Listeria monocytogenesexploits host exocytosis to promote cell-to-cell spread

Abstract

The facultative intracellular pathogen Listeria monocytogenes uses an actin-based motility process to spread within human tissues. Filamentous actin from the human cell forms a tail behind bacteria, propelling microbes through the cytoplasm. Motile bacteria remodel the host plasma membrane into protrusions that are internalized by neighboring cells. A critical unresolved question is whether generation of protrusions by Listeria involves stimulation of host processes apart from actin polymerization. Here we demonstrate that efficient protrusion formation in polarized epithelial cells involves bacterial subversion of host exocytosis. Confocal microscopy imaging indicated that exocytosis is up-regulated in protrusions of Listeria in a manner that depends on the host exocyst complex. Depletion of components of the exocyst complex by RNA interference inhibited the formation of Listeria protrusions and subsequent cell-to-cell spread of bacteria. Additional genetic studies indicated important roles for the exocyst regulators Rab8 and Rab11 in bacterial protrusion formation and spread. The secreted Listeria virulence factor InlC associated with the exocyst component Exo70 and mediated the recruitment of Exo70 to bacterial protrusions. Depletion of exocyst proteins reduced the length of Listeria protrusions, suggesting that the exocyst complex promotes protrusion elongation. Collectively, these results demonstrate that Listeria exploits host exocytosis to stimulate intercellular spread of bacteria.

Mitochondrial respiration restricts Listeria monocytogenes infection by slowing down host cell receptor recycling

“…Strikingly, expression of a dominant-negative (GDP-bound) form of Rab11a was shown to decrease bacterial cell-cell spread and thus infection efficiency at 6 h post-infection (Dowd et al, 2020). Furthermore, Dowd et al (2020) showed that exocytosis is upregulated in L. monocytogenes-containing protrusions, which is a process partially associated with recycling Rab GTPases. Interestingly, another recent study with intestinal organoids showed that L. monocytogenes hijacks Rab11a-dependent E-cadherin recycling to translocate across the intestinal epithelium (Kim et al, 2020), pointing toward another important role of endocytic recycling in in vivo L. monocytogenes infections.…”

Pathogenicity and virulence of Listeria monocytogenes: A trip from environmental to medical microbiology

“…The propulsion generated by actin filament polymerization results in membrane protrusions containing bacteria that penetrate adjacent host cells. Efficient cell-to-cell spread requires the secreted virulence factor Internalin C, which diminishes the cortical tension between cells and recruits the host exocyst complex, thereby facilitating formation and elongation of the protrusion [ 248 , 249 ]. Finally, LLO damages host cell membrane at the protrusion by its pore-forming activity.…”

Distribution of PDLIM1 at actin‐rich structures generated by invasive and adherent bacterial pathogens

“…L . monocytogenes is an invasive pathogen that uses surface bound (and secreted) effector proteins to exploit an array of host endocytic/exocytoic (Dowd et al, 2020; Gianfelice et al, 2015; Veiga et al, 2007; Veiga & Cossart, 2005), cytoskeletal (Theriot, Rosenblatt, Portnoy, Goldschmidt‐Clermont, & Mitchison, 1994; Chakraborty et al, 1995; Welch, Iwamatsu, & Mitchison, 1997; Welch, Rosenblatt, Skoble, Portnoy, & Mitchison, 1998; Dhanda et al, 2018; see also Lambrechts, Gevaert, Cossart, Vandekerckhove, & Van Troys, 2008 for a review) and cytosolic (Dhanda, Lulic, Vogl, et al, 2019; Faralla et al, 2018; Gouin et al, 2019; Rajabian et al, 2009; Walker, Chua, & Guttman, 2018) proteins over the course of their infectious cycle. A crucial target of these microbes is the host actin cytoskeleton as they rearrange it into five distinct actin‐rich structures: (a) clathrin‐mediated endocytic cups for their initial invasion (Veiga & Cossart, 2005; Veiga et al, 2007; see also Pizarro‐Cerdá, Kühbacher, & Cossart, 2012 for a review), (b) actin clouds, (c) comet/rocket tails to move intracellularly (Tilney & Portnoy, 1989; see also Lambrechts et al, 2008 for a review), (d) membrane protrusions to spread between cells (Tilney & Portnoy, 1989; see also Lamason & Welch, 2017; Weddle & Agaisse, 2018 for reviews), and (e) membrane invaginations that engulf the corresponding membrane protrusions in adjacent cells (Dhanda et al, 2020).…”