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Cell-autonomous responses in Listeria monocytogenes infection

Helena Pillich1, Trinad Chakraborty1 & Mobarak Abu Mraheil*,1

Abstract Listeria monocytogenes is a facultative intracellular bacterium causing listeriosis, a food-borne infection with a high mortality rate. The mechanisms and the role of cells and tissular components in generating protective adaptive immune responses are well studied, and cell biological studies provide a detailed understanding of the processes targeted by the bacterial products. Much less is known of the cellular responses activated to limit infection in individual cells when confronted with stress or infection. Eukaryotic cellular responses depend on multitiered homeostatic systems that ensure maintenance of proteostatis, organellar integrity, function and turnover, and overall cellular viability (‘the cell-autonomous response’). Here, we review the cell-autonomous responses induced during extracellular and intracellular L. monocytogenes growth and discuss their contribution to limiting infection. Listeria monocytogenes is a Gram-positive, facultative intracellular bacterium present ubiquitously in the environment [1] , and is the causative agent of listeriosis, a life-threatening food-borne disease [2] . The bacterium can adjust to harsh environmental conditions such as wide temperature ranges, high salt concentrations and extremes of pH thus posing a threat to the food industry [2] . Infection with L. monocytogenes follows consumption of contaminated food such as meat, vegetables, seafood, unpasteurized milk and soft cheese [2] . Immunocompromised patients, the elderly, pregnant women and newborns are primarily susceptible to infection, showing symptoms of febrile gastroenteritis, bacteremia, sepsis, meningitis and fetal death [2] . Despite its low incidence, the mortality rate is very high, ranging from 20 to 30% [2] . The long incubation period of up to 70 days [2] makes disease detection difficult and leads to delays of contaminated food recalls. This problem is illustrated by the current (in September 2014) ongoing outbreak of listeriosis in Denmark which is attributed to pork sausages. This outbreak, which began in September 2013, has to date recorded 38 cases with 15 individuals succumbing to the infection (Danish Statens Serum Institute, SSI). L. monocytogenes is estimated to colonize between 1 and 10% of the population without causing any symptoms [2] . This transition from an in-apparent low-level subdued infection state to the onset of fulminant disease is increasingly being recognized, however, the mechanisms underlying this progression are not understood. Suppression of host immune response through different mechanisms such as deacetylation of peptidoglycan to avoid recognition by pattern recognition receptors (PRRs) or internalin (Inl) C-mediated inhibition of NF-κB activation [3,4] have only recently been discovered and could contribute to asymptomatic colonization and long incubation periods observed. L. monocytogenes can infect phagocytic as well as nonphagocytic cells [5] . Its internalization in nonphagocytic cells is mediated by three bacterial surface proteins: InlA, which binds to the host molecule

Keywords 

• autophagy • cytosolic receptors • histone modification • inflammasome • Listeria monocytogenes • SUMOylation • unfolded

protein response

1 Institute of Medical Microbiology, German Center for Infection Giessen-Marburg-Langen Site, Justus Liebig University Giessen, Schubertstrasse 81, 35392 Giessen, Germany *Author for correspondence: Tel.: +49 641 99 39861; Fax: +49 641 99 41259; [email protected]

10.2217/FMB.15.4 © 2015 Future Medicine Ltd

Future Microbiol. (2015) 10(4), 583–597

part of

ISSN 1746-0913

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Review  Pillich, Chakraborty & Mraheil Ecad; InlB, which interacts with Met [1] ; and virulence protein (Vip), which binds to Grp94 (also known as Gp96) upon its L. monocytogenesinduced translocation from the endoplasmic reticulum (ER) to the plasma membrane [6,7] . Entry is promoted by exploiting and modulating several host GTPases such as Rac1 and Arf6, as well as the microtubule-associated GTPases such as Dynamin 2 and Septin 2 [8–12] . InlA and InlB show a high species specificity with regard to their receptor affinity with humans and gerbils being the only fully permissive host [1] . Thus, InlA binds guinea pig and rabbit Ecad whereas InlB specifically engages the mouse and rat Met receptor  [1] . In laboratory strains, oral infection of mice results in low-level translocation of bacteria across the intestinal barrier [13] . Recombinant knock-in transgenic mice expressing human Ecad have been developed and now permit studies of oral infection of mice [13] and thus the investigation of InlA-mediated host L. monocytogenes interactions in the gastrointestinal tract. Following cellular invasion, L. monocytogenes is trapped within phagosomes [1] . Maturation of these vacuoles is delayed by the action of bacterial GAPDH on the GTPase Rab5a [14] . The pore-forming toxin LLO and two phospholipases, PlcA and PlcB, allow bacterial escape from this compartment into the host cytoplasm [1] . Using the actin cytoskeleton-binding surface protein ActA [1] bacterial cytosolic movement is promoted by the recruitment of components of the host actin–cytoskeleton complex including the Arp2/3 complex, Ena/VASP as well as actin and the actin-binding protein profilin [15] . L. monocytogenes invade neighboring cells by inhibition of other GTPases such as Cdc42 and its effector protein N-WASP [16,17] and by remodeling the host plasma membrane to induce protrusion formation [1] . Thus, the host cell serves as pathogen’s replicative niche. The expression of the virulence genes required for invasion (inlA, inlB), escape from the phagosome (hly, plcA, plcB), intracellular motility (actA) as well as cellto-cell spread (inlC) is regulated by PrfA which is activated during infection [5] . The intracellular lifestyle (Figure 1) enables L. monocytogenes to avoid humoral immune response [18] . Initial interactions at the gut–epithelia interface The initial contact between L. monocytogenes and the host occurs in the GI tract and several host defense mechanisms are in place to

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prevent L. monocytogenes infection. First, the gut microbiota has an influence on the infection progress. Treatment of mice with Lactobacillus paracasei and L. casei decreases translocation of L. monocytogenes from the intestine to the liver and spleen [19] . Lactobacillus also modulates the intestinal expression of microRNAs (miRNAs) and that of host genes, especially IFN-stimulated genes  [19] . Germ-free (GF) mice are more susceptible to oral L. monocytogenes infection than conventional mice [20] . L. monocytogenes-infected GF mice showed increased bacterial burden and higher mortality when infected intravenously, whereas prior re-colonization of GF mice decreased the bacterial burden [21] suggesting that composition of the gut microbiota can affect L. monocytogenes infection. The intestine is layered by mucus which prevents microbial contact with host cells [22] . In vitro L. monocytogenes-infection induces mucus secretion in an LLO-dependent manner  [23] . Membrane-bound mucin inhibits L. monocytogenes invasion [24] suggesting that the induced mucus secretion functions as a defense mechanism. Paneth cells residing in the crypts of the small intestine produce bactericidal effectors (cryptdin 1 and 2) against L. monocytogenes [25] representing a further defense mechanism. Indeed, oral infection of mice devoid of Paneth cells results in higher numbers of L. monocytogenes in the feces as well as in the liver [26] . The roles of listerial products that promote colonization and disease have also been studied. Engagement of the Ecad receptor by InlA in susceptible hosts results in internalization of the bacterium [1] . Recently, it was shown that ActA promotes aggregation and biofilm formation both in vitro and in vivo, inducing long-term colonization of the gut lumen [27] . Furthermore, oral infection of hEcad-transgenic mice with wild-type and LLOnegative L. monocytogenes revealed that the epithelial host response within the intestinal lumen depends exclusively on LLO [28] . Dissemination of L. monocytogenes from the intestine to the spleen is also dependent on LLO [28] . Enteric bacteria can withstand the high concentrations of bile encountered throughout the GI tract [29] . This is also the case for L. monocytogenes, but the mechanisms for bile tolerance are not only restricted to pathogenic Listeria [30] . Resistance is mediated by a number of mechanisms involving adaptive changes of the membrane, induction of bile salt transporters and

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Cell-autonomous responses in Listeria monocytogenes infection 

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Lm (A) Invasion lnlA, lnlB, Vip

(B) Vacuolar lysis LLO, PlcA, PlcB, Mpl

(C) Intracellular replication Uhpt, GlpD, GlpK, chaperones, proteases, LexA, RecA

(F) Vacuolar lysis LLO, PlcA, PlcB

(E) Cell-to-cell spread ActA, lnlC

(D) Intracellular motility ActA

Figure 1. Listeria monocytogenes infection cycle. Following invasion of L. monocytogenes into host cells, the bacterium reaches the host cell cytoplasm where it replicates, moves and infects neighboring cells. Each step of the infection cycle and the bacterial factors required are shown (A–F). InlA: Internalin A; InlB: Internalin B; InlC: Internalin C; LLO: Listeriolysin O; Lm: Listeria monocytogenes; Mpl: Metalloprotease; PlcA: Phospholipase A; PlcB: Phospholipase B

stress responses almost all of which are regulated by the alternative sigma factor σB [29,31–33] . An additional challenge to listeria growth is posed by the acidic environments of the GI tract. Induction of the adaptive acid tolerance response (ATR) for survival, whereby a short adaptive period at a nonlethal pH can lead to metabolic changes, that allow the organism to survive a lethal pH, has been described for L. monocytogenes. This adaptation involves a variety of regulatory responses, for example, induction of the LisRK two-component regulatory system as well as elements of the SOS response and the σB regulon, changes in membrane fluidity and activation of the F0F1ATPase proton pump and two enzymatic systems, glutamate decarboxylase and arginine deiminase, that regulate internal hydrogen ion concentration (reviewed in [34,35]). Evidence that the innate immunity is crucial in limiting L. monocytogenes have come from studies on bactericidal factors produced by vertebrate intestinal crypt cells as well as from

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model infections with invertebrate hosts [25,36,37] . Critically, in insect models, pre-induction of the innate response induced protection to a subsequent lethal infection of L. monocytogenes [37] . In addition, application of signaling inhibitors such as diclofenac, arachidonic acid and rapamycin led to a significant reduction of the effects of pathogenic L. monocytogenes in invertebrate models [38] , suggesting the contribution of cell survival pathways to disease attenuation. These observations indicate an important role for universally operating homeostatic systems such as the unfolded protein response (UPR) and autophagy (‘cellautonomous responses’) in restricting pathogen growth and improving survival of the infected host cell. Indeed, data are now accumulating on how these systems are triggered and modulated by the bacterium during infection. Unfolded protein response In eukaryotic cells, secreted and transmembrane proteins are folded and assembled within the ER [39] . Accumulation of unfolded proteins

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Review  Pillich, Chakraborty & Mraheil within the ER results in activation of a signaling cascade, the unfolded protein response (UPR), which re-establishes ER homeostasis [39] . UPR comprises three branches, IRE1, ATF6 and PERK-branch [39] . Induction of IRE1 results in oligomerization and activation of its ribonuclease function that cleaves the mRNA of xbp1 at two positions [39] . Activation of ATF6 permits the translocation of ATF6 to the Golgi apparatus where it is cleaved by two proteases [39] . PERK is a kinase which oligomerizes, phosphorylates itself and eIF2α inhibiting mRNA translation [39] . However, some mRNAs such as that of atf4 are efficiently translated under this condition [39] . Spliced XBP1, the cytoplasmic portion of ATF6 and ATF4 enter the nucleus and activate UPR target genes which are involved in protein folding (hspa5 [also known as bip], pdi, grp94) and transcription (ddit3 [also known as chop]) [39] . Increased bacterial numbers in the feces and liver were seen in knock-out mice lacking xbp1 following oral infection with L. monocytogenes [26] . Further analysis indicated that xbp1 deletion caused depletion of Paneth cells from the intestinal crypt with concomitant loss in the production of antimicrobial peptides [26] . In vivo splicing of xbp1was shown upon intravenous infection of mice with the pathogenic L. monocytogenes-OVA in CD8 + T cells [40] . Cell-based studies demonstrate that L. monocytogenes activates all three UPR branches of target host cells when extracellular L. monocytogenes growth is permitted and LLO is produced (Figure 2)  [41] . Drug-induced ER stress prior to infection leads to reduction of intracellular bacterial load at early stages of an in vitro infection suggesting that UPR functions as a defense mechanism [41] . A potential mechanism of UPR to eliminate intracellular bacteria is mediated by UPR-induced autophagy [42] which plays a role in L. monocytogenes growth restriction (see below). A connection between UPR and autophagy upon L. monocytogenes infection has however not been clearly established. In addition, prolonged L. monocytogenes-mediated UPR results in apoptosis [41] , a condition which takes place if the ER homeostasis cannot be re-established [39] . Thus, UPR contribute to defense also by elimination of pathogen’s replicative niche. SUMOylation SUMOylation is a reversible post-translational modification of proteins mediated by the small ubiquitin-related modifier (SUMO),

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an ubiquitin-like protein [43] . Proteins that are involved in several processes such as transcription, DNA damage repair, actin cytoskeleton dynamics, etc. are targeted for SUMOylation  [43] . SUMOylation regulates downstream pathways by different mechanisms: prevention of interactions by masking an interaction surface, induction of conformational changes and interaction with downstream effectors  [43] . The modification is achieved by several steps catalyzed by three SUMO enzymes, E1, E2 and E3 [43] . SUMOylation is reversible and SUMO is removed by SUMO-specific proteases that cleave the bond between SUMO and its target protein [43] . This modification is essential and failure of protein SUMOylation is associated with diseases such as cancer and heart failure [43] . Infection of HeLa cells with L. monocytogenes resulted in a decrease of SUMO-conjugated host proteins (Figure 2) [44] . This event occurred prior to bacterial invasion in an LLO-dependent manner and was attributed to the degradation of E2 SUMO enzyme [44] . Increase of SUMOylated host proteins by the overexpression of SUMO revealed that this modification is detrimental for L. monocytogenes invasion and/or replication as the bacterial number following infection was reduced [44] . Recently, a method combining SILAC-based quantitative proteomics and peptide immunocapture to identify SUMOylation sites was established  [45] . Using this method, it was shown that extracellular LLO causes deSUMOylation of particular proteins involved in nuclear, DNA-binding, transcription regulation and zinc finger proteins whereas other protein substrates such as cytoskeleton proteins are not targeted for deSUMOylation by LLO [45] . As SUMOylation is involved in DNA damage repair and transcription [43] , this suggests that using the SUMOylation machinery, LLO has general overall effects on cell transcription and DNA repair. Autophagy Macroautophagy (hereafter autophagy) is a highly conserved process that serves as a degradation system in eukaryotic cells, thus enabling the recycling of protein aggregates (called aggrephagy) and damaged organelles (called mitophagy, pexophagy, reticulophagy) as well as the degradation of pathogens (xenophagy) [46] . Cytosolic molecules are sequestered by specific

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Cell-autonomous responses in Listeria monocytogenes infection 

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LLO

X E2

E1

E3

X SUMO UPR deSUMOylation

Low intracellular Lm load

Efficient Lm infection

Apoptosis

Figure 2. Induction of unfolded protein response and deSUMOylation by listeriolysin O. Extracellular LLO induces the activation of the UPR as well as deSUMOylation of host proteins. Whereas UPR functions as a defense mechanism by reducing the intracellular bacterial number as well as eliminating of the pathogen’s replicative niche by apoptosis, deSUMOylation of host proteins promotes L. monocytogenes infection. E1, E2, E3: SUMO enzymes; LLO: Listeriolysin O; Lm: Listeria monocytogenes; SUMO: Small ubiquitin-related modifier; UPR: Unfolded protein response.

autophagy cargo-adaptor proteins (hereafter autophagy adaptors) into LC3-containing double-membrane vesicles, termed autophagosomes, which fuse with lysosomes for cargo degradation [46] . Autophagy proteins play also a role in the noncanonical autophagy pathway that is independent of double-membrane formation [46] . Different autophagy pathways are induced during L. monocytogenes infection (Figure 3) . It was shown that extracellular LLO induces autophagy suggesting that membrane damage plays a role in autophagy activation [47] . In contrast to studies described below, this form of autophagy induction, also measured by LC3lipidation, had no influence on intracellular L. monocytogenes growth [47] . One possible explanation for this finding is the induction of aggrephagy to limit the membrane-damaging properties of LLO. Indeed, LLO is found in small aggregates, autophagosome-like structures and large protein aggregates within the host cell [48] .

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The large protein aggregates contain ubiquitinated proteins, SQSTM1 (also called p62) and LC3 [48] , molecules that all are involved in autophagy [46,49] . LLO also mediates the noncanonical autophagy LC3-associated phagocytosis (LAP) which promotes the formation of specialized phagosomes termed spacious Listeria-containing phagosomes (SLAPs) that are LC3-positive single-membrane phagosomes containing L. monocytogenes  [50] . Unlike autophagosomes, L. monocytogenes replication in these structures is very low and associated with a low-level production of LLO [51] . These effects appear to be cell-type specific and dependent on the immune status of the infected cell. However they suggest that LAP may be a mechanism for restricting listerial growth by reducing the expression of virulence factors. Other studies showed that intracellular L. monocytogenes induces xenophagy. This was first described by Rich et al. who showed that

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LLO

TLR2

Lm SLAPs

Aggrephagy

Low LLO

Low replication

Xenophagy Xenophagy Degradation HMGB1 HMGB1

Figure 3. Activation of autophagy pathways during Listeria monocytogenes infection. L. monocytogenes activates three types of autophagy: aggrephagy, SLAP formation and xenophagy. While aggrephagy is induced by extracellular LLO, SLAP formation occurs when bacteria secrete low LLO levels. SLAPs provide L. monocytogenes a niche for slow replication. Xenophagy, which enables the degradation of L. monocytogenes, is induced by activation of TLR2 from the extracellular site and from the intracellular site when bacteria are present in damaged vacuoles and within the cytoplasm. However, by the action of phospholipases PlcA and PlcB, L. monocytogenes is able to evade from the autophagosomes into the cytoplasm. In addition, L. monocytogenes evades the recognition by autophagy machinery upon expression of ActA and InlK within the cytoplasm. HMGB1: High-mobility group box 1; LLO: Listeriolysin O; Lm: Listeria monocytogenes; SLAP: Spacious Listeria-containing phagosome.

metabolically arrested cytoplasmic L. monocytogenes were internalized into double-membrane vacuoles which were subsequently delivered to the endocytic pathway [52] . As cytoplasmic bacteria are targeted by autophagy [52] , LLO is required for autophagy induction [53,54] . L. monocytogenes containing phagosomes that are damaged by LLO might also be targeted by autophagy [53,54] . L. monocytogenes is internalized into autophagosomes for degradation prior to actin polymerization mediated by ActA  [54] . However, the pathogen disrupts the autophagosomal membrane compartment by the action of PlcA and PlcB [53,54] suggesting that a competition between the degradation within the autophagosomes and escape from the autophagosomes takes place.

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●●Induction of xenophagy

Autophagy is induced either by the regulation of AMPK and mTOR or activation of PRRs, by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [46] . L. monocytogenes was shown to induce both pathways. Inhibition of mTOR signaling is achieved by a rapid induction of host amino acid starvation in an LLO-dependent manner [55] . This condition induces autophagy [49] . The second mechanism involves cytosolic PRRs that detect peptidoglycan: PGRP-LE as well as NOD1 and NOD2, expressed in Drosophila melanogaster and mammals, respectively [56–58] , and were shown to target cytosolic L. monocytogenes to autophagy [59,60] . Prior to invasion, lipoproteins

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Cell-autonomous responses in Listeria monocytogenes infection  of L. monocytogenes are recognized by the extracellular TLR2 [61] , leading to autophagy activation  [60] . Autophagy regulated by PGRP-LE, NOD as well as TLR2 signaling pathways leads to the restriction of bacterial growth suggesting that autophagy functions as an innate defense mechanism [59,60] . Furthermore, autophagy can be induced by DAMPs that are produced due to cell injury or microbial infection [62] . Recently, it was demonstrated that production of reactive oxygen species (ROS) induces the translocation of the DAMP HMGB1 from the nucleus to the cytoplasm where it activates autophagy [63] . HMGB1 protects L. monocytogenes intraperitoneally infected mice and autophagy was reduced in an HMGB1dependent manner upon in vitro L. monocytogenes infection suggesting that HMGB1 is involved in bacterial clearance by autophagy [64] . In addition, loss of HMGB1 results in mitochondrial fragmentation [65] . Mitochondrial fragmentation occurs during L. monocytogenes infection in an LLO-dependent manner and leads to the loss of intracellular ATP levels [66] . ●●The role of autophagy adaptors in

xenophagy

Host factors termed autophagy adaptors deliver ubiquitin-tagged cargo to the autophagosomal membrane  [49] . L. monocytogenes was shown to be ubiquitinated within the host cell [67] . Two autophagy adaptors, namely, SQSTM1 and NDP52, are involved in L. monocytogenes detection recognizing the highly ubiquitinated ActA-negative bacteria and delivering them to LC3-containing autophagosomes [68,69] . In cells infected with wild-type L. monocytogenes, expression of the surface protein ActA within the host cytoplasm coats L. monocytogenes with host proteins and thereby impedes its detection by the autophagosomal machinery [68] . However, even bacteria coated with components of the actin cytoskeleton can be targeted for autophagy. The actin-bundling protein fascin1 interacts with LC3 suggesting that the actin-fascin1LC3 complex would enable the host to overcome autophagosomal evasion and to capture L. monocytogenes wild-type bacteria within the autophagosomes  [70] . Indeed, fascin1 is essential for the elimination of L. monocytogenes in dendritic cells [70] . Furthermore, expression of the surface protein InlK, which interacts with MVP, also allows L. monocytogenes to prevent autophagosomal recognition [71] .

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In addition to recognizing cytoplasmic ActAnegative L. monocytogenes [69] , NDP52 interacts with galectin 8 which binds to host glycans exposed on damaged vacuoles [72] . Galectin 8 accumulates around L. monocytogenes  [72] suggesting that L. monocytogenes is targeted by autophagy immediately after invasion and disruption of the phagosomal membrane. Recently, the newly discovered autophagy adaptor, Tollip [73] was shown to play a role during L. monocytogenes infection [74] . Tollip interacts with ubiquitin, LC3 [73] and the GTPase Rac1 [74] . Interestingly, Met-mediated internalization of L. monocytogenes is Rac1dependent [75] and knockdown of Tollip reduces L. monocytogenes invasion [74] . Inflammasome activation The inflammasome is a multiprotein complex cleaving and activating caspase-1 [76] . To date, several inflammasome complexes have been described, each named after the protein which initiates signaling: NLR or HIN-200 [76] . NLR or HIN200 interacts with ASC which contain CARD responsible for recruiting caspase-1 to the inflammasome complex [76] . Active caspase-1 proteolytically cleaves pro-IL-1β and pro-IL-18 leading to cytokine secretion [76] . Because inflammasome components such as IL-1β are expressed at low levels, their expression is primed, for example, by NF-κB activating cytokines or TLR ligands [76] . In addition, caspase-1 induces cell death known as pyro­ ptosis, a specialized form of programmed and proinflammatory cell death [76] . Inflammasome activation by L. monocytogenes was first identified in cell-culture experiments and was associated with NLRP3 (also termed Cryopyrin or NALP3) and ASC-dependent caspase-1 activation as well as IL-1β and IL-18 secretion  [77–79] . This response is dependent on LLO  [77,79] . Release of IL-1β but not caspase-1 activation was dependent on TLR2 [79] as transcription of pro-IL-1β is induced by TLR activation  [76] . NLRP3 is also required for caspase-1 activation upon stimulation with listerial RNA or with RNA from other bacteria but not with mouse liver RNA [78] . LLO-mediated pore-formation of the plasma membrane results in K+ efflux [80] which can result in NLRP3 activation [76] . Purified LLO induces IL-1β secretion which is abrogated in nlrp3 knockdown cells as well as by inhibition of K+ efflux by excess of KCl in the cell culture

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Review  Pillich, Chakraborty & Mraheil medium  [81] . Additionally, caspase-1 is activated by LLO-mediated K+ efflux [80] . Recently, MyD88, IRAK1 and IRAK4 were shown to be required for caspase-1 activation upon L. monocytogenes infection suggesting involvement of TLRs in inflammasome activation [82,83] . This response is associated with IFN-γ production in an IRAK1-, IRAK4- and IL-18R-dependent manner [83] . Upon cell invasion, L. monocytogenes is trapped within a phagosome. Escape of L. monocytogenes from the vacuole via LLO results in translocation of bacteria to the cytoplasm as well as cathepsin B release [81] . The disruption of the phagosomal membrane and cathepsin B release is sensed by NLRP3 mediating IL-1β secretion [81] . In addition, at late time points of infection, p60, a hydrolytic enzyme required for virulence [84] , is responsible for the secretion of IL-1β and IL-18 in an NLRP3-dependent manner [85] . P60 induces the production of ROS which is activating NLRP3  [76] and is essential for IL-1β but not for IL-18 release [85] . Within the cytoplasm, L. monocytogenes DNA released by bacterial lysis activates AIM2 inflammasome leading to caspase-1 activation as well as IL-1β and IL-18 release [86–90] . In vitro infection with a SecA2-deficient mutant which secretes reduced levels of DNA and RNA results in lower release of IL-1β as well as reduced caspase-1 in an RIG-I dependent manner (see also below) [91] . Cytoplasmic L. monocytogenes is also detected by NLRC4 (also termed IPAF) inflammasome recognizing flagellin, a process that is associated with caspase-1 activation as well as IL-1β secretion [92] . Recently, GBP5 was shown to promote ASC oligomerization by interaction with NLRP3 [93] . Infection of gbp5-/- cells with L. monocytogenes results in impaired release of IL-1β [93] . This process is induced by GBP5-mediated recognition of bacterial cell wall components such as muramyl dipeptide or isoglutamate diaminopimelic acid [93] . Thus, the host has a recognition system that enables the detection of L. monocytogenes factors at different stages of its life cycle contributing to defense through release of pro-inflammatory cytokines, IL-1β and IL-18, as well as elimination of the pathogen’s replicative niche by caspase-1-mediated cell death (Figure 4) . However, L. monocytogenes in turn has established mechanisms to avoid inflammasome activation. Flagellin

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expression is reduced at 37°C [94] thus avoiding recognition by NLRC4. Furthermore, low replicative rates and lysis of L. monocytogenes within the cytosol avoids release of bacterial DNA thereby enabling evasion of AIM2 recognition [88] . Chromatin remodeling Eukaryotic DNA is packaged into a structure called chromatin which comprises nucleosomes  [95] . The nucleosome is formed by an octamer of four core histones (H2A, H2B, H3, H4) and 147 base pair DNA wrapped around the octamer [95] . Post-translational histone modifications such as phosphorylation, acetylation and methylation determine the accessibility required for gene transcription [95] . Previous studies showed that L. monocytogenes induces the acetylation at Lys8 of H4 and phosphorylation/acetylation at Ser10 /Lys14 of H3 at the promoter of il8 contributing to its expression  [96] . Recent studies describe L. monocytogenes effector proteins and the induction of LLO-mediated processes that extensively modify host histones and chromatin structure (Figure 5A) . Prior to invasion, L. monocytogenes induces dephosphorylation of Ser10 of H3 and deacetylation of H4 via LLO [97] . Dephosphorylation of Ser10 of H3 is attributed to the LLO-mediated pore-dependent K+ efflux [80] . LLO-mediated dephosphorylation at Ser10 of H3 and H4 deacetylation correlates with transcriptional repression of the cxcl2  [97] which is involved in the recruitment of neutrophils [98] , key effector cells in the innate immune response against L. monocytogenes [99] . The L. monocytogenes secreted factor LntA enters the nucleus and interacts with BAHD1 preventing its binding to the promoter of IFNstimulated genes such as ifit3 and ifitm1  [100] . This event is associated with acetylation of Lys9 at H3, describing a transcriptional activity [100] . Interestingly, either constitutive expression or depletion of LntA decreases bacterial colonization in vivo suggesting a tight control of LntA expression [100] . Binding of InlB to the Met receptor is associated with the activation of Pi3K/AKT downstream signaling pathway which induces the translocation of SIRT2 from the cytoplasm to the nucleus in vitro  [101] . Within the nucleus, SIRT2 deacetylates Lys18 of H3 at a subset of genes [101] . Deacetylation of Lys18 of H3 occurs also after in vivo L. monocytogenes infections in

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Cell-autonomous responses in Listeria monocytogenes infection 

LLO

Review

TLR

Lm

Myd88

K+ efflux

Inflammasome pro-IL-1β

Cleavage pro-IL-18

Casp-1 Pyroptosis pro-IL-1β

Cleavage

Pro-inflammation

Figure 4. Inflammasome activation during Listeria monocytogenes infection. L. monocytogenes activates the inflammasome from the extracellular site by LLO-mediated K+ efflux and TLR activation. In addition, L. monocytogenes induces the inflammasome during its intracellular life cycle. The inflammasome activates caspase-1 which cleaves pro-IL-1β and pro-IL-18. Both, release of IL-1β and IL-18 as well as caspase-1 activation contribute to host cell defense against L. monocytogenes. Casp-1: Caspase-1; LLO: Listeriolysin O; Lm: Listeria monocytogenes; Myd88: Myeloid differentiation primary response 88; TLR: Toll-like receptor.

an SIRT2-dependent manner [101] . The SIRT2mediated modulation of Lys18 of H3 is necessary for efficient L. monocytogenes infection in vitro as well as in vivo [101] . The L. monocytogenes mediated regulation of histone acetylation is not limited to mammalian cells but also occurs in the insect Galleria mellonella where HDACs and histone acetyltransferases (HATs) expression is affected [102] . Cell autonomous response induction by intracellular L. monocytogenes PAMPs occur in both viable and dead bacteria, and can be therefore excluded as inducers of protective immunity whose generation requires certain bacterial components of live Listeria particularly effective at inducing protective immunity. Hence, distinguishing growing from dying bacteria is beneficial for the host to mount an appropriate immune response.

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DNA replication and transcription can only occur in live bacteria. As RNA is rapidly degraded, its detection within the cytoplasm of infected cells can be linked to viability of infecting bacteria. The expression of Escherichia coli nucleic acids in the cytosol of macrophages and dendritic cells is essential for the generation of antimicrobial immunity indicating that the immune system tailors pathogen-specific immune responses by discriminating between live and dead bacteria [103] . The cytosolic RIG-I-like receptor (RLR) family comprises three subfamilies: RIG-I, MDA5 and LGP2  [104] . RIG-I and MDA5 recognize microbial RNA and contain two N-terminal CARDs which are essential for their signaling activity. Intracellular L. monocytogenes induce IFN-β production due to the recognition of secreted bacterial RNA/DNA by the cytosolic sensors RIG-I, MDA5 and stimulator of IFN genes (STING) (Figure 5B) [91] . The

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lnlB LLO

SIRT2

Lm

K+ efflux

Met

Lm Secreted Lm components LntA

c-d-A c-d-G

DNA

RNA

Histone modification STING

Efficient Lm infection

Modulation of innate immunity

MDA5

RIG-1

IRF3 NF-κB

INF-β INF-α

Figure 5. Chromatin remodeling and sensing of secreted Listeria monocytogenes components during infection. (A) Histone modification occurs upon LLO-mediated pore formation on the plasma membrane, interaction of InlB with Met and is induced by intracellularly secreted LntA which enters the nucleus. (B) Listeria monocytogenes components (DNA, RNA, c-di-AMP and c-di-GMP) are secreted and recognized by the cytosolic sensors RIG-I, MDA5 or STING and induce type-I IFN response are illustrated in the figure. c-d-A: c-di-AMP (cyclic diadenosine monophosphate); c-d-G: c-di-GMP (cyclic diguanosine monophosphate); InlB: Internalin B; LLO: Listeriolysin O; Lm: Listeria monocytogenes; SIRT2: Sirtuin 2; STING: Stimulator of IFN genes.

secretion mechanism of nucleic acids during infection is still poorly understood. SecA2, an auxiliary protein secretion system identified in several Gram-positive pathogenic bacteria [105] , is involved in this process as a secA2 deletion mutant shows significantly reduced levels of secreted RNA and DNA in comparison to wild-type L. monocytogenes  [91] . Interestingly, mice immunized with SecA2-deficient L. monocytogenes cannot mount an effective adaptive immune response, which is required to confer protection against a secondary challenge with wild-type L. monocytogenes [106,107] . Recently, the secretion of listerial RNA upon infection was confirmed by using a novel RNA labeling technique [108] . In contrast to eukaryotic mRNA, bacterial mRNA is not capped and contains 15% 5’ triphosphorylated RNA [109] , which would render bacterial RNA an ideal ‘vita PAMP’ due to its recognition by cytosolic RNA receptors. In addition, second messengers of bacteria, such as c-di-AMP and

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c-di-GMP secreted by cytosolic L. monocytogenes initiate type-I IFN production via the signaling molecule STING [110,111] . Activation of RLRs initiate a signaling cascade resulting in the activation of transcription factors, including NF-κB and IRF3 triggering antibacterial and inflammatory responses against the infection [99,112] . Conclusion & future perspective Listerial infections have been previously described as a fulminant, disseminating disease. However, nonspecific symptoms such as fever or gastrointeritis have been overlooked and up to 10% of the population may be colonized with L. monocytogenes without displaying overt clinical symptoms. Even in susceptible populations, a long incubation period of up to 70 days may precede overt disease. This transition from an inapparent low-level subdued infection state to the onset of fulminant disease is increasingly being recognized. One of the most striking observations

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Cell-autonomous responses in Listeria monocytogenes infection  in contrast to other invasive food-borne pathogens such as Salmonella, is that L. monocytogenes

Review

induces less inflammation in the host, both at the intestinal level and systemically. This suggests

Executive summary Initial interactions at the gut–epithelia interface ●●

The gut microbiota influences Listeria monocytogenes infection.

●●

The host established defense mechanisms against L. monocytogenes within the intestine: mucus secretion, cryptdin 1 and 2 secretion.

●●

Listeria monocytogenes is resistant to acid and bile found within the GI tract.

Unfolded protein response ●●

Unfolded protein response (UPR) is a mechanism which is induced to re-establish endoplasmic reticulum homeostasis.

●●

Extracellular L. monocytogenes growth and listeriolysin O (LLO) production activate all three UPR branches of target host cells.

●●

L. monocytogenes induced UPR functions as a defense mechanism.

SUMOylation ●●

SUMOylation is a reversible post-translational modification of proteins mediated by the small ubiquitin-related modifier (SUMO).

●●

L. monocytogenes infection results in deSUMOylation of host cell proteins in an LLO-dependent manner.

●●

DeSUMOylation of host proteins promotes L. monocytogenes infection.

Autophagy ●●

Autophagy is a degradation system in eukaryotic cells.

●●

L. monocytogenes induces three forms of autophagy: aggrephagy, the noncanonical autophagy LC3-associated phagocytosis and xenophagy.

●●

Aggrephagy is induced by LLO.

●●

LC3-associated phagocytosis promotes the formation of spacious Listeria-containing phagosomes. Spacious Listeriacontaining phagosomes are produced by low LLO levels and provide a niche for slow L. monocytogenes replication.

●●

Xenophagy is induced by extracellular and intracellular L. monocytogenes. It enables to degrade intracellular L. monocytogenes. However, L. monocytogenes has established mechanisms to escape from autophagosomal compartments as well as from autophagosomal recognition.

Inflammasome activation ●●

The inflammasome is activated by extracellular and intracellular L. monocytogenes.

●●

Inflammasome activation results in caspase-1 activation as well as IL-1β and IL-18 secretion contributing to host defense.

Chromatin remodeling ●●

During L. monocytogenes infection host histones and chromatin structure is modified.

●●

L. monocytogenes mediated chromatin remodeling leads to modulation of host innate immunity and affects L. monocytogenes infection.

Cell-autonomous response induction by intracellular L. monocytogenes ●●

Intracellular L. monocytogenes induces IFN-β production due the recognition of secreted bacterial RNA, DNA, c-di-AMP and c-di-GMP by the cytosolic sensors RIG-I, MDA5 and STING.

●●

SecA2 is involved in secretion of DNA/RNA as a secA2 deletion mutant shows significantly reduced levels of secreted RNA and DNA in comparison to wild-type L. monocytogenes.

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Review  Pillich, Chakraborty & Mraheil that primary interactions of listeria with host cells may be prolonged and that the response of the individual cells to restrict bacterial growth and spread are intricately linked. As detailed in this review, L. monocytogenes uses a distinct set of bacterial proteins to elicit far-ranging effects on the host cell physiology, from induction and modulation of processes associated with maintenance of proteostatis, organellar integrity, function and turnover, to remodeling of gene expression and modulation of innate immune responses and cellular viability. The responses of these host cell homeostatic systems probably represent checkpoints that limit the progress of listerial growth. Data emerging from recent studies that address the role of universally operating homeostatic systems both in vertebrate and invertebrate models suggest that their contribution to limiting disease may be more significant than previously suspected. Thus, the study of cell-autonomous responses as well as the adaptation of L. monocytogenes represents important References Papers of special note have been highlighted as: • of interest 1

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Financial & competing interests disclosure This work was supported by the Bundesministerium für Bildung und Forschung (ER A-NET PathoGenoMics LISTR ESS and Infect-ER A PROA NTILIS to T Chakraborty) and Landes-Offensive zur Entwicklung Wissenschaftlich Ökonomischer Exzellenz (LOEWE) Medical RNomics to T Hain and T Chakraborty. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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Cell-autonomous responses in Listeria monocytogenes infection.

Listeria monocytogenes is a facultative intracellular bacterium causing listeriosis, a food-borne infection with a high mortality rate. The mechanisms...
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