Improved survival in mice given systemic gene therapy in a gram negative pneumonia model

Background: We previously demonstrated an essential role for lipopolysaccharide binding protein (LBP) in the pulmonary immune response to Gram-negative bacterial infection. LBP knockout mice had significantly higher mortality, greater rates of bacteremia, and higher counts of viable bacteria in their lungs at sacrifice compared with wild-type controls. We postulate that systemic LBP gene therapy will reconstitute a protective innate immune response in LBP knockout mice and that overexpression of LBP in wild-type mice may offer a survival advantage. Methods: 12-16 week old female C57BL/6 wild-type mice and age matched LBP knockout mice were given 5 × 10⁹ PFU of recombinant adenovirus containing either the gene for LBP or the irrelevant control protein β-galactosidase by tail vein injection. 72 hours later each mouse was administered 1 × 10³ CFU of Klebsiella pneumoniae by intratracheal injection. Results: Administration of LBP by systemic gene therapy to LBP knockout mice improved survival from Klebsiella pneumonia to a level equivalent or better than wild-type mice exposed to the same dose of bacteria (36 versus 25%). Wild-type mice given the LBP gene therapy demonstrated increased 7 day survival from Klebsiella pneumonia when compared with controls treated with β-galactosidase (68 versus 30%, p = 0.03). Conclusions: Systemic gene therapy with intravenous adenoviral vector transfer of LBP significantly improves survival in LBP knockout mice. Overexpression of LBP in wild-type mice improves survival from Klebsiella pneumonia. Raising levels of LBP in the setting of Gram-negative pneumonia may be of therapeutic benefit.