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 x 10(9) PFU of recombinant adenovirus containing either the gene for LBP or the irrelevant control protein beta-galactosidase by tail vein injection. 72 hours later each mouse was administered 1 x 10(3) 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 beta-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.
Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan 48109-0033, USA. mhemmila@umich.edu
Mark R
MR
Hemmila
Ming-Hui
MH
Fan
Jiyoun
J
Kim
Jian M
JM
Sun
Lars
L
Steinstraesser
Ke Q
KQ
Gong
Saman
S
Arbabi
Rebecca M
RM
Minter
Daniel G
DG
Remick
Grace L
GL
Su
Stewart C
SC
Wang
D000209:Acute-Phase Proteins / Q000276:immunology*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D007150:Immunohistochemistry; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008070:Lipopolysaccharides / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D001616:beta-Galactosidase / Q000378:metabolism; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D001616:beta-Galactosidase; D000099231:Lipopolysaccharide-Binding Protein