Synthetic influenza viral double-stranded RNA induces an acute-phase response in rabbits

Abstract

Numerous studies have characterized the physiological effects of synthetic, high-molecular-weight, homopolymeric, double-stranded RNA (dsRNA), particularly polyriboinosinic.polyribocytidylic acid [Carter and De Clercq (1974): Science 186:1172-1178], but limited information exists regarding the physiological effects of dsRNA of viral composition and size. In this report, we determined sleep and fever responses of rabbits to intracerebroventricular injection of different doses of synthetic viral dsRNA (either 108 base pairs or 661 base pairs) derived from the N-terminal sequence of gene segment 3 of the A/PR/8/34-H1N1 (PR8) influenza virus. Both the108-mer and the 661-mer dsRNAs increased nonrapid eye movement sleep, suppressed rapid eye movement sleep, and induced fever. The 661-mer dsRNA had more potent somnogenic and pyrogenic effects than the 108-mer dsRNA on the basis of weight. Neither single-stranded RNA from the corresponding sequences had significant effects on sleep or brain temperature. These results demonstrate for the first time that low-molecular-weight, viral dsRNA has the stability in vivo that is required to induce the fever and sleep changes found in natural viral infections, and the hypothesis is supported that virus-associated dsRNA may be responsible for initiating the acute-phase response during viral infections.

Intratracheal double-stranded RNA plus interferon-γ: A model for analysis of the acute phase response to respiratory viral infections

“…We have demonstrated that the response of rabbits to ICV virus-associated dsRNA extracted from influenza-infected lung (Majde et al, 1991) is similar to the response to poly [rI Á rC]. We have also demonstrated that the APR induced by synthetic influenza dsRNA resembles the APR induced by poly[rI Á rC], though the much smaller viral dsRNA fragments are considerably less potent than high molecular weight poly[rI Á rC] (Fang et al, 1999). The rabbit APR induced by all of these forms of dsRNA is similar to that induced by large doses of IV abortive influenza virus (Kimura-Takeuchi et al, 1992a), which may synthesize dsRNA during partial replication.…”

Length-dependent innate antiviral effects of double-stranded RNA in the rainbow trout (Oncorhynchus mykiss) cell line, RTG-2

“…DsRNA length effects were observed in vesicular stomatitis virus-infected mouse embryonic fibroblasts (MEFs), where longer in vitro transcribed dsRNA molecules resulted in lower EC 50 values than did molecules of shorter lengths and in uninfected MEFs IFN and ISG transcripts were induced in a dsRNA length dependent manner [11]. A study in rabbits found that longer dsRNA molecules induced greater somnogenic and pyrogenic responses compared to shorter molecules [14]. Similar to what has been observed here in fish, poly I:C and in vitro transcribed dsRNA induce similar but not exactly the same innate immune responses in mammals [11,19].…”

Viral Double-Stranded RNA, Cytokines, and the Flu

“…Mengo viral dsRNA is also toxic in vivo, (28) indicating that it is resistant to mixed tissue nucleases. Studies by my research group confirm that dsRNA of viral composition is stable in vivo and that fragments as small as 108 bp are capable of inducing an APR, (29) although at doses 100-fold higher than those required for high molecular weight poly[rI ? rC].…”

“…rC], (45-4 8) by low molecular weight dsRNA (309 bp) of mixed base composition, (12 ) and presumably by comparable virus-associated dsRNA capable of inducing an APR. (29,49) Early gene induction by poly[rI ? rC], including induction of the chemokine IP-10, is independent of its induction of IFN or any other proteins, but later gene induction requires protein synthesis and IFN production.…”

“…(49) The sources of the dsRNA in these toxic preparations are not defined and could be from any of the dsRNA sources described. However, synthetic fragm ents of influenza replicative form s as small as 108 bp can induce an APR, (29) indicating that dsRNA of viral composition meets the stability criteria required to be toxic in vivo.…”