Smallpox WORLD OF MICROBIOLOGY AND IMMUNOLOGY520•
An unconventional agent causing slow infections has
now been identified as a non-viral “proteinaceous, infectious”
agent, or prion. Prionsgive rise to the group of diseases now
called transmissible spongiform encephalopathies. In animals
these include scrapie in sheep and bovine spongiform
encephalopathy (BSE) in cows. Human prion infections
include rare dementing diseases like kuru, Creutzfeldt-Jakob
disease (CJD), Gerstmann-Straussler-Scheinker (GSS) syn-
drome, and fatal familial insomnia (FFI). The prion agent is
replicated without provoking any antibodyresponse, appears
not to have any recognizable nucleic acid component, and is
resistant to conventional inactivation techniques for infectious
agents. Current evidence suggests that the prion protein is an
abnormal isoform of a normal host encoded protein known as
PrP, which is coded on the short arm of chromosome 20.
Prions appear to “replicate” by a novel form of protein-protein
information transfer, the abnormal PrP seemingly inducing the
normal protein to undergo a structural change into the abnor-
mal form. Most pathological changes observed with transmis-
sible spongiform encephalopathies are confined to the brain;
however, scrapie-induced disorders of the pancreas have also
been described. The neuropathology sometimes shows a dra-
matic spongiform disruption of brain tissue but may also be
subtle and non-characteristic, even at the terminal stages of the
disease. In the latter cases, diagnosis has to rely on features
like clinical signs, transmissibility, detection of abnormal PrP
or identification of mutationsin the PrPgene.
In humans, prion diseases may be sporadic, acquired or
inherited. Iatrogenic transmissions of the prion have occurred
following medical procedures such as pituitary growth hor-
mone injections, where the hormone source was contaminated
with prion tissue, or corneal transplants, where a patient acci-
dentally received an infected cornea. The first recognized
human prion disease was kuru, which emerged among the
South Fore people of New Guinea and is now generally
thought to have been transmitted by the practice of ritual can-
nibalism. CJD is today the most common human prion disease
occurring worldwide with a frequency of about one per mil-
lion per year. The peak incidence occurs in older people
between the ages 55 and 65 although recently a “new variant”
has emerged in the U.K., which affects individuals at a much
earlier age. It is widely believed that the new variant CJD is
closely related to the variety causing BSE in cattle and may be
contracted by the ingestion of infected beef.
Inherited prion disease can arise from specific point
mutations in the PrP gene. Perhaps 10–15% of CJD cases are
familial with an autosomal dominant pattern of inheritance.
Gerstmann-Straussler-Scheinker syndrome is another rare
familial condition that is vertically transmitted in an appar-
ently autosomal dominant way. As with other prion diseases it
can be horizontally transmitted to non-human primates and
rodents through intracerebral inoculation of brain
homogenates from patients with the disease. The exact inci-
dence of the syndrome is unknown but is estimated to be
between one and ten per hundred million per year and the con-
dition appears to be an allelic variant of familial Creutzfeldt-
Jakob disease. Fatal familial insomnia is the third most
common inherited human prion disease. The region of thebrain most affected in this condition is the thalamus which
monitors sleep patterns. The symptoms of the disease are char-
acterized by progressive insomnia and, as with other prion dis-
eases, eventual motor signs.See alsoViral geneticsSSmallpoxMALLPOX
Smallpox is an infection caused by the variola virus, a mem-
ber of the poxvirus family. Throughout history, smallpox has
caused huge epidemicsresulting in great suffering and enor-
mous death tolls worldwide. In 1980, the World Health
Organization(WHO) announced that a massive program of
vaccinationagainst the disease had resulted in the complete
eradication of the virus (with the exception of stored virus
stocks in two laboratories).
Smallpox is an extraordinarily contagious disease. The
virus can spread by contact with victims, as well as in con-
taminated air droplets and even on the surfaces of objects used
by other smallpox victims (books, blankets, etc.). After acqui-
sition of the virus, there is a 12–14 day incubation period, dur-
ing which the virus multiplies, but no symptoms appear. The
onset of symptoms occurs suddenly and includes fever and
chills, muscle aches, and a flat, reddish-purple rash on the
chest, abdomen, and back. These symptoms last about three
days, after which the rash fades and the fever drops. A day or
two later, the fever returns, along with a bumpy rash starting
on the feet, hands, and face. This rash progresses from the feet
along the legs, from the hands along the arms, and from the
face down the neck, ultimately reaching and including the
chest, abdomen, and back. The individual bumps, or papules,
fill with clear fluid, and, over the course of 10–12 days,
became pus-filled. The pox eventually scabs over, and when
the scab falls off it leaves behind a pock-mark or pit, which
remains as a permanent scar on the skin of the victim.
Death from smallpox usually follows complications
such as bacterial infectionof the open skin lesions, pneumo-
nia, or bone infections. A very severe and quickly fatal form of
smallpox was “sledgehammer smallpox,” and resulted in
hemorrhage from the skin lesions, as well as from the mouth,
nose, and other areas of the body. No treatment was ever dis-
covered for smallpox nor could anything shorten the course of
the disease. Up until its eradication, smallpox was diagnosed
most clearly from the patients’ symptoms. Electron micro-
scopicstudies could identify the variola virus in fluid isolated
from disease papules, from infected urine, or from the blood
prior to the appearance of the papular rash.
Smallpox is an ancient disease. There is evidence that a
major epidemic occurred towards the end of the eighteenth
Egyptian dynasty. Studies of the mummy of Pharaoh Ramses
V (d. 1157 B.C. ) indicate that he may have died of smallpox.
Several historical accounts, some dating to the sixth century,
describe how different peoples attempted to vaccinate against
smallpox. In China, India, and the Americas, from about the
tenth century, it was noted that individuals who had even a
mild case of smallpox could not be infected again. Materialwomi_S 5/7/03 8:20 AM Page 520