Abstract
Control of host cell death is of paramount importance for the survival and replication of obligate intracellular bacteria. Among these, human pathogenic Chlamydia induces the inhibition of apoptosis in a variety of different host cells by directly interfering with cell death signaling. However, the evolutionary conservation of cell death regulation has not been investigated in the order Chlamydiales, which also includes Chlamydia-like organisms with a broader host spectrum. Here, we investigated the apoptotic response of human cells infected with the Chlamydia-like organism Simkania negevensis (Sn). Simkania infected cells exhibited strong resistance to apoptosis induced by intrinsic stress or by the activation of cell death receptors. Apoptotic signaling was blocked upstream of mitochondria since Bax translocation, Bax and Bak oligomerisation and cytochrome c release were absent in these cells. Infected cells turned on pro-survival pathways like cellular Inhibitor of Apoptosis Protein 2 (cIAP-2) and the Akt/PI3K pathway. Blocking any of these inhibitory pathways sensitized infected host cell towards apoptosis induction, demonstrating their role in infection-induced apoptosis resistance. Our data support the hypothesis of evolutionary conserved signaling pathways to apoptosis resistance as common denominators in the order Chlamydiales.
Highlights
Simkania negevensis (Sn) is a Chlamydia-like organism [1] belonging to the family Simkaniaceae, order Chlamydiales [2]
Apoptosis resistance was found to be dependent on the multiplicity of infection (MOI); cells infected with higher MOI acquired apoptosis resistance much faster as demonstrated in a quantification of the presence of cycloheximide (TNF/Chx)-induced apoptosis at day 1 using MOIs ranging from 0.5 to 20 (Figure 2C)
Apoptosis resistance has been a common denominator as an outcome of infection with and a likely prerequisite for the development of obligate intracellular pathogenic Chlamydia
Summary
Simkania negevensis (Sn) is a Chlamydia-like organism [1] belonging to the family Simkaniaceae, order Chlamydiales [2] They are obligate intracellular gram-negative bacteria which replicate within endocytic vacuoles of eukaryotic cells i.e. amoebae, human epithelial cells and macrophages [3]. The active replication cycle of Sn takes about 3–5 days and extensive long term relationship with the host cell of about 10–15 days has been reported [14]. The strategy that this pathogen takes to keep its host alive for such a long period of time is unknown
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