The administration of cortisone to chick embryos inoculated with large quantities of inactive influenza B virus results in a rate of viral increase greater than is concommittantly observed with inocula of comparable infectivity which are devoid of inactive particles. Thus, more than a mere negation of autointerference is effected. It is concluded that in the presence of cortisone reactivation has occurred of non-infective virus to a state in which it can participate in viral synthesis. Cortisone-induced viral reactivation is dependent upon a high partide/cell ratio and is thus analogous to the previously described phenomenon of "multiplicity reactivation." Cortisone does not influence either homologous or heterologous viral interference unless reactivation of the inactive interfering virus occurs. Virus reactivable with cortisone possesses both interfering and enzymatic properties. Reactivation of virus with cortisone cannot be effected in vitro but is mediated by the host cell. Two hypotheses concerning the action of cortisone are presented.
The interference with viral synthesis which is induced by large quantities of non-infective influenza B virus is inhibited or negated with small quantities of cortisone and other C-21 steroids. The specificity of this effect is attested by the inactivity of 11-alpha hydroxy epimers of highly active compounds. Maximal activity in negation of interference is associated with the presence of oxygen at the C-11 position of the steroid molecule. In view of the demonstration that negation of interference can occur, it is concluded that the phenomenon of multiplicity reactivation of non-infective virus is not primarily influenced by cortisone. Rather, it is suggested that the reactivation phenomenon is unmasked by cortisone through its inhibiting effect on the autointerference intrinsic in multiplicity infection. If it is accepted that influenza virus infections in ovo are self-limited in part by viral autointerference, present evidence is consistent with the view that negation of this autointerference is the mechanism by which cortisone induces definitively increased yields of virus.
Virtually all reports of the influence of cortisone on viral infections have stressed the deleterious effects of cortisone on the infected host and an associated increase in concentrations of the infecting virus. The first such study in which viral concentrations were measured was of influenza virus infection of the chicken embryo (1). More recent investigations of the dynamics of influenza virus increase in cortisone-injected embryos has confirmed the original report of increased final concentrations of virus, but has disclosed the paradox of an initial inhibition of virus formation with cortisone (2). The present report will describe more fully the inhibition of influenza A and B virus multiplication with cortisone and will discuss preliminary inquiries into the mechanism of this effect. Materials and MethodsMost of the material and methods employed have been described fully (2, 3). In addition, the following materials and methods were used:Purified growth hormone was obtained through the kindness of Dr. C. H. Li. It was used in aqueous solution with an initial concentration of 10 mg./ml.Cortisone.--Hydrocortisone diethylaminoacetate hydrochloride (aqueous solubility 100 mg./ml.) and desoxyhydrocortisone (compound S) were kindly provided by Dr. G. M. Shull of Chas. Pfizer and Co., Inc., Brooklyn.Dry weight determinations of chicken embryos were made following desiccation of pooled groups of 4 to 8 embryos at 100°C. in a dry oven for 24 to 48 hours. EXPERIMENTAL RESULTS Measurement of Virus.--Earlier
In the Spring of 1947 an epidemic of streptococcal pharyngitis and scarlet fever attacked a large permanent army post 5 numbering about eight thousand troops. A carrier survey just prior to this outbreak had disclosed a high rate (17 per cent) of carriers of beta hemolytic streptococci. Study of these organisms and those isolated from patients during the epidemic revealed that all were of Lancefield Group A. Seven-eighths of those isolated from carriers, and all streptococci isolated from patients, were either type 23 or 19. Infections caused by type 23 predominated and constituted about 70 per cent of all cases.During a 60-day period, 184 patients received a preliminary diagnosis of streptococcal pharyngitis or scarlet fever and were placed in a special study group at the time of their admission to the post station hospital.The objectives of this study were: (1) to evaluate and delineate the natural history of streptococcal pharyngitis in the young male, (2) to assess the value of three treatment schedules (detailed below), and (3)
Earlier publications have presented evidence that the course of influenza virus infection in chicken embryos, mice, and tissue culture is strikingly affected by the administration of corticosteroid hormones. It has been shown that under appropriate experimental conditions final yields of virus are increased (1-3), that antibody formation, acquired immunity (4), and inflammatory reaction (3) are depressed, that the survival time of infected chicken embryos is prolonged (3), and that "multiplicity reactivation" of non-infective virus is clearly demonstrable (5).Ensuing studies have clarified the mechanisms of cortisone action in the influenza virus-chicken embryo system. The results of these studies are presented in this and two companion papers. It will be demonstrated that cortisone and related steroids have two distinct effects on the course of influenza virus multiplication: (a) inhibition of viral synthesis, and (b) inhibition of the autointerference caused by large numbers of viral particles. Yields of virus will be shown to be the resultant of these two contrasting effects.The present paper is concerned with the influence of cortisone on the dynamics of influenza virus increase. It will be evident that consideration of these kinetics has been essential in defining the mechanisms of cortisone action. Materials and MethodsViruses.--The Lee strain of influenza B virus and the PR8 strain of influenza A virus were used as allantoic fluid suspensions. Dilutions of virus were made in 0.01 M phosphate buffered NaC1 (0.85 per cent) solution. To "inactive" viral inocula derived from thermally inactivated virus were added streptomycin (1 mg./ml.) and penicillin (100 units/ml.). Preparations designated as "active" virus were prepared as suggested by Horsfall (6, 7) to contain a relatively high proportion of infective viral particles (see Kilbourne (5)). Viruses were stored at --68°C. in a special CO~ box in which CO2 is excluded from the specimen compartment (8). RDE *
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