Chlamydia trachomatis-infected cells and uninfected-bystander cells exhibit diametrically opposed responses to interferon gamma

Abstract

The intracellular bacterial pathogen, Chlamydia trachomatis, is a tryptophan auxotroph. Therefore, induction of the host tryptophan catabolizing enzyme, indoleamine-2,3-dioxgenase-1 (IDO1), by interferon gamma (IFNγ) is one of the primary protective responses against chlamydial infection. However, despite the presence of a robust IFNγ response, active and replicating C. trachomatis can be detected in cervical secretions of women. We hypothesized that a primary C. trachomatis infection may evade the IFNγ response, and that the protective effect of this cytokine results from its activation of tryptophan catabolism in bystander cells. To test this hypothesis, we developed a novel method to separate a pool of cells exposed to C. trachomatis into pure populations of live infected and bystander cells and applied this technique to distinguish between the effects of IFNγ on infected and bystander cells. Our findings revealed that the protective induction of IDO1 is suppressed specifically within primary infected cells because Chlamydia attenuates the nuclear import of activated STAT1 following IFNγ exposure, without affecting STAT1 levels or phosphorylation. Critically, the IFNγ-mediated induction of IDO1 activity is unhindered in bystander cells. Therefore, the IDO1-mediated tryptophan catabolism is functional in these cells, transforming these bystander cells into inhospitable hosts for a secondary C. trachomatis infection.

Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells

“…This, in turn, activates the JNK pathway ( 9) resulting in a decrease of E2F1 expression in bystander cells (10). Echoing the effect in infected cells, E2F1 downregulation decreases the expression of numerous miRNAs (11), with a net effect of priming these cells for Salmonella infection, by favoring bacterial binding to bystander cells, as well as by promoting bacterial internalization and intracellular replication (12).…”

“…In this case, reactive oxygen intermediates mediate the paracrine activation of bystander cells. Similarly, during Chlamydia trachomatis infection the response of infected cells to interferon-γ is blocked, whereas that of bystander cells is unhindered contributing to limiting the spread of infection 12 . Along the same line, we have shown that Shigella flexneri infection induces plasma membrane remodeling in infected and bystander cells, through the activation of the acid sphingomyelinase and strong accumulation of ceramide at the cell surface 13 .…”

Alternatively Activated Macrophages Are Host Cells for Chlamydia trachomatis and Reverse Anti-chlamydial Classically Activated Macrophages

“…A recent example demonstrated the modulation of STAT1 phosphoactivated in response to IFN-γ. Ibana et al (2018) reported that in infected endocervical epithelial cells, phosphorylated STAT1 (pSTAT1) did not translocate to the nucleus, in contrast to observations in neighboring uninfected cells. Transcription mediated by the AP-1- transcription factor was also enhanced in C. trachomatis -infected HeLa cells through the indirect action of C. trachomatis via the host proteins Pin1 and Men1, which are known AP-1 regulators (Olive et al, 2014).…”

Genetic Transformation of a C. trachomatis Ocular Isolate With the Functional Tryptophan Synthase Operon Confers an Indole-Rescuable Phenotype

“…A recent study has identified an additional immune evasion tactic employed by C. trachomatis that blocks the host cell's response to IFN-γ. As a result only (uninfected) bystander cells can respond to IFN-γ, preventing the spread of the infection beyond the initially infected cell (Ibana et al, 2018). Timing appears to be critical as the authors found that pre-treatment of cells with IFN-γ prevents progression of C. trachomatis along the normal developmental cycle, whereas an existing infection will block IDO-1 expression.…”