Abstract
Remarkably little is known about how intracellular pathogens exit the host cell in order to infect new hosts. Pathogenic chlamydiae egress by first rupturing their replicative niche (the inclusion) before rapidly lysing the host cell. Here we apply a laser ablation strategy to specifically disrupt the chlamydial inclusion, thereby uncoupling inclusion rupture from the subsequent cell lysis and allowing us to dissect the molecular events involved in each step. Pharmacological inhibition of host cell calpains inhibits inclusion rupture, but not subsequent cell lysis. Further, we demonstrate that inclusion rupture triggers a rapid necrotic cell death pathway independent of BAK, BAX, RIP1 and caspases. Both processes work sequentially to efficiently liberate the pathogen from the host cytoplasm, promoting secondary infection. These results reconcile the pathogen's known capacity to promote host cell survival and induce cell death.
Highlights
Little is known about how intracellular pathogens exit the host cell in order to infect new hosts
The asynchronous nature of chlamydial egress has, impeded further dissection of the process and remarkably little is known about the molecular events involved, the identity of the cysteine proteases involved in inclusion rupture
It is recognised that cysteine protease activity is required for inclusion rupture and intracellular calcium signalling is necessary for subsequent cell lysis[6], the manifest asynchronous nature of inclusion rupture has proven refractory to more detailed investigation of the molecular events involved in chlamydial egress
Summary
Little is known about how intracellular pathogens exit the host cell in order to infect new hosts. We demonstrate that inclusion rupture triggers a rapid necrotic cell death pathway independent of BAK, BAX, RIP1 and caspases Both processes work sequentially to efficiently liberate the pathogen from the host cytoplasm, promoting secondary infection. As an obligate intracellular pathogen, Chlamydia maintains exquisite control over an assortment of host cellular processes during its dimorphic growth cycle Most prominent among these is the formation of an intracellular replicative niche from the host cell’s membranetrafficking pathways[2] and the profound pro-survival influence the pathogen promotes during the replicative phase of infection[3,4]. During the later stages of the pathogen’s life cycle, Chlamydia asynchronously transforms back into its EB form before it egresses from the cell by one of three independent mechanisms: exocytosis[5], extrusion of the intact chlamydial inclusion from the host cell or rupture of the inclusion immediately prior to cell lysis[6]. The asynchronous nature of chlamydial egress has, impeded further dissection of the process and remarkably little is known about the molecular events involved, the identity of the cysteine proteases involved in inclusion rupture
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