Listeria monocytogenes transiently alters mitochondrial dynamics during infection

Abstract

Mitochondria are essential and highly dynamic organelles, constantly undergoing fusion and fission. We analyzed mitochondrial dynamics during infection with the human bacterial pathogen Listeria monocytogenes and show that this infection profoundly alters mitochondrial dynamics by causing transient mitochondrial network fragmentation. Mitochondrial fragmentation is specific to pathogenic Listeria monocytogenes, and it is not observed with the nonpathogenic Listeria innocua species or several other intracellular pathogens. Strikingly, the efficiency of Listeria infection is affected in cells where either mitochondrial fusion or fission has been altered by siRNA treatment, highlighting the relevance of mitochondrial dynamics for Listeria infection. We identified the secreted pore-forming toxin listeriolysin O as the bacterial factor mainly responsible for mitochondrial network disruption and mitochondrial function modulation. Together, our results suggest that the transient shutdown of mitochondrial function and dynamics represents a strategy used by Listeria at the onset of infection to interfere with cellular physiology.bacterial infection | calcium influx | bioenergetics

The arsenal of virulence factors deployed byListeria monocytogenesto promote its cell infection cycle

“…Since mitochondria constitute important innate immune response signaling integrators, the short-term fragmentation of these organelles, as elicited by extracellularly secreted LLO, may be another way for Listeria to interfere with host immune response-activating events to its own advantage. 109 Post-translational modifications allow cells to quickly, locally and specifically modify the activity or interactions between key proteins. Some of these modifications, including phosphorylation and ubiquitinylation, can be induced by pathogens.…”

“…108 This LLO-dependent calcium flux modulation was further demonstrated to cause a transient mitochondrial network fragmentation which appears to briefly slow down the host cell bio-energetic state, promoting a more efficient entry of L. monocytogenes. 109 GAG receptors facilitate the detachment of InlB from the bacterial surface and InlB clustering at the host cell surface, thus promoting strong Met activation and bacterial entry. 81,82 Although InlB has several receptors, it is well accepted that Met is the major InlB signaling receptor.…”

Entry of Listeria monocytogenes in Mammalian Epithelial Cells: An Updated View

“…Indeed, transient increases in cellular calcium from the extracellular milieu (and not from intracellular reservoirs) induced by extracellular LLO increase the InlB-dependent bacterial invasion of HEp-2 cells (Dramsi and Cossart 2003). Transient mitochondrial fragmentation, mitochondrial membrane potential loss, and drop in respiration and cellular ATP levels also correlate with the LLO-induced calcium fluxes and increased bacterial entry in HeLa cells, suggesting that the bioenergetic state of resting cells represents a barrier to L. monocytogenes invasion and the LLO-induced metabolic cell reprogramming promotes efficient bacterial internalization (Stavru et al 2011); the molecular mechanisms that link this reprogramming with phagocytosis are currently unknown. A direct role for LLO in promoting bacterial adhesion to epithelial cells has been proposed (Krawczyk-Balska and Bielecki 2005), and a recent study shows that LLO is sufficient to induce L. monocytogenes entry in HepG2 and HeLa cells in the absence of InA or InlB signaling (Vadia et al 2011).…”

Crystal structure of listeriolysin O reveals molecular details of oligomerization and pore formation

“…In addition, LLO has been implicated in inducing autophagy 11 as well as in the suppression of reactive oxygen species produced by the NOX2 NADPH oxidase 12 . Over the past few years it has emerged that LLO activates diverse cellular processes including the dysregulation of post-translational modifications mediated by SUMOlyation 13 , induction of endoplasmic reticulum stress and reversible fragmentation of mitochondria 14 as well as regulatory epigenetic changes due to the post-translational modification of histone tails 15 .…”