title: AP-1 Transcription Factor Serves as a Molecular Switch between Chlamydia pneumoniae Replication and Persistence.
abstract: 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.
authors.affiliation: Division of Immunology, Paul Ehrlich Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Krämer
authors.affiliation: Division of Immunology, Paul Ehrlich Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Crauwels
authors.affiliation: Division of Immunology, Paul Ehrlich Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Bohn
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Luebeck, Luebeck, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Radzimski
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Luebeck, Luebeck, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Szaszák
authors.affiliation: Institute of Anatomy, Center for Structural and Cell Biology in Medicine, University of Luebeck, Luebeck, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Klinger
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Luebeck, Luebeck, Germany Department of Molecular und Clinical Infectious Diseases, University of Luebeck, Luebeck, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Rupp
authors.affiliation: Division of Immunology, Paul Ehrlich Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany Institute of Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany Ger.Zandbergen@pei.de.
authors.forename: G
authors.initials: G
authors.lastname: van Zandbergen
mesh_terms: D058491:Bacterial Load; D016993:Chlamydophila pneumoniae / Q000254:growth & development*; D015964:Gene Expression Regulation, Bacterial; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000382:microbiology* / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D018808:Transcription Factor AP-1