Intracellular persistence of Chlamydia trachomatis has been implicated in the development of
chronic infection that can result in
pelvic inflammatory disease and tubal
sterility. By inhibition of host cell apoptosis, chlamydiae have evolved a strategy to maintain the intracellular environment for replication and persistence. Both antiapoptotic host cell-derived factors and the chlamydial
protease-like activity factor (
CPAF) are involved in Chlamydia-mediated apoptosis resistance. Here, we show that in HeLa cells infected with
gamma interferon (IFN-γ)-induced persistent C. trachomatis serovar D, the expression of
CPAF is downregulated, and proapoptotic
protease substrates are not cleaved.
Persistent infection protected HeLa cells from apoptosis when they were exposed to
staurosporine.
Small-interfering RNA-mediated inhibition of myeloid cell
leukemia 1 (Mcl-1)
protein upregulation sensitized persistently infected cells for apoptosis. The
inhibitor of apoptosis protein 2 (IAP-2) seems not to be relevant in this context because IAP-2
protein was not induced in response to IFN-γ treatment. Although apoptosis was inhibited,
persistent infection caused cell membrane disintegration, as measured by the increased release of
cytokeratin 18 from HeLa cells. Moreover, persistently infected cells released significantly increased amounts of high mobility group box 1 (
HMGB1) protein which represents a proinflammatory damage-associated pattern molecule. The data of this study suggest that cells infected with persistent C. trachomatis are protected from apoptosis independently of
CPAF but may promote chronic
inflammation through
HMGB1 release.