<unk>  was caused by infection with Variola virus, which belongs to the family Poxviridae, subfamily Chordopoxvirinae, and genus Orthopoxvirus. Evolution The date of the appearance of<unk>  is not settled. It most probably evolved from a terrestrial African rodent virus between 68,000 and 16,000 years ago. The wide range of dates is due to the different records used to calibrate the molecular clock. One clade was the Variola major strains (the more clinically severe form of<unk>  which spread from Asia between 400 and 1,600 years ago. A second clade included both Alastrim minor (a phenotypically mild<unk>  described from the American continents and isolates from West Africa which diverged from an ancestral strain between 1,400 and 6,300 years before present. This clade further diverged into two subclades at least 800 years ago. A second estimate has placed the separation of variola from Taterapox (an Orthopoxvirus of some African rodents including gerbils) at 3,000 to 4,000 years ago. This is consistent with archaeological and historical evidence regarding the appearance of<unk>  as a human disease which suggests a relatively recent origin. If the mutation rate is assumed to be similar to that of the herpesviruses, the divergence date of variola from Taterapox has been estimated to be 50,000 years ago. While this is consistent with the other published estimates, it suggests that the archaeological and historical evidence is very incomplete. Better estimates of mutation rates in these viruses are needed. Examination of a strain that dates from c. 1650 found that this strain was basal to the other presently sequenced strains. The mutation rate of this virus is well modeled by a molecular clock. Diversification of strains only occurred in the 18th and 19th centuries. Virology Variola is a large brick-shaped virus measuring approximately 302 to 350 nanometers by 244 to 270 nm, with a single linear double stranded DNA genome 186 kilobase pairs (kbp) in size and containing a hairpin loop at each end. The two classic varieties of<unk>  are variola major and variola minor. Four orthopoxviruses cause infection in humans: variola, vaccinia, cowpox, and monkeypox. Variola infects only humans in nature, although primates and other animals have been infected in an experimental setting. Vaccinia, cowpox, and monkeypox viruses can infect both humans and other animals in nature. The life cycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. Poxviruses are unique among DNA viruses in that they replicate in the cytoplasm of the cell rather than in the nucleus. To replicate, poxviruses produce a variety of specialized proteins not produced by other DNA viruses, the most important of which is a viral-associated DNA-dependent RNA polymerase. Both enveloped and unenveloped virions are infectious. The viral envelope is made of modified Golgi membranes containing viral-specific polypeptides, including hemagglutinin. Infection with either variola major or variola minor confers immunity against the other. Transmission Transmission occurred through inhalation of airborne Variola virus, usually droplets expressed from the oral, nasal, or pharyngeal mucosa of an infected person. It was transmitted from one person to another primarily through prolonged face-to-face contact with an infected person, usually, within a distance of , but could also be spread through direct contact with infected bodily fluids or contaminated objects (fomites) such as bedding or clothing. Rarely,<unk>  was spread by virus carried in the air in enclosed settings such as buildings, buses, and trains. The virus can cross the placenta, but the incidence of congenital<unk>  was relatively low.<unk>  was not notably infectious in the prodromal period and viral shedding was usually delayed until the appearance of the rash, which was often accompanied by lesions in the mouth and pharynx. The virus can be transmitted throughout the course of the illness, but this happened most frequently during the first week of the rash when most of the skin lesions were intact. Infectivity waned in 7 to 10 days when scabs formed over the lesions, but the infected person was contagious until the last<unk>  scab fell off.<unk>  was highly contagious, but generally spread more slowly and less widely than some other viral diseases, perhaps because transmission required close contact and occurred after the onset of the rash. The overall rate of infection was also affected by the short duration of the infectious stage. In temperate areas, the number of<unk>  infections was highest during the winter and spring. In tropical areas, seasonal variation was less evident and the disease was present throughout the year. Age distribution of<unk>  infections depended on acquired immunity. Vaccination immunity declined over time and was probably lost within thirty years.<unk>  was not known to be transmitted by insects or animals and there was no asymptomatic carrier state.
Smallpox
Monkeypox
Cowpox
Impetigo
Chickenpox
Sealpox
Molluscum contagiosum
Mumps