To Catch a Virus. John Booss
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target="_blank" rel="nofollow" href="#ulink_cc48e101-f2e8-585b-a6e9-8c1003d28111">36 Sternberg, G. M. 1890. Report on the Etiology and Prevention of Yellow Fever. U.S. Government Printing Office, Washington, DC.
37 Stokes, A., J. H. Bauer, and N. P. Hudson. 1928. Experimental transmission of yellow fever to laboratory animals. Am. J. Trop. Med. 8:103–164.
38 Theiler, M. 1930. Susceptibility of white mice to the virus of yellow fever. Science 71:367.
39 Theiler, M. 1930. Studies on the action of yellow fever virus in mice. Ann. Trop. Med. Parasitol. 24:249–272.
40 Winslow, C.-E. A. 1944. The Conquest of Epidemic Disease: a Chapter in the History of Ideas. Princeton University Press, Princeton, NJ.
41 Wright, W. 1930. Hieronymi Fracastorii: de Contagione et Contagiosis Morbis et Eorum Curatione, Libri III. G. P. Putnam’s Sons, New York, NY.
2
Of Mice and Men: Animal Models of Viral Infection
Our results with ferrets, so far as they have gone, are consistent with the view that epidemic influenza in man is caused primarily by a virus infection.
Smith, Andrewes, and Laidlaw, 1933 (57)
Introduction
Work with human volunteers for the study of yellow fever had created a backlash in Cuba, and Walter Reed had recognized that it was impossible to proceed. Unlike bacterial agents, which could often be grown on artificial media, viral agents required living cells in which to replicate. In viral diseases of plants, such as tobacco mosaic disease, the natural host was readily available and appropriate. The same was true of viral zoonoses, such as foot-and-mouth disease. For human diseases, such as rabies and polio, nonhuman hosts were necessary to isolate and characterize the etiological agent. Hence, efforts were made to isolate filterable viruses in a range of animal hosts. In addition, the embryonated egg was adapted from studies of embryology and physiology for the study of filterable viruses. In the case of rabies, a zoonosis that spreads from animals to humans with catastrophic results, the development of animal models might be expected to be productive. In contrast, polio and human influenza were not known to have animal hosts, nor was an animal host known for yellow fever. Yet, isolation and study of the agents for each of these diseases were achieved in experimental hosts. First for discussion is rabies.
Rabies: Dogs and Rabbits
Extensive experimental work on what would turn out to be the second human disease shown to be caused by a filterable virus, rabies, had been under way for virtually a century. The medical historian Lise Wilkinson credits Georg Gottfried Zinke’s 1804 publication as being “. . . the first description of experiments specifically intended to follow the transmission of the unknown agent of rabies” (69). Zinke reported successful transmission of rabies to several species, including dogs, cats, rabbits, and fowl (72). While certain characteristics, such as incubation time and clinical characteristics, differed from those in later reports, Zinke’s published work was an important landmark. Studies of diseases in animals in the 18th and 19th centuries involved agents of agricultural import—cattle plague (rinderpest), foot-and-mouth disease, bovine pleuropneumonia, and glanders—and established the basis for comparative medicine, the study of human diseases in animals (68). Rabies straddled human and animal medicine.
Rabies is horrific in all aspects: in the savage bites by crazed wolves or dogs to implant infection, in the anxiety and fear in anticipation of whether the disease will develop, in the torturing expression of the acute disease, and in the knowledge that once expressed, rabies is an essentially fatal disease. The fear induced by the approach of a rabid dog was used to good effect in Harper Lee’s To Kill a Mockingbird: “. . . motivated by an invisible force that was inclining him toward us. We could see him shiver like a horse shedding flies; his jaw opened and shut; he was alist, but he was being pulled gradually toward us” (35) (Fig. 1). Accounts of terrifying attacks by rabid wolves in country villages have played a role in the development of treatment. It has often been cited that one of the motivations for Pasteur’s study of rabies was a childhood memory of a rabid wolf attack on the village of Villers-Farlay and the town of Arbois (21) (Fig. 2). It was reported that Pasteur was 8 when he listened in horror to the screams of victims who had come to a blacksmith’s shop for “treatment”—cauterization. In 1886, soon after Pasteur’s publicity spread worldwide concerning postexposure prophylaxis treatment of rabies, 19 Russians came to Paris seeking treatment. In the cases of two victims of a rabid wolf’s attack, one had a lip and cheek bitten off, and the other’s face had been ripped off. Of the 19, 3 died during treatment and 16 ultimately returned to Russia (11). In 1955, the WHO, reporting on the use of hyperimmune serum and vaccine, described the effects of a rabid wolf’s attack on an Iranian village (2). Twenty-nine persons were bitten, 18 with severe head wounds, including a 6-year-old boy in whom a skull bone was crushed and the dura mater covering of the brain slashed. Remarkably, 25 of 29 wounded survived, including the young boy, who received intensive treatment with hyperimmune serum and vaccine.
Figure 1 Mad Dog. The fear of rabid dogs has been portrayed throughout history. This caricature by T. L. Busby was published in London in 1826. (Courtesy Yale University, Harvey Cushing/John Whitney Medical Library.)
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Figure 2 Louis Pasteur. Pasteur was one of the principal founders of germ theory. He disproved the theory of spontaneous generation; linked agricultural, animal, and human diseases to specific infections; and developed vaccinations, including that to prevent rabies. (Courtesy of the National Library of Medicine.)
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Rabies in humans may start after an incubation period of weeks or months with itching at the site of the bite and growing apprehension. Thereafter, aerophobia and hydrophobia may develop. The description of hydrophobia by D. A. Warrell et al. serves well: “The patient picks up a cup to drink but, even before the liquid has reached his lips, his arm begins to shake, he takes a rapid succession of inspiratory gasps, his neck muscles are seen to contract forcibly, and the spasm ends with throwing away his cup and falling back with neck extended” (64).