Hif-1 Alpha Is Involved In Mediating Apoptosis Resistance To Chlamydia Trachomatis-Infected Cells

Chlamydiae are obligate intracellular Gram-negative bacteria that cause widespread diseases in humans. Due to the intimate association between bacterium and host, Chlamydia evolved various strategies to protect their host cell against death-inducing stimuli, allowing the bacterium to complete its development cycle. An RNA interference (RNAi)-based screen was used to identify host cell factors required for apoptosis resistance of human epithelial cells infected with Chlamydia trachomatis serovar L2. Among the 32 validated hits, the antiapoptotic Bcl-2 family member Mcl-1 was identified as a target. Protein network analyses implicated the transcription factor hypoxia-induced factor 1 alpha (HIF-1 alpha) to be central to the regulation of many of the identified targets. Further mechanistic investigations showed that HIF-1 alpha was stabilized within the host cell cytoplasm during early infection time points, followed by its translocation to the nucleus and eventual transcriptional activation of Mcl-1. siRNA-mediated depletion of HIF-1 alpha led to a drastic decrease in Mcl-1, rendering the cell sensitive to apoptosis induction. Taken together, our findings identify HIF-1 alpha as responsible for upregulation of Mcl-1 and the maintenance of apoptosis resistance during Chlamydia infection.