Chlamydia pneumoniae is a Gram-negative bacterium that causes acute or chronic
respiratory infections. As obligate intracellular pathogens, chlamydiae efficiently manipulate host cell processes to ensure their intracellular development. Here we focused on the interaction of chlamydiae with the host cell
transcription factor activator protein 1 (AP-1) and its consequence on chlamydial development. During
Chlamydia pneumoniae infection, the expression and activity of
AP-1 family
proteins c-Jun, c-Fos, and ATF-2 were regulated in a time- and dose-dependent manner. We observed that the c-Jun
protein and its phosphorylation level significantly increased during C. pneumoniae development.
Small interfering RNA knockdown of the c-Jun
protein in HEp-2 cells reduced the chlamydial load, resulting in smaller inclusions and significantly lower chlamydial recovery. Furthermore, inhibition of the c-Jun-containing
AP-1 complexes using
tanshinone IIA changed the replicative
infection phenotype into a persistent one.
Tanshinone IIA-dependent persistence was characterized by smaller, aberrant inclusions, a strong decrease in the chlamydial load, and significantly reduced chlamydial recovery, as well as by the reversibility of the reduced recovery after the removal of
tanshinone IIA. Interestingly, not only was
tanshinone IIA treatment accompanied by a significant decrease of
ATP levels, but fluorescence live cell imaging analysis by two-photon microscopy revealed that
tanshinone IIA treatment also resulted in a decreased fluorescence lifetime of
protein-bound
NAD(P)H inside the chlamydial inclusion, indicating that chlamydial reticulate bodies have decreased metabolic activity. In all, these data demonstrate that the
AP-1 transcription factor is involved in C. pneumoniae development, with
tanshinone IIA treatment resulting in persistence.