Host Cell Responses to Chlamydia pneumoniae in Gamma Interferon-Induced Persistence Overlap Those of Productive Infection and Are Linked to Genes Involved in Apoptosis, Cell Cycle, and Metabolism

Abstract

The respiratory pathogen Chlamydia (Chlamydophila) pneumoniae is associated with chronic diseases, including atherosclerosis and giant-cell arteritis, which are accompanied by the occurrence of these obligate intracellular bacteria in blood vessels. There, C. pneumoniae seems to be present in a persistent state. Persistence is characterized by modified bacterial metabolism and morphology, as well as a reversible arrest of chlamydial development. In cell culture, this persistent state can be induced by gamma interferon (IFN-␥). To elucidate this long-term interaction between chlamydiae and their host cells, microarray screening on epithelial HeLa cells was performed. Transcription of persistently (and productively) infected cells was compared with that of mock-infected cells. Sixty-six host cell genes were regulated at 24 h and/or 96 h of IFN-␥-induced persistence. Subsequently, a set of 17 human host cell genes related to apoptosis, cell cycle, or metabolism was identified as permanently up-or down-regulated by real-time PCR. Some of these chlamydiadependent host cell responses were diminished or even absent in the presence of rifampin. However, other expression patterns were not altered by the inhibition of bacterial RNA polymerase, suggesting two different modes of host cell activation. Thus, in the IFN-␥ model, the persisting bacteria cause long-lasting changes in the expression of genes coding for functionally important proteins. They might be potential drug targets for the treatment of persistent C. pneumoniae infections.The spectrum of illness caused by Chlamydia (also Chlamydophila) pneumoniae ranges from severe community-acquired pneumonia to bronchitis, pharyngitis, laryngitis, or sinusitis (31). Chlamydial infections show high rates of recurrence (3,11,12). The increasingly strong association between C. pneumoniae and several chronic conditions, including asthma, follicular conjunctivitis, chronic bronchitis, giant-cell arteritis, and atherosclerosis, has been studied by many research groups (9,18,19,32,47,53,58) and supports the assumption that the organism can persist for extended periods in its human host. Several studies have shown that C. pneumoniae can cause longlasting and chronic infections that do not respond to chlamydicidal antibiotic treatment (1,16,17,20,21,48,55). Consequently, there is an urgent need to elucidate the mechanisms of persistence, to reveal markers of the persistent infection, and to identify new potential drug targets in host cells and bactericidal drugs that are effective against persisting chlamydia.The obligate intracellular bacterium C. pneumoniae has a unique productive developmental cycle. An infectious, metabolically inert form called an elementary body (EB) initiates the infection by attaching to and stimulating uptake by the host cell. The internalized EB remains within a host-derived vacuole (inclusion) and differentiates into a larger, metabolically active, and replicative form termed the reticulate body (RB). The RB multiplies by 8 to 12 rounds of binary divisio...

Microarray Analysis of aChlamydia pneumoniae–Infected Human Epithelial Cell Line by Use of Gene Ontology Hierarchy

“…All validated genes were silenced with corresponding siRNAs (table 4). The effect of the target-gene silencing on C. pneumoniae infection was measured by TR-FIA, and The genes that inhibit the Wnt signaling pathway [19], a path- [20]. Insulin-like growth factor 2 has previously been shown to enhance C. pneumoniae infection [21] and, using a GO approach, we were able to show the significant increase in the binding activity of this growth factor family (GO:0005520 3 target gene: CYR61).…”

Elucidating Novel Serum Biomarkers Associated with Pulmonary Tuberculosis Treatment

“…Three additional markers stood out in a logistic regression analysis of disease severity: DKK-1, serum amyloid P and adiponectin. DKK-1 an inhibitor of wnt signaling has also been shown to alter fibrosis [67] and expression is up-regulated in a Chlamydia infection model [68]. Serum amyloid P is a member (as is CRP) of the pentraxin family of proteins involved in pattern recognition and complement activation [59] and levels have been shown to correlate with disease severity and rapidity of burn wound healing [69].…”

Metabolic host responses to infection by intracellular bacterial pathogens

“…It will be interesting to find out whether these transporter proteins are incorporated into the host cell cytoplasmic membrane or recruited to the Chlamydia containing vacuole (“inclusion body”). Not surprisingly, none of these transporter genes upregulated in the tissue samples have been found differentially expressed in productively and persistently Chlamydia -infected HeLa or HL cells using transcriptomic (Eickhoff et al, 2007; Alvesalo et al, 2008) or proteomic approaches (Savijoki et al, 2008). As discussed above, nutrient uptake is already induced in these transformed cell lines.…”