Smallpox and genetics

DEFINITION: Smallpox is a poxvirus, any of the family of viruses that produce pustules on the surface of the skin. It is a disease of humans existing in two forms. The more virulent and frequently lethal form is Variola major, and a milder form is Variola minor. Smallpox is very contagious, requiring strict quarantine measures and aggressive vaccination programs to contain and eradicate outbreaks.

Smallpox is a member of the Poxviridae family of viruses, which are the largest and most complex of all known viruses. Poxviruses are named for the characteristic rash or pox lesions that occur during most poxvirus infections. The poxviruses include a number of familiar diseases, such as smallpox, cowpox, rabbitpox, sheeppox, and fowlpox. Two subfamilies of poxviruses are recognized based on their hosts. The orthopoxvirus subfamily comprises viruses that affect vertebrates and includes smallpox; the poxviruses of the subfamily parapoxviruses infect invertebrates, primarily insects. There are two types of variola, the poxvirus that causes smallpox: V. major causes the more virulent and lethal form of smallpox in humans, and V. minor causes a milder form of smallpox. Both varieties infect only humans and monkeys. Other names or synonyms for smallpox include alastrim, amaas, Kaffir mil pox, West Indian modified smallpox, and para-smallpox.

Humans have had a long and unfortunate history of association with smallpox. The disease apparently originated in India and spread westward into the Middle East and northern Africa several thousand years ago. An Egyptian mummy of the Twentieth Dynasty shows the characteristic scarring associated with smallpox. Warriors returning from the Crusades brought the disease back with them. In the following centuries, smallpox became endemic throughout much of Europe and became a rite of passage for much of the population—those who contracted smallpox and survived were marked by its scars throughout life. In time, the population built up a partial immunity to the disease. Smallpox was carried by Europeans to the New World and to Australia during the age of exploration. It was spread to the immunologically defenseless Amerindians of North America and Aboriginals of Australia with devastating effect and may have contributed to the ease of European settlement, as it caused widespread death and devastation among the indigenous populations and was at least partly responsible for the depopulation of natives in the newly discovered lands. Before its eradication, smallpox was endemic throughout the world, with major centers of the disease in Africa, Asia, and the Middle East.

Risk Factors

Smallpox is a highly contagious disease, and therefore anyone who comes in contact with it is susceptible to it. Patients who have weak immune systems—such as those with human immunodeficiency virus (HIV) or cancer and organ transplant recipients—are at risk for severe cases of smallpox and would have higher mortality rates. People born after 1971 who did not receive primary immunization would also be highly susceptible.

Etiology and Genetics

The poxviruses are the largest and most complex of all the viruses that have so far been identified in animals. The variola virus that causes smallpox has a brick-shaped outer envelope and a dumbbell-shaped core that contains the smallpox genome. The smallpox genome is composed of linear, double-stranded DNA containing more than two hundred genes. Chemically, the smallpox virion consists of 90 percent protein, 3 percent DNA, and 5 percent lipid. The DNA genome codes for several hundred polypeptides, including several transcriptases responsible for of the virus within the cells of the host.

Replication of smallpox begins when the virus attaches to the surface of a host cell. After binding to receptors on the plasma membrane of the host cell, the host cell passes the virus into the cytoplasm by endocytosis. Once inside the cell, the virus becomes trapped in a lysosome vesicle in the cytoplasm. The first step in removing its viral coat probably occurs at this stage, as host cell enzymes dissolve the viral envelope. The viral core, containing the DNA, then exits the lysosome and enters the cytoplasm, where the viral genome can be expressed. One of the first steps involves the production of enzymes that degrade the proteins of the viral core, which releases the naked viral DNA into the cytoplasm. Additional transcription takes place, initially producing structural proteins and enzymes, including DNA polymerase, which promotes the replication of the viral DNA. Finally, the late messenger RNA (mRNA) is transcribed, producing additional structural proteins and assembly enzymes that complete virion construction. During viral replication, most host-cell protein synthesis is blocked because transport of host-cell mRNA molecules through the nuclear envelope into the cytoplasm is prevented.

Newly completed virions exit the host cell through microvilli on the cell surface or fuse with the cell membrane, after which they exit the cell by the process of exocytosis. Once in the tissue, fluids, and bloodstream, the newly released and highly infectious viral particles can invade and replicate in other host cells.

Smallpox is transmitted from one human to another, either by direct contact or via droplets released into the air during sneezing and coughing fits. The virus does not live long outside the human body and does not reproduce outside the human body. No natural animal carriers of variola other than monkeys, which are also susceptible, are known for the smallpox disease. In extremely rare cases, smallpox is transmitted by carriers that are themselves immune to the disease but can transmit the disease to others. Still, only a few droplets settling on another person are sufficient to transmit smallpox. Because of the virulence and mode of transmission, public health regulations specify decontamination procedures. Living quarters, bedding, clothes, and other articles of infected persons must be thoroughly cleansed by heat or with formaldehyde, or destroyed altogether.

Symptoms

Historically one of the most devastating and lethal of all human diseases, smallpox is named for the small pustules that occur as a rash over the skin of the victim. Smallpox symptoms include a rash that spreads over the entire body, high fever, chills, aches and pains, and vomiting. The most lethal form, black or hemorrhagic smallpox, results in death within two to six days. The fatality rate varies with health and previous exposure of the local population but ranges from 30 to 90 percent.

Infection occurs when the variola virus enters the respiratory mucosa of the nasal or pharyngeal region of the upper respiratory tract of humans. Apparently, only a few viral particles are needed to produce an infection. After a few hours or a few days, the virus migrates to and invades cells in the lymph nodes of the nasopharyngeal region, where it enters the cells, following which rapid reproduction occurs. After a few days, it enters the bloodstream, a condition called viremia. At this time, symptoms of smallpox appear. The virus spreads into lymph nodes, spleen, and bone marrow, where reproduction continues rapidly. By the eighth day of infection, the virus is contained in white blood cells, or leukocytes, which transmit it to the small blood vessels in the dermis of the skin as well as in the mucosa that lines the mouth and pharynx.

Following an incubation period of about two weeks (the range is between seven and seventeen days), symptoms appear, including high fever, headache, nausea, malaise, and often backache. Accompanying these symptoms is a rash that begins in the mouth and spreads across the face, forearms, trunk, and legs. The rash is first confined to a reddish or purplish swelling of the blood vessels but soon becomes pustular as little round nodules appear on the surface of the body. If the patient recovers, the pustules crust over and the resultant scabs eventually split, which causes scarring of the face.

Death occurs within a few days following the appearance of the rash, most commonly from toxemia caused by variola antigens and various immune complexes circulating in the blood. In some cases, the disease is followed by encephalitis. Smallpox fatalities typically occur because of complications such as pneumonia, septicemia, and nephritis (kidney failure). Survivors often suffer from general scarring, ulcers, scarring of the cornea leading to blindness, and skin abscesses. Treatment of survivors with chemotherapy has reduced the severity of many of these complications.

The considerably less virulent form of smallpox, Variola minor, produces a much less severe illness characterized by fever, chills, and a milder rash. The same conditions are sometimes seen in patients who have previously been vaccinated or even as a response to vaccinations.

Screening and Diagnosis

The Centers for Disease Control and Prevention (CDC) or a CDC Laboratory Response Network-designated variola testing facility can conduct a definitive examination for smallpox by testing a tissue sample from a lesion on the skin of an infected person. Even a single confirmed case of smallpox would be deemed an international emergency because of the devastating nature of the disease and concern that it may be used as a biological weapon.

Treatment and Therapy

Despite decades of research, there is no specific treatment for smallpox other than bed rest and the application of antibiotics to prevent secondary infections. Therefore, only prevention of spread by quarantine of infected persons prevents epidemics. Immediate recognition of the disease remains the strongest control measure, followed by vaccination of all health care personnel and others who may come in contact with infected persons.

Widespread and aggressive inoculation programs conducted during the first half of the twentieth century eradicated smallpox from most regions of the world, including North America, Eurasia, and Oceania, largely as a result of the success of the vaccination process originally developed by Edward Jenner. By 1967, smallpox was found only in thirty-three countries and had an annual infection rate of 10 million to 15 million cases. In that year, the World Health Organization (WHO) initiated a campaign to eliminate smallpox completely as a human disease, concentrating in Africa, India, and Indonesia. The last case of smallpox in Asia was reported in Bangladesh in 1975, and the last known smallpox victim was recorded in Somalia in October 1977. Smallpox eradication was considered accomplished by 1979. The cost of the eradication campaign was $150 million.

Most researchers conclude that the effective eradication of smallpox was made possible for several reasons: smallpox cases could be quickly and positively identified; there are no natural carriers that serve as disease reservoirs; humans were the only carriers; individuals who survived did not continue to harbor the virus; and the smallpox vaccine proved highly effective.

Vaccinia viruses (the active ingredient of the smallpox vaccine) can absorb comparatively large amounts of foreign DNA without losing their ability to replicate, giving rise to the idea that they may provide a vehicle for providing immunity for other viral diseases of humans. One of several ongoing investigations involves the insertion of twenty-two to twenty-five kilobase pairs into vaccinia. Experiments using this technique have produced vaccinia strains that encode surface proteins (antigens) of a number of important viruses, including influenza, hepatitis B, and herpesvirus. One possible outcome of these recombinant DNA experiments is the production of vaccinia strains that can serve as vaccines for several viral diseases simultaneously.

Prevention and Outcomes

Although smallpox was eradicated globally in 1979, at least two research stocks exist, and there is concern that clandestinely held stocks of the virus may be used as weapons of bioterrorism, the use of living organisms as instruments of terror, such as the deliberate introduction of diseases into civilian populations.

Since 1979, only two stocks of smallpox officially remain: one stock is held at the Centers for Disease Control in Atlanta, Georgia, and the other is kept at VECTOR, Novosibirsk, in central Russia. However, there remains the possibility that clandestine stocks still exist, and these stocks may serve as potential bioterrorism weapons, either to be used against military or civilian populations or to be mounted as international threats. The use of smallpox as a bioterrorism weapon would be classified as an international crime, but prevention of its use is difficult unless all existing stocks can be identified and destroyed.

Smallpox is a potential bioterrorism weapon because of its transmissibility, its known lethality, and the general lack of immunity of much of the global population. Because of its bioterrorism potential, research is now centered on rapid identification methods that enable the early detection of smallpox, as well as aggressive vaccination programs for individuals most at risk who have been identified as health care workers. In addition, smallpox vaccinations were reinstated in 2002 for some US military personnel and some health care workers, essentially those considered at highest risk. The vaccine is made from a live but weakened vaccinia virus that is pricked into the skin. The characteristic blisters scab over within three weeks. During this time, it is possible to transmit the virus to other parts of the body and to other people. Reactions to the vaccine range from a mild soreness around the vaccination site to more severe effects that may include brain inflammation and a rare and progressive bacterial inflammation called vaccinia that is sometimes fatal. For these reasons, mass vaccinations of the general public have been discouraged. In 2024, however, the US Food and Drug Administration approved the use of a smallpox vaccine in people who were at high risk of infection with mpox, a smallpox-related viral disease formerly known as monkeypox.

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