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First-Generation Adenovirus Vectors Shorten Survival Time in a Murine Model of Sepsis¹

Kevin Doerschug^2,3,*,,, Salih Sanlioglu^2,*,¶, Dawn M. Flaherty^*,, Rebecca L. Wilson^*,, Timur Yarovinsky^*,, Martha M. Monick^*,, John F. Engelhardt^*,,, and Gary W. Hunninghake^*,,

^* Division of Pulmonary, Critical Care and Occupational Medicine, Department of Internal Medicine, Veteran’s Administration Medical Center, Center for Gene Therapy, and Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, IA 52242; and ^¶ Department of Medical Biology and Genetics, College of Medicine, Akdeniz University, Antalya, Turkey

Adverse immunological reactions to adenoviral vectors have significantly impacted the utility of this virus for treating genetic and environmentally induced diseases. In this study, we evaluate the effect of adenoviral vectors on an animal model of sepsis. Systemic delivery of first-generation adenoviral vectors to septic mice (cecal ligation and puncture) resulted in a shortened survival time. This effect was not observed with second-generation or inactivated first-generation vectors. The accelerated death was accompanied by a number of important changes in the disease. These changes included increased liver cell apoptosis (including Kupffer cells) and a marked increase in liver bacterial load. In the lung, the combination induced an increase in bacterial load, as well as greater lung injury. In the serum, the combination was associated with decreased TNF- levels and an increase in bacterial load. Finally, a profound degree of lymphocyte apoptosis was observed in these animals. These observations suggest that prior exposure to first-generation adenovirus gene therapy vectors may worsen the outcome of some forms of sepsis.

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