Experimental Transmission of Yellow Fever to Laboratory Animals 1

Stokes, Adrian; Bauer, Johannes H.; Hudson, N. Paul

doi:10.4269/ajtmh.1928.s1-8.103

Cited by 137 publications

(39 citation statements)

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“…Strains of Virus.--The strain of virus used to initiate these series of tissue culture experiments was the so called Asibi strain (1). The history of this strain from the time of its isolation from man to adaptation and growth in tissue culture has already been reported in full (8).…”

Section: Methodsmentioning

confidence: 99%

The Effect of Prolonged Cultivation in Vitro Upon the Pathogenicity of Yellow Fever Virus

Theiler

Smith

1937

Journal of Experimental Medicine

211

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1. Experimental evidence is presented to show that prolonged cultivation of yellow fever virus in vitro results in a change in its pathogenicity, and that this change varies with the type of tissues used for the cultivation. 2. In the tissue cultures used for the propagation of the virus, three different types of tissues were used. They included whole mouse embryo, chick embryo from which the head and spinal cord had been removed, and testicular tissues of mice and guinea pigs. 3. The changes in the pathogenicity of the virus cultivated for a period of over 3 years in a medium containing the tissues of whole mouse embryo were not striking. The viscerotropic virulence of the virus appeared somewhat diminished, in that when injected subcutaneously into rhesus monkeys or hedgehogs it failed to produce a fatal infection, although there is evidence to indicate that a generalized infection takes place as demonstrated by the appearance of virus in the circulating blood in relatively high concentration during infection. The neurotropic virulence of the virus remained unaltered during the cultivation in this medium. 4. The changes in the pathogenicity of the virus cultivated in medium containing tissues of chick embryo from which the head and spinal cord had been removed were very pronounced. The viscerotropic virulence of the virus was lost to a large extent. When injected subcutaneously into monkeys there was as a rule a very mild generalized infection, as demonstrated by the minimal quantities of virus found in the circulating blood. Its neurotropism was also much diminished. When injected into monkeys intracerebrally, it no longer produced a fatal encephalitis but only a moderate febrile reaction, followed by recovery and solid immunity to reinoculation with a highly virulent strain of virus. When injected intracerebrally into mice, the mortality ratio was not diminished but the incubation period was markedly prolonged. 5. The changes in the pathogenicity of the virus cultivated in medium containing testicular tissues were somewhat similar to those observed after cultivation in chick embryo medium which contained only a minimal amount of nervous tissue. Its viscerotropic affinity had been largely lost and only very small amounts of virus were found in the circulating blood of monkeys inoculated subcutaneously. Given intracerebrally, it produced death from encephalitis in monkeys. The incubation period in mice inoculated intracerebrally with this virus was also prolonged but somewhat less so than with the virus grown in chick embryo tissues without the central nervous system.

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Section: Methodsmentioning

confidence: 99%

The Effect of Prolonged Cultivation in Vitro Upon the Pathogenicity of Yellow Fever Virus

Theiler

Smith

1937

Journal of Experimental Medicine

211

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“…Because there was no recognized, susceptible laboratory host, many years elapsed before the virus responsible was isolated by the Rockefeller Foundation's West Africa yellow fever commission. In 1927, these workers succeeded in isolating a virus from the blood of a young Ghanian named Asibi by monkey/monkey passage (3). This Asibi strain of yellow fever causes an invariably fatal disease when inoculated into rhesus monkeys.…”

mentioning

confidence: 99%

Comparison of the virulent Asibi strain of yellow fever virus with the 17D vaccine strain derived from it.

Hahn¹,

Dalrymple²,

Strauss³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

211

154

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We have sequenced the virulent Asibi strain of yellow fever virus and compared this sequence to that of the 17D vaccine strain, which was derived from it. These two strains of viruses differ by more than 240 passages. We found that the two RNAs, 10,862 nucleotides long, differ at 68 nucleotide positions; these changes result in 32 amino acid differences. Overall, this corresponds to 0.63% nucleotide sequence divergence, and the changes are scattered throughout the genome. The overall divergence at the level of amino acid substitution is 0.94%, but these changes are not randomly distributed among the virus proteins. The capsid protein is unchanged, while proteins NS1, NS3, and NS5 contain 0.5% amino acid substitutions, and proteins ns4a and ns4b average 0.8% substitutions. In contrast, proteins ns2a and ns2b have 3.0 and 2.3% amino acid divergence, respectively. The envelope protein also has a relatively high rate of amino acid change of 2.4% (a total of 12 amino acid substitutions). The large number of changes in ns2a and ns2b, which are largely conservative in nature, may result from lowered selective pressure against alteration in this region; among flaviviruses, these polypeptides are much less highly conserved than NS1, NS3, and NS5. However, many of the amino acid substitutions in the E protein are not conservative. It seems likely that at least some of the difference in virulence between the two strains of yellow fever virus results from changes in the envelope protein that affect virus binding to host receptors. Such differences in receptor binding could result in the reduced neurotropism and vicerotropism exhibited by the vaccine strain.

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“…The tragic ends of Guillet, Adrian Stokes, Young, and Noguchi on the West Coast of Africa dramatically directed attention to the dangers of direct infection, while, as Hindle (1930) points out, the frequency of laboratory infections in Europe and America during the past two years has proved beyond all doubt the danger to man of direct virus transmission from contact with the blood of infected monkeys during life, or with their organs at necropsy. As a result of the death of Adrian Stokes, who had not been working with infected mosquitos for several months, Bauer and Hudson (1928) investigated the passage of virus through the skin of monkeys. They showed that yellow fever resulted if infected blood was merely rubbed on the normal intact skin of the abdomen of Macacus rhesus, but they stress the delicacy of the dermis in this situation, and point out that these experimental results did not determine whether the virus was capable of penetrating the normal -unimpaired human skin of the hands, which is of thicker and denser texture.…”

Section: Discussionmentioning

confidence: 99%