Studies on the Pathogenesis of Fever With Influenzal Viruses

Abstract

A substance with pyrogenic properties appears in the blood streams of rabbits made febrile by the intravenous inoculation of the PR8 strain of influenza A and Newcastle disease viruses (NDV). By means of a technique involving passive transfer of sera from animals given virus to recipient rabbits, the titer of circulating pyrogen was found to be closely correlated with the course of fever produced by virus. Certain properties of the pyrogen are described which differentiate it from the originally injected virus and suggest that the induced pyrogen is of endogenous origin. These properties resemble those of endogenous pyrogens occurring in other forms of experimental fever. The source of virus-induced pyrogen is unknown. In vitro incubation of virus with various constituents of the circulation did not result in the appearance of endogenous pyrogen. Granulocytopenia induced by HN2 failed to influence either fever or the production of endogenous pyrogen in rabbits injected with NDV. Similarly, the intraperitoneal inoculation of NDV into prepared exudates did not modify the febrile response. These findings do not lend support to the possibility that the polymorphonuclear leukocyte is a significant source of endogenous pyrogen in virus-induced fever. It is concluded that the liberation of an endogenous pyrogen from some as yet undefined source is an essential step in the pathogenesis of fever caused by the influenza group of viruses.

Studies on the Pathogenesis of Fever With Influenzal Viruses

“…Although daily injections of endotoxin are given up to the time of the experiment, clearance of exogenous pyrogen is so rapid that no detectable endogenous pyrogen is present in the sera of this group (2,19,20). On the other hand, all of the recipients which have a monophasic response to endogenous pyrogen have had an injection of a pyrogenic agent on the preceding day and s Fever accompanying the intramuscular injection of epinephrine is unassociated with a detectable level of endogenous pyrogen (8).…”

“…GeneraL--The preparation and titration of Newcastle disease virus (NDV) and PR8 strain of influenza virus have been described (8). Methods of determining circulating endogenous pyrogen after the inoculation of virus into rabbits were performed as outlined in the preceding papers of this series (8,9).…”

“…Infectivity Titration.--lO-or ll-day-old embryos were inoculated with serial tenfold dilutions of each serum sample as outlined previously (8). After incubation of embryos at 35°C.…”

“…Methods of determining circulating endogenous pyrogen after the inoculation of virus into rabbits were performed as outlined in the preceding papers of this series (8,9).…”

“…Donors reinjected with PR8 on the 2nd day remained afebrile and were bled at 4 hours. There was no transferable endogenous pyrogen (8).…”