Orthopoxvirus genomes encode about 176 to 266 proteins, including a number of enzymes and factors that are necessary for self-replication and maturation. The central region of the genome contains highly conserved genes that are essential for viral replication, and the terminal regions contain less conserved genes that are important for virus-host interactions. Although it is well known that replication occurs in the cytoplasm, it is not clear how or if host cell nuclear factors are involved in viral replication or maturation.
Viral replication begins with attachment of viral particles to host cell surface, most likely through cell receptors, e.g., epidermal growth factor in the case of Vaccinia, and involves expression of early, intermediate, and late genes. Initial uncoating occurs during entry, followed by synthesis of early mRNAs which are translated to facilitate further uncoating and transcription of intermediate mRNAs. Intermediate mRNAs, in turn, are translated to allow transcription of the late mRNAs. The late mRNAs are translated into structural and enzymatic components of the virions. These components, along with DNA concatemers that are formed during the early phase of replication, are assembled into genomic DNA and packaged into immature virions, then infectious intracellular mature virions (IMV). The last step of viral replication is the acquisition by IMV of virus-altered Golgi membranes and plasma membranes, and formation of infectious extracellular mature virus (EMV).
The newly replicated progeny exits the lysed cells and invades other cells, repeating the cycle. The entire replication cycle is completed within about 12 hr. Within a few hours after infection, the virus takes over the cell machinery, inhibiting cellular DNA, RNA, and protein synthesis, and causing cell death.
Although orthopox viruses have highly similar morphological and genomic characteristics, they have distinct host preferences and vary considerably in their infectivity and pathogenicity.
Variola virus is specific for humans, but it has also been shown experimentally to cause lethal infections in nonhuman primates. The severity of human infections depends on the host immune response and the viral strain. Infections with Variola major induce severe, generalized, or systemic disease with fatality rates up to 40%, whereas infections with Variola minor cause a milder form of the disease with case fatality rates of 1% or less.
Vaccinia virus has no definitive host, but it has been isolated from camels, buffalos, cows, pigs, and rabbits. Vaccinia has been used in humans as a vaccine against smallpox infections because it produces mild, localized infections; however, it can also induce life-threatening complications in immune-compromised individuals.1-3-1
Cowpox virus is probably maintained in rodent reservoirs in nature, but can occasionally infect humans, elephants, cattle, cheetahs, cats, and other animals. Human infections with cowpox were known for centuries, but have been brought to public attention since the early vaccination attempts by Edward Jenner. Although most infections with cowpox produce localized lesions, severe infections were reported.
Monkeypox virus was first identified in laboratory-maintained cynomolgus monkeys. The virus is believed to have been circulating for a long time in numerous animal hosts, particularly squirrels, in central and western Africa. Human infections with monkeypox virus were first recognized in Zaire and later in Liberia and Sierra Leone. The disease caused by monkeypox virus closely resembles smallpox, but the pustular rash is mostly localized in the neck and groin areas. Most infections occur by direct contact with infected animals. Person-to-person transmission rarely occurs.
Mousepox (ectromelia) virus was first recognized as a mouse pathogen in 1930. Its pathogenesis differs from other orthopox viruses in that the virulent strains induce severe hepatitis in mice. It is highly infectious and can easily decimate mouse colonies in laboratories and breeding facilities. Vaccinating mice with the Vaccinia confers protection and has been used to control infections in mouse colonies. No human infections have been reported due to ectromelia. However, the virus was useful as model to study the molecular basis of Orthopoxvirus virulence despite the fact that the mouse disease differs significantly from smallpox.
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