To Catch a Virus. John Booss
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Wilkinson, L. 2002. History, p. 1–22. In A. C. Jackson and W. H. Wunner (ed.), Rabies. Academic Press, Amsterdam, The Netherlands.
70 Williams, G. 1959. Virus Hunters. Alfred A. Knopf, New York, NY.
71 Woodruff, A. M., and E. W. Goodpasture. 1931. The susceptibility of the chorio-allantoic membrane of chick embryos to infection with the fowl-pox virus. Am. J. Pathol. 7:209–222.
72 Zinke, G. G. 1804. Neue Ansichten der Hundswuth, ihrer Ursachen und Folgen, nebst einer sichern Behandlungsart der von tollen Tieren gebissenen Menschen. C. B. Gabler, Jena, Germany.
3
Filling the Churchyard with Corpses: Smallpox and the Immune Response
In the final analysis, only an antibody response in the host constitutes definitive evidence of infection with a specific virus.
Principles of Internal Medicine, 1962 (16)
Introduction
The host is well defended against virus infections, for the immune system has several weapons at its disposal. Among these weapons are antibodies which develop in response to and are specifically targeted against the infecting agent. Antibodies perform a number of host defense functions, including combining with the virus, thereby neutralizing it, and attaching to infected cells to promote their destruction. Each of these activities prevents further multiplication and spread of the virus. Antibodies develop from days to weeks after infection, leaving evidence of specific viral infection. For decades the measurement of antibodies was the principal means by which viral diagnostic labs established the identity of a viral infection. Serological measurement of antibodies was less cumbersome and costly than the isolation of viruses in animal hosts. In addition to its highly accurate specificity, another remarkable feature of the immune system is memory, the basis by which the host recognizes the appearance of a previously encountered virus (32). Immunological memory is also the basis of vaccination. If a host can be exposed by vaccination to a virus or its components in a less harmful fashion than natural infection, immunity will be induced to protect against future infection.
The emergence of immunological concepts in the latter half of the 19th century and at the start of the 20th century and the development of assays to measure antibodies against invading pathogens transformed therapeutic approaches and management of infectious diseases. Like virology, the science of immunology developed in the wake of advances in bacteriology. Crucial to the development of immunology was the understanding of mechanisms of defense. These were first understood in the protection against reinfection for certain well-recognized diseases such as smallpox.
The early story of the immune response includes smallpox vaccination and the phagocytosis-versus-humoral immunity debate with the joint award of the Nobel Prize to Elie Metchnikoff and Paul Ehrlich in 1908 for their seminal work (1). Early assays including complement fixation, neutralization, and hemagglutination were fundamental to early viral diagnostic labs and made clinical laboratory diagnosis more accessible. With these key discoveries, Koch’s postulates gained new meaning as applied by T. M. Rivers for viral diseases (36).
Protection: the Case of Smallpox
The role of recovery from a first episode of an infectious disease in providing protection against another attack has been known for centuries. Characteristic traces of smallpox, pockmarks on the skin, were recognized as evidence of past infection and hallmarks of immunity to reinfection. Acute smallpox infection had to be distinguished from other viral exanthema such as measles. Rhazes, a Persian physician of the 10th century in Baghdad, wrote A Treatise on the Smallpox and Measles, which is regarded as a landmark in clinical description (34). Rhazes reported the symptoms that may precede the skin eruptions: “. . . a continued fever, pain in the back, itching in the nose, and terrors in sleep.” The authority of this treatise in Europe extended into the 17th century.
Two millennia before Rhazes, Ramses V died in 1157 BCE of what was assumed to be smallpox, and his body was mummified. Donald R. Hopkins recounts a remarkable episode in which he was granted permission by Egyptian president Anwar el Sadat to examine the front upper half of the unwrapped mummy in 1979 (19). After describing the rash of elevated “pustules,” Hopkins concluded that the appearance and distribution were “similar to smallpox rashes I have seen in more recent victims.” Hopkins, a physician who participated in the WHO Smallpox Global Eradication Programme, also wrote the classic treatise on the history of smallpox, Princes and Paupers. It was first published in 1983 and republished in 2002 with a new introduction as The Greatest Killer. While the exact origins of smallpox cannot be documented with certainty, it has been assumed that it arose millennia ago when aggregations of populations in towns and small cities emerged that supported epidemic spread.
The terror and dread occasioned by smallpox were well captured by the British historian Thomas Babington Macaulay in his History of England: “. . . the smallpox was always present, filling the churchyards with corpses, tormenting with constant fears all whom it had not yet stricken, leaving on those whose lives it spared the hideous traces of its power, turning the babe into a changeling at which the mother shuddered, and making the eyes and cheeks of the betrothed maiden objects of horror to the lover” (quoted in reference 10). Macaulay’s characterization of “all whom it had not yet stricken” is an implicit statement of the immunological protection of those “whose lives it spared.”
In contrast to lands where “the smallpox was always present,” populations in which smallpox had not previously existed were devastated on its first appearance. Nowhere, perhaps, is this more stunning and graphically illustrated than with its introduction into the western hemisphere—so stunning, in fact, that the American historian William McNeill began his seminal Plagues and Peoples asking how Hernando Cortez, with fewer than 600 soldiers, was able to conquer the Aztec empire of Mexico with its millions of inhabitants and later how Pizarro was able to conquer the Inca empire in South America (25). The scourge of smallpox nearly wiped out the previously unexposed Aztec and Inca populations, allowing Cortez easy victory over his diminished opposition. McNeill implicitly notes the role of immunological protection in that the Spaniards had the advantage of previous exposure to smallpox, whereas the Amerindians had not. He writes that smallpox was “. . . . a disease that killed only Indians and left Spaniards unharmed.” McNeill comments, “the lopsided impact of infectious disease upon Amerindian populations therefore offered a key to understanding the ease of the Spanish conquest of America—not only militarily but culturally as well.” Elsewhere on the North American continent, Francis Parkman wrote of a smallpox outbreak among the Huron Indians north of Lake Ontario in 1636: “Terror was universal . . . its ravages were appalling. . . . No house was left unvisited. . . . Everywhere was heard the wail of the sick and dying children” (quoted in reference 11). European history was also significantly influenced by smallpox: McNeill documents that smallpox altered the course of British political history. Hopkins termed the killing of kings, queens, an emperor, and a tsar in or around the 18th century “. . . a regicidal rampage without parallel . . .”