Infection of macrophages by influenza A virus: Characteristics of tumour necrosis factor-alpha (TNF alpha) gene expression

Human monocytes and murine macrophages were found to be susceptible to influenza A virus infection. We could show that virus was absorbed and de novo virus protein synthesis was initiated, but actual virus replication was extremely low; 24-36 h after infection, monocytes and macrophages died of apoptosis. Before cell death, an influenza A virus infection induced strong mRNA accumulation of cytokines: tumour necrosis factor-alpha (TNF alpha), interleukin-1 (IL1) and IL6. However, the translation into bioactive cytokine protein was rather low, and high cytokine production was only found when a secondary signal such as LPS was added. Influenza A virus infection of mononuclear phagocytes displayed a characteristic feature at the level of cytokine gene transcription which was not found with other viruses such as vesicular stomatitis virus: in addition to the regular 1.7-kb TNF alpha mRNA, a high molecular weight (hmw) TNF alpha mRNA of 2.4 kb was detected. This hmw TNF alpha mRNA did not contain intron or intergenic region elements, was polyadenylated and carried the regular 5' and 3' untranslated regions. The generation of hmw TNF alpha mRNA required exposure to fully infectious influenza A virus, since virus inactivation at 56 degrees C induced only regular and not hmw TNF alpha mRNA. Whether this unique hmw TNF alpha mRNA represents a virus-induced abnormality or only a superinduction of an otherwise minor TNF alpha transcript, and whether this mRNA species codes for a biologically active product, remain to be further studied.