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Infection and Immunity, October 2004, p. 6012-6022, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.6012-6022.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of Apoptosis by Escherichia coli K1 Is Accompanied by Increased Expression of Bcl_XL and Blockade of Mitochondrial Cytochrome c Release in Macrophages

Sunil K. Sukumaran,^1, Suresh K. Selvaraj,¹ and Nemani V. Prasadarao^1,2*

Division of Infectious Diseases, The Saban Research Institute, Childrens Hospital Los Angeles,¹ Keck School of Medicine, University of Southern California, Los Angeles, California²

Received 3 May 2004/ Returned for modification 14 June 2004/ Accepted 14 July 2004

Escherichia coli K1 survival in the blood is a critical step for the onset of meningitis in neonates. Therefore, the circulating bacteria are impelled to avoid host defense mechanisms by finding a niche to survive and multiply. Our recent studies have shown that E. coli K1 enters and survives in both monocytes and macrophages in the newborn rat model of meningitis as well as in macrophage cell lines. Here we demonstrate that E. coli K1 not only extends the survival of human and murine infected macrophage cell lines but also renders them resistant to apoptosis induced by staurosporine. Macrophages infected with wild-type E. coli expressing outer membrane protein A (OmpA), but not with OmpA^– E. coli, are resistant to DNA fragmentation and phosphatidylserine exposure induced by staurosporine. Infection with OmpA⁺ E. coli induces the expression of Bcl_XL, an antiapoptotic protein, both at the mRNA level as assessed by gene array analysis and at the protein level as evaluated by immunoblotting. OmpA^– E. coli infection of macrophages induced the release of cytochrome c from mitochondria into the cytosol and the activation of caspases 3, 6, and 9, events that were significantly blocked in OmpA⁺ E. coli-infected macrophages. In addition, OmpA⁺ E. coli-infected cells were resistant to a decrease in the transmembrane potential of mitochondria induced by staurosporine as measured by the MitoCapture fluorescence technique. Complementation of OmpA^– E. coli with a plasmid containing the ompA gene restored the ability of OmpA^– E. coli to inhibit the apoptosis of infected macrophages, further demonstrating that E. coli OmpA expression is critical for inducing macrophage survival and thereby finding a safe haven for its growth.

Editor: A. D. O'Brien

Present address: Institute of Molecular and Cellular Biology, Singapore 11709, Republic of Singapore.

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