First-generation adenovirus vectors shorten survival time in a murine model of sepsis.
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-alpha 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.
Doerschug
Kevin
K
Division of Pulmonary, Critical Care and Occupational Medicine, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242, USA. kevin-doerschug@uiowa.edu
Sanlioglu
Salih
S
Flaherty
Dawn M
DM
Wilson
Rebecca L
RL
Yarovinsky
Timur
T
Monick
Martha M
MM
Engelhardt
John F
JF
Hunninghake
Gary W
GW
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015169:Colony Count, Microbial; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors; D007728:Kupffer Cells / Q000473:pathology; D008099:Liver / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012449:Safety; D018805:Sepsis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013154:Spleen / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha