Apoptosis Functions in Defense against Infection of Mammalian Cells with Environmental Chlamydiae

Abstract

Apoptotic cell death can be an efficient defense reaction of mammalian cells infected with obligate intracellular pathogens; the host cell dies and the pathogen cannot replicate. While this is well established for viruses, there is little experimental support for such a concept in bacterial infections. All <i>Chlamydiales</i> are obligate intracellular bacteria, and different species infect vastly different hosts. <i>Chlamydia trachomatis</i> infects human epithelial cells; <i>Parachlamydia acanthamoebae</i> replicates in amoebae. We here report that apoptosis impedes growth of <i>P. acanthamoebae</i> in mammalian cells. In HeLa human epithelial cells, <i>P. acanthamoebae</i> infection induced apoptosis, which was inhibited when mitochondrial apoptosis was blocked by codeletion of the mediators of mitochondrial apoptosis, Bax and Bak, by overexpression of Bcl-X_L or by deletion of the apoptosis initiator Noxa. Deletion of Bax and Bak in mouse macrophages also inhibited apoptosis. Blocking apoptosis permitted growth of <i>P. acanthamoebae</i> in HeLa cells, as measured by fluorescence <i>in situ</i> hybridization, assessment of genome replication and protein synthesis, and the generation of infectious progeny. Coinfection with <i>C. trachomatis</i> inhibited <i>P. acanthamoebae</i>-induced apoptosis, suggesting that the known antiapoptotic activity of <i>C. trachomatis</i> can also block <i>P. acanthamoebae</i>-induced apoptosis. <i>C. trachomatis</i> coinfection could not rescue <i>P. acanthamoebae</i> growth in HeLa; in coinfected cells, <i>C. trachomatis</i> even suppressed the growth of <i>P. acanthamoebae</i> independently of apoptosis, while <i>P. acanthamoebae</i> surprisingly enhanced the growth of <i>C. trachomatis</i> Our results show that apoptosis can be used in the defense of mammalian cells against obligate intracellular bacteria and suggest that the known antiapoptotic activity of human pathogenic chlamydiae is indeed required to permit their growth in human cells.