Protection of Mice from Lethal Escherichia coliInfection by Chimeric Human Bactericidal/Permeability-Increasing Protein and Immunoglobulin G1 Fc Gene Delivery

ABSTRACTTo evaluate the potentiality of applying gene therapy to bacterial infections, especially for preventing infection in high-risk patients, we investigated protection of mice from challenge with lethal Escherichia coliinfection by adeno-associated virus serotype 2 (AAV2)-mediated gene transfer of a chimeric BPI23-Fcγ1 gene, which consisted of human bactericidal/permeability-increasing protein (BPI) gene encoding the functional N terminus (amino acid residues 1 to 199) of human BPI and an Fcγ1 gene encoding the Fc segment of human immunoglobulin G1. Here we show that the target protein that was expressed and secreted into the serum of the gene-transferred mice demonstrated the activity of a neutralizing endotoxin, killing E. coliand mediating opsonization. After lethal E. coliinfection, the count of bacteria and the levels of endotoxin and proinflammatory cytokines in the gene-transferred mice were decreased. The survival rate of BPI23-Fcγ1 gene-transferred mice markedly increased, especially in conjunction with antibiotics. Our data suggest that AAV2-mediated chimeric BPI23-Fcγ1 gene delivery could potentially be used clinically for the protection and treatment of infection with gram-negative bacteria in high-risk individuals.