclusão intracitoplasmáticos do tipo Bollinger. Na microscopia eletrônica foram visualizadas partículas virais características de pox vírus, incluindo Bubo virginianus como um hospedeiro do vírus. Havia, ainda, infiltrado inflamatório de células mononucleares e focos de colônias bacterianas na derme. Nos pulmões havia congestão e presença de granulomas com hifas fúngicas, que pela técnica de Grocott, apresentaram ramificação dicotômica compatível com Aspergillus spp., identificado na cultura como A. fumigatus. O diagnóstico de infecção por avipoxvirus pode contribuir para estudos relacionados com a ocorrência desta doença nas populações de vida livre e como informação auxiliar para o manejo e conservação desta espécie. Sugere-se, ainda, a inclusão do uso de raios-X nos protocolos de centros de reabilitação como o diagnostico de aspergilose em aves rapinantes com bom estado corporal, porém incapazes de voar.(AU)

This paper describes a case of mixed infection by pox virus and Aspergillus fumigatus in Bubo virginianus (Owl Jacurutu). An adult male Bubo virginianus was referred to the Núcleo de Reabilitação da Fauna Silvestre, Instituto de Biologia, Universidade Federal de Pelotas (NURFS/CETAS/UFPEL). The owl was active and had a good body condition but with flight disability. After three days of their admission at NURFS the owl developed crusty and verrucous lesions at the dorsal surface of their feet. Also it had nodes on the left eyelid and cera with the same aspect. The owl died 15 days after its arrival. Necropsy and histopatological examination were carried out. The warty lesions had hyperplasia of the epithelium and intracytoplasmic Bollinger-like inclusion bodies in the basal, spinal, granulosa layer and cornea. Viral particles characteristic of pox viruses were shown by electron microscopy. This case includes Bubo virginianus as a host of the avipoxvirus. There were also a mononuclear inflammatory cell infiltrate and bacterial colonies in the dermis. In the lugs, there was congestion and presence of granulomas with intralesional fungal hyphae. With the Grocott stain those structures showed dichotomous branching which was later identified in mycological culture as characteristic for A. fumigates. The diagnosis of avipoxvirus infection can contribute to studies related to the occurrence of this disease in free-living populations and as auxiliary information for the management and conservation of this raptor species. It is also suggested to include the use of X-rays in rehabilitation center protocols as screening test to diagnose aspergillosis in birds of prey with good body condition but inability to fly.(AU)

Myxoma virus selectively disrupts type I interferon signaling in primary human fibroblasts by blocking the activation of the Janus kinase Tyk2.

Poxviruses currently are known to disrupt Jak-STAT signal transduction induced by interferon (IFN) through two distinct mechanisms: (1) secreted poxviral IFN decoy receptors that prevent the initiation of IFN signaling from type I or II receptors at the cell surface; and (2) poxviral phosphatase that dephosphorylates STAT1 intracellularly. Here, we report a novel mechanism by which poxviruses can inhibit Jak-STAT signaling in response to type I IFN. Myxoma virus (MV) is a highly species-restricted member of the poxvirus family that infects only rabbits under the natural setting. Interestingly, primary human fibroblasts support a permissive MV infection that is only partially sensitive to the antiviral state induced by type I IFN. In this study we show that when type I IFN is added to primary human fibroblasts following MV infection, the tyrosine phosphorylation of the Janus kinase Tyk2 is specifically blocked, thereby preventing the subsequent activation of downstream STAT1 and STAT2. In stark contrast, type II IFN-induced activation of Jak1, Jak2 and STAT1 remains largely unaffected in MV-infected human fibroblasts. Unlike the de-activation of STAT1 by the poxvirus phosphatase, which is delivered into the cell by the input virions, the Tyk2 inhibition by MV infection requires new viral gene expression. Thus, our study documents a previously unrecognized immune evasion mechanism exploited by a poxvirus to selectively disrupt the type I IFN-Jak-STAT signaling cascade.

Construction and evaluation of live attenuated myxoma virus vaccines with targeted virulence gene deletions.

Three deletion mutant viruses were constructed as potential vaccines against myxomatosis using the naturally attenuated Uriarra strain of myxoma virus. The viruses had the M007 (encodes a secreted gamma-interferon receptor homologue), M010 (encodes an epidermal growth factor homologue) and M011 (encodes an inhibitor of apoptosis in T lymphocytes) genes insertionally inactivated as either DeltaM007, DeltaM010/M011 or DeltaM007/M010/M011. All three viruses induced high serum antibody titres. Rabbits immunized with these deletion mutants were protected from lethal challenge. However, immunization of adult rabbits with DeltaM007 or DeltaM010/M011 was associated with mild clinical signs that would make these viruses unacceptable as vaccines. The triple gene knock-out virus (DeltaM007/M010/M011) termed Ur-TKO was very well tolerated by adult and juvenile rabbits. The low pathogenicity of Ur-TKO was confirmed by pathogenesis studies in domestic and wild rabbits.

Poxvirus host range genes.

As a family of viruses, poxviruses collectively exhibit a broad host range and most of the individual members are capable of replicating in a wide array of cell types from various host species, at least in vitro. At the cellular level, poxvirus tropism is dependent not upon specific cell surface receptors, but rather upon: (1) the ability of the cell to provide intracellular complementing factors needed for productive virus replication, and (2) the ability of the specific virus to successfully manipulate intracellular signaling networks that regulate cellular antiviral processes downstream of virus entry. The large genomic coding capacity of poxviruses enables the virus to express a unique collection of viral proteins that function as host range factors, which specifically target and manipulate host signaling pathways to establish optimal cellular conditions for viral replication. Functionally, the known host range factors from poxviruses have been associated with manipulation of a diverse array of cellular targets, which includes cellular kinases and phosphatases, apoptosis, and various antiviral pathways. To date, only a small number of poxvirus host range genes have been identified and studied, and only a handful of these have been functionally characterized. For this reason, poxvirus host range factors represent a potential gold mine for the discovery of novel pathogen-host protein interactions. This review summarizes our current understanding of the mechanisms by which the known poxvirus host range genes, and their encoded factors, expand tropism through the manipulation of host cell intracellular signaling pathways.

Experimental infection of Macaca mulatta monkeys with Lednice (Yaba 1) virus.

Macaca mulatta monkeys were inoculated with Lednice (Yaba 1) virus strain 6118. The animals developed no clinical signs and the body temperature and values of complete haematological examination remained within normal limits. In spite of positive immunofluorescence in regional lymph nodes, no virus could be recovered from them by passages in mice. Viraemia was not demonstrated. The antibody response was directly proportional to the amount of virus inoculated, i.e. it was significant after a higher virus dose or after repeated inoculation. The results obtained are discussed in respect of and in comparison with serological findings in man.