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Antimicrobial Agents and Chemotherapy, February 2007, p. 724-731, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.00360-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Protection of Mice from Lethal Escherichia coli Infection by Chimeric Human Bactericidal/Permeability-Increasing Protein and Immunoglobulin G1 Fc Gene Delivery{triangledown}

Jindong Chen,1,2 Chengyao Li,3 Yuanzhi Guan,4 Qingli Kong,1 Chen Li,1 Xianghua Guo,1 Qinghua Chen,1 Xuefang Jing,1 Zhe Lv,1 and Yunqing An1*

Department of Microbiology and Immunology, Capital University of Medical Sciences, Beijing, China,1 Department of Immunology, Cancer Institute and Cancer Hospital of CAMS and PUMC, Beijing, China,2 Division of Transfusion Medicine, National Blood Service and University of Cambridge, Cambridge CB2 2PT, United Kingdom,3 Department of Microbiology, Institute of Basic Medical Sciences of CAMS and PUMC, Beijing, China4

Received 13 March 2006/ Returned for modification 6 August 2006/ Accepted 22 November 2006

To 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 coli infection by adeno-associated virus serotype 2 (AAV2)-mediated gene transfer of a chimeric BPI23-Fc{gamma}1 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 Fc{gamma}1 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. coli and mediating opsonization. After lethal E. coli infection, the count of bacteria and the levels of endotoxin and proinflammatory cytokines in the gene-transferred mice were decreased. The survival rate of BPI23-Fc{gamma}1 gene-transferred mice markedly increased, especially in conjunction with antibiotics. Our data suggest that AAV2-mediated chimeric BPI23-Fc{gamma}1 gene delivery could potentially be used clinically for the protection and treatment of infection with gram-negative bacteria in high-risk individuals.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Capital University of Medical Sciences, Beijing 100069, China. Phone: 86-10-83911439. Fax: 011-86-10-83911439. E-mail: anyunq{at}ccmu.edu.cn.

{triangledown} Published ahead of print on 4 December 2006.

Antimicrobial Agents and Chemotherapy, February 2007, p. 724-731, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.00360-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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