ABSTRACTEscherichia coliK1 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. coliK1 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. coliK1 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. coliexpressing 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. coliinduces the expression of BclXL, 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. coliinfection of macrophages induced the release of cytochrome cfrom 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. coliwith a plasmid containing the ompAgene restored the ability of OmpA−E. colito inhibit the apoptosis of infected macrophages, further demonstrating that E. coliOmpA expression is critical for inducing macrophage survival and thereby finding a safe haven for its growth.