Extrusions are phagocytosed and promoteChlamydiasurvival within macrophages

Abstract

The precise strategies that intracellular pathogens use to exit host cells have a direct impact on their ability to disseminate within a host, transmit to new hosts, and engage or avoid immune responses. The obligate intracellular bacterium Chlamydia trachomatis exits the host cell by two distinct exit strategies, lysis and extrusion. The defining characteristics of extrusions, and advantages gained by Chlamydia within this unique double‐membrane structure, are not well understood. Here, we define extrusions as being largely devoid of host organelles, comprised mostly of Chlamydia elementary bodies, and containing phosphatidylserine on the outer surface of the extrusion membrane. Extrusions also served as transient, intracellular‐like niches for enhanced Chlamydia survival outside the host cell. In addition to enhanced extracellular survival, we report the key discovery that chlamydial extrusions are phagocytosed by primary bone marrow‐derived macrophages, after which they provide a protective microenvironment for Chlamydia. Extrusion‐derived Chlamydia staved off macrophage‐based killing and culminated in the release of infectious elementary bodies from the macrophage. Based on these findings, we propose a model in which C. trachomatis extrusions serve as “trojan horses” for bacteria, by exploiting macrophages as vehicles for dissemination, immune evasion, and potentially transmission.

Chlamydia trachomatis Cellular Exit Alters Interactions with Host Dendritic Cells

“…These findings mirror our previous results in macrophages (27), indicating a similar extrusion-mediated benefit to Chlamydia during interactions with both of these cell types. A marked and provocative contrast, however, was that extrusion engulfment resulted in dramatically different host cell outcomes for DCs and macrophages.…”

“…Chlamydia trachomatis survival in DCs is low, in contrast to the robust growth seen in its main target, the epithelial cell (26). We have previously shown that containment within extrusions increases the survival of Chlamydia in macrophages, prolonging the period during which viable bacteria can be recovered from these cells (27). As innate phagocytic cells and potent stimulators of cell-mediated adaptive immunity, DCs are likely to play a key role in generating protective host responses to Chlamydia (28, 30, 31, 33).…”

“…The inner membrane originates from the inclusion membrane which surrounds the Chlamydia bacteria within an infected host epithelial cell, while the outer extrusion membrane is generated from the epithelial cell plasma membrane. Phosphatidylserine (PS) is externalized to the extrusion surface over time (27), a process which we hypothesize may allow the extrusion to mimic an apoptotic cell. We have previously shown that macrophages engulf extrusions in a partially PS-dependent manner (27).…”

“…Phosphatidylserine (PS) is externalized to the extrusion surface over time (27), a process which we hypothesize may allow the extrusion to mimic an apoptotic cell. We have previously shown that macrophages engulf extrusions in a partially PS-dependent manner (27). During infection, DCs are likely among the first host cells to encounter Chlamydia bacteria.…”

“…Survival of C. trachomatis within macrophages and DCs is dramatically reduced compared to that in epithelial cells (26). Previous work from our group has shown that murine bone marrow macrophages phagocytose extrusions and that containment within extrusions enhances the survival of Chlamydia within these cells (27). DCs are a critical intermediary between innate and adaptive immunity, possessing high phagocytic capacity and potent activity as antigen-presenting cells.…”