Chlamydia trachomatis Cellular Exit Alters Interactions with Host Dendritic Cells

Abstract

The strategies utilized by pathogens to exit host cells are an area of pathogenesis which has received surprisingly little attention, considering the necessity of this step for infections to propagate. Even less is known about how exit through these pathways affects downstream host-pathogen interactions and the generation of an immune response. Chlamydia trachomatis exits host epithelial cells through two equally active mechanisms: lysis and extrusion. Studies have characterized the outcome of interactions between host innate immune cells, such as dendritic cells and macrophages, and free, extracellular Chlamydia bacteria, such as those resulting from lysis. Exit via extrusion generates a distinct, host-membranebound compartment of Chlamydia separate from the original infected cell. In this study, we assessed the effect of containment within extrusions upon the interaction between Chlamydia and host dendritic cells. Extrusion dramatically affected the outcome of Chlamydia-dendritic cell interactions for both the bacterium and the host cell. Dendritic cells rapidly underwent apoptosis in response to engulfment of an extrusion, while uptake of an equivalent dose of free Chlamydia had no such effect. Containment within an extrusion also prolonged bacterial survival within dendritic cells and altered the initial innate immune signaling by the dendritic cell.KEYWORDS Chlamydia, apoptosis, dendritic cell, extrusion C hlamydia trachomatis is a highly successful Gram-negative bacterial pathogen, being the leading bacterial cause of sexually transmitted infections and the leading cause of infectious blindness globally (1-3). In the absence of diagnosis and treatment, Chlamydia infections can lead to severe long-term outcomes, such as chronic pelvic pain, infertility, and ectopic pregnancy (4, 5). During infection, innate and adaptive immune responses are mounted against Chlamydia; however, approximately 50% of infections last for a year or more (6). Even after the resolution of infection, only partial protective immunity is achieved and reinfection is common (7-9). This suggests that Chlamydia is adept at establishing and sustaining infection in the face of immune recognition.Due to Chlamydia's obligate intracellular nature and a historically limited genetic toolbox, key attributes of the host-Chlamydia interaction are still unknown. Chlamydia infection is initiated by the uptake of metabolically inactive elementary bodies (EB) into mucosal epithelial cells, which transition into reticulate bodies (RB) within a vacuole called an inclusion. Here, the metabolically active RB replicates robustly to generate hundreds of Chlamydia bacteria that undergo transition back to EB (10). Chlamydia inhibits apoptosis of the host epithelial cell, ensuring its ability to complete this replication cycle before exit from the cell (11-13). Bacterial exit from host cells is a crucial but underscrutinized stage of the life cycle of this and other intracellular pathogens. Chlamydia possesses two distinct, equally prevalent exit mechan...

Inter‐species lateral gene transfer focused on the Chlamydia plasticity zone identifies loci associated with immediate cytotoxicity and inclusion stability

“…HeLa and McCoy cells were infected with wild type C. trachomatis L2 or chimera strains and analyzed for phosphatidylserine externalization and caspase 3/7 activation using the Annexin V Alexa Fluor 594 and Image-iT live caspase 3/7 assay kits (Molecular Probes), respectively, using established procedures (Sherrid & Hybiske, 2017).…”

Chlamydial Infection From Outside to Inside

“…Furthermore, results showed that survival of C. trachomatis was significantly lower when infecting macrophages or DCs compared to epithelial cells (Steele et al, 2004). However, the group of Hybiske has proven that bone marrow macrophages as well as DCs engulf extrusions and that subsequent survival of chlamydiae is hence promoted by the lipid barrier surrounding them (Sherrid and Hybiske, 2017; Zuck et al, 2017). Nevertheless, the engulfment of extrusions initiated fast DC apoptosis and significantly modified the transcriptional upregulation of biologically relevant DC cytokines (Sherrid and Hybiske, 2017).…”

“…However, the group of Hybiske has proven that bone marrow macrophages as well as DCs engulf extrusions and that subsequent survival of chlamydiae is hence promoted by the lipid barrier surrounding them (Sherrid and Hybiske, 2017; Zuck et al, 2017). Nevertheless, the engulfment of extrusions initiated fast DC apoptosis and significantly modified the transcriptional upregulation of biologically relevant DC cytokines (Sherrid and Hybiske, 2017). Hybiske and Stephens also claimed that both processes, extrusion and lysis, are prevalent among genital as well as LGV biovars of C. trachomatis and that they occur at nearly equivalent frequencies (Hybiske and Stephens, 2007), thus objecting the papers of Banks et al (1970) and Todd and Caldwell (1985).…”

Host cell death during infection withChlamydia: a double-edged sword

“… 2017 ). While this process enabled enhanced pathogen survival in the phagocytes, likely by preventing phagocyte activation, and was suggested to enable the bacteria to exploit these cells as vehicles for dissemination, it did only infrequently result in productive infection of the phagocytes (Sherrid and Hybiske 2017 ; Zuck et al . 2017 ).…”