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Adenovirus Infection Dramatically Augments Lipopolysaccharide-Induced TNF Production and Sensitizes to Lethal Shock¹

György Fejér^2,*, Katalin Szalay^*, Ildikó Gyry^*, Mária Fejes^*, Erzsébet Kúsz^*, Saviana Nedieanu^*, Tibor Páli^*, Tibor Schmidt, Botond Siklódi, György Lázár, Jr, György Lázár, Sr and Ern Duda^3,*,¶

^* Biological Research Center, Szeged, Hungary; Biological Research Department, TEVA Pharmaceutical Works Ltd, Debrecen, Hungary; and Department of Surgery, Institute of Pathophysiology, and ^¶ Institute of Medical Microbiology and Immunology, University of Szeged, Szeged, Hungary

We observed a remarkable synergism of adenoviruses and LPS in triggering the production of TNF in intact animals. We found that in mice pre-exposed to adenoviruses, LPS injections generated extremely high levels of TNF with altered kinetics. The elevated TNF synthesis stemmed mostly from posttranscriptional up-regulation of TNF production, although transcription of the TNF gene was also induced. Adenoviruses and LPS exhibited a significant but less dramatic synergism in the induction of IL-6, IFN-, and NO. Only marginal changes were detected in the synthesis of a panel of other cytokines. Different serotypes of the virus showed practically identical effects. As deletion mutants lacking indispensable viral genes or UV inactivated virions exhibited similar activities as the infectious, wild-type virus, it seems unlikely that the viral genome plays any significant role in the phenomenon. Published data indicate that other viruses also show some kind of synergism with LPS, although by different cellular mechanisms. T cells and their IFN- production—crucial in the synergism of influenza viruses and LPS—were dispensable in our experiments. We suggest that the phenomenon is probably a general one: an overlap between different molecular mechanisms detecting bacterial and viral pathogens and inducing mediators of nonspecific cell-mediated host defense. The synergism of viruses and LPS (bacteria) could be a concern in medical practice as well as in gene therapy experiments with high doses of recombinant adenoviruses.

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