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Microbiology and Biotechnology Letters

총설(Review)

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Molecular and Cellular Microbiology (MCM)  |  Host-Microbe Interaction and Pathogenesis

Microbiol. Biotechnol. Lett. 2022; 50(4): 441-456

https://doi.org/10.48022/mbl.2209.09004

Received: September 21, 2022; Revised: October 24, 2022; Accepted: October 25, 2022

Host Cellular Response during Enterohaemorrhagic Escherichia coli Shiga Toxin Exposure

Kyung-Soo Lee1,2†, Seo Young Park1†, and Moo-Seung Lee1,2*

1Environmental Diseases Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
2Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea

Correspondence to :
Moo-Seung Lee,      msl031000@kribb.re.kr

Abstract

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Shiga toxins (Stxs) are major virulence factors from the enterohemorrhagic Escherichia coli (EHEC), a subset of Stx-producing Escherichia coli. Stxs are multi-functional, ribosome-inactivating proteins that underpin the development of hemolytic uremic syndrome (HUS) and central nervous system (CNS) damage. Currently, therapeutic options for the treatment of diseases caused by Stxs are limited and unsatisfactory. Furthermore, the pathophysiological mechanisms underpinning toxin-induced inflammation remain unclear. Numerous works have demonstrated that the various host ribotoxic stress-induced targets including p38 mitogen-activated protein kinase, its downstream substrate Mitogen-activated protein kinase-activated protein kinase 2, and apoptotic signaling via ER-stress sensors are activated in many different susceptible cell types following the regular retrograde transportation of the Stxs, eventually leading to disturbing intercellular communication. Therapeutic options targeting host cellular pathways induced by Stxs may represent a promising strategy for intervention in Stx-mediated acute renal dysfunction, retinal damage, and CNS damage. This review aims at fostering an in-depth understanding of EHEC Stxs-mediated pathogenesis through the toxin-host interactions.

Keywords: STEC, shiga toxins, hemolytic uremic syndrome, host responses, inflammation

Graphical Abstract


Introduction

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Shiga toxins (Stxs; also called verotoxins) are produced by certain strains of Stx-producing bacteria including Escherichia coli (STEC) and Shigella dysenteriae serotype 1, and are major virulence factors contributing to the pathogenesis of severe extraintestinal complications including diarrhea-associated hemorrhagic colitis, hemolytic uremic syndrome, systemic inflammation, blindness, and central nervous system (CNS) disorders [1−3]. Major outbreaks of STEC-associated diarrheal disease are frequent in children and the elderly following ingestion of contaminated water, unpasteurized milk, and uncooked meat [4]. Whilst the highest burdens of bacillary dysentery are present in developing countries, STEC-associated diseases are more common in developed countries, in which residents consume higher levels of beef and beef products [5, 6]. Antibiotic therapy is not recommended during the prodromal diarrheal phase, as bacterial lysis leads to enhanced release of Stxs, which may worsen the disease course [7]. Development of more effective drugs and vaccines targeting Shiga toxin-producing bacteria requires a greater understanding of the pathogenesis of infection by the toxinproducing pathogen.

The regional distribution and source of Shiga toxin-producing Escherichia coli

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Regional distribution of STEC

Escherichia coli is a major constituent of the gut microbiota of mammals. Despite this frequent symbiosis, some strains of E. coli are pathogenic. E. coli can be divided into six groups or pathotypes: Shiga toxin (Stx)-producing (STEC), enteropathogenic, enterotoxigenic, enteroinvasive, enteroaggregative, and diffusely adherent [8]. According to the World Health Organization, foodborne STEC caused more than 1,000,000 illnesses, leading to more than 100 deaths and approximately 13,000 disability-adjusted life years in 2020 [9]. STEC outbreaks were most frequent in the Americas (78% of cases), followed by Europe (18%) and the western pacific region (4%). Although the western pacific region harbors a small proportion of total STEC outbreaks, the largest O157 outbreak ever recorded occurred in Japan in 1996 [10]. Patients infected with STEC display wide clinical presentations, from mild intestinal disorders, to hemolytic uremic syndrome (HUS), or end-stage renal disease (ESRD) and death [1, 11].

Source of infection and reservoirs

STEC is a human-adapted pathogen transmitted via contaminated food and/or water. Contaminated beef was responsible for the highest proportion of STEC outbreaks (15%), followed by fresh produce (14%). In addition, pork, dairy products, alfalfa sprouts, and grains and beans have also been associated with STEC contamination [12, 13]. Reservoirs of STEC include mammals, invertebrates, fish, birds, and amphibians [14−16]. Ruminants in particular appear to be a major reservoir for STEC. As in humans, ruminants are infected with STEC via contaminated feed and drinking water, or by exposure to the feces of STEC-infected animals [16, 17]. Cattle are frequent reservoirs of STEC but display no signs of disease after infection [18−20]. Cattle lack expression of the Stxs receptor (globotriaosylceramide; Gb3) in the intestine, leading to asymptomatic spread of STEC within the cattle herd, promoting STEC transmission through the food chain [21]. In addition to the cattle, other ruminants such as alpacas, antelopes, deer, elk, moose, water buffalo, and yaks are considered to be STEC reservoirs [22−26]. Smaller ruminants such as sheep and goats are also frequent asymptomatic carriers of STEC [27].

The virulence of STEC

EHEC harbors a type 3 secretion system (T3SS) produced by the locus of enterocyte effacement (LEE). LEE is a 35.6 kb pathogenicity island encoded by bacteria including EHEC and EPEC. LEE encodes a functional T3SS, in addition to other secreted proteins, including the bacterial outer membrane protein intimin, and translocated intimin receptor (Tir) protein [28]. Intimin is required for intimate bacterial adhesion to human intestinal epithelial cells. Upon contact, LEE-encoded intimin and Tir are secreted into human intestinal epithelial cells via the T3SS [29, 30]. The surface expression of fimbrial adhesions induces adhesion of STEC to host epithelial cells. Once STEC adhere, characteristic attaching and effacing lesions (A/E) are formed leading to destroy the microvilli [31]. This attachment of E. coli O157:H7 induces various pro-inflammation in the host (Table 1).

Table 1 . Various STEC-associated virulence factors. Virulence factors related to STEC are described, and EHEC Shiga toxin is the principal virulence factor.

Virulence factorGenetypeSizeLocationFunctionReference
Shiga toxin (Stx)Stx1, Stx270 kDaStx prophage in E. coli O157:H7 strainsexpressed toxins that target the intestine, kidney, neutrophil, monocytes, and CNS.[32-34]
Stx1
• CP-933V
• VT1-Sakai
• YYZ-2008
• Stx1φ		Stx2
• 933W
• VT2-Sakai
• Stx2φ-I
• Stx2φ-II
• VT2φ_272
Type 3 secretion system (T3SS)Several gene35 kbLEE islandTranslocation of proteins[35]
Intimineae35 kbLEE islandA/E lesion[36]
Translocated intimin recetorTir35 kbLEE islandintimin recetor[36]
Secreted proteinsEspF, EspG, EspH, EspZ35 kbLEE islandadherence[37]
Catalase-peroxidasekatP3900 bpplasmidreducing oxidative stress[38]
Extracellular serine proteaseespP2208 bpplasmidcleaved pepsin A and human coagulation factor V[39]

Characterization of Shiga toxin

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Structure of Shiga toxin isotypes

Shiga toxins (Stxs) are major virulence factors produced by Shigella dysenteriae serotype 1 and Shiga toxinproducing Escherichia coli (STEC). Two structural types of Stxs, type 1 (Stx1) and type 2 (Stx2), have been identified. Each of these is further divided into subtypes, Stx1a, Stx1c, and Stx1d; and Stx2a, Stx2b, Stx2c, Stx2d, Stx2e, Stx2f, Stx2g [32, 40], Stx2h [41], and Stx2i [42, 43]. X-ray crystallographic analysis revealed that the molecular configuration of the Stxs comprises six protein subunits; an A subunit that is non-covalently associated with homo-pentameric B subunits (i.e., AB5) [44]. The complete 32 kDa A subunit is composed of the 27.5 kDa A1 fragment linked by disulfide bonds between residues 242 and 261 of the 4.5 kDa A2 fragment. A subunits possess N-glycosidase activity, which inhibits protein synthesis by depurinating a single adenine in the 28S rRNA component of eukaryotic ribosomes [45]. The five identical 7.7 kDa B subunits form a pentameric ring structure that harbors three toxin receptor binding sites for each that enables high-affinity binding to the toxin receptor Gb3 (also known as CD77 or the Pk blood group antigen) located on the surface of the host cells [46].

Circulation of Shiga toxins in the bloodstream and their site of action

To cause systemic diseases and inflammation, Stxs require access to the bloodstream. Shigella dysenteriae serotype 1 are invasive pathogens that replicate within the cytoplasm of colonic epithelial cells, eventually leading to host cell lysis, and loss of barrier integrity promoting translocation of Shiga toxin to the bloodstream. By contrast, STEC is a non-invasive pathogen, and in this case Stxs must pass through the intestinal epithelium to promote systemic diseases. Numerous studies have demonstrated that Stxs are associated with microvesicles and exosomes derived from host cells that may promote translocation of Stxs to the bloodstream and then to peripheral organs [3, 47, 48]. Furthermore, Toll-like receptor (TLR) 4 on the surface of neutrophils was shown to associate with Stxs, promoting their translocation to the bloodstream [49]. Once Stxs access the circulation, they damage endothelial cells expressing Gb3 lining the target organs including the intestinal tract, the kidneys, and the brain. For instance, Paneth cells which are endothelial cells lining the intestinal tract, express Gb3 may lead to being a target of Stxs resulting in intestinal dysfunction [50]. Stxs also damage kidney glomerular endothelial cells through Gb3 on the cellular membrane leading to renal filtering dysfunction [51]. Furthermore, Stx2 was also reported to damage brain associated glial cells through Gb3, indicating that the CNS is a direct target of Stxs (Fig. 1) [52].

Figure 1.Pathogenesis of S. dysenteriae and EHEC. Schematic diagram of Shiga toxin-mediated pathogenesis during disease progression of extra-intestinal/extra-renal complications in patients infected with the EHEC or S. dysenteriae serotype 1. STEC, Shiga toxin-producing E. coli; A&E lesions, attaching and effacing lesions; CNS, central nervous system; ER, endoplasmic reticulum; HUS, hemolytic uremic syndrome; Stxs, Shiga toxins; u.d., undefined.

Binding of Shiga toxins to toxin receptors on the host cell

Globotriaosylceramide (Gb3) is the predominant mammalian cell surface receptor for most Shiga toxin families. Globotetraosylceramide (Gb4) is also reported as a minor receptor for Shiga toxin, especially the Stx2e variant. Gb3 is synthesized in the Golgi before being transported to the plasma membrane, exposing its trisaccharide moiety, and non-covalently linking its hydrocarbon ceramide (C-16 to C-24) with the plasma membrane. The B subunits of Stxs recognize the terminal alpha-1,4 di-galactose of the trisaccharide moiety [53]. Interestingly, a single B subunit of Stx has three Gb3 binding sites [54]. Several studies have indicated that targeting Gb3 can reduce Stxs-induced cytotoxicity. For example, addition of Gb3 to the tissue culture medium dramatically reduces the biological activities of Stxs. Furthermore, digestion of membrane glycolipids by galactosidase blocks glycolipid synthesis and subsequently reduces Stxs-mediated cytotoxicity [55]. While numerous studies have focused on targeting Gb3 to reduce Stxs-induced cytotoxicity, it is important to note that Gb3 expression and processing are regulated by many factors. For instance, bacterial lipopolysaccharides (LPS), lymphotoxin (TNF-β), TNF-α, and interleukin-1 (IL-1) have been reported to increase the synthesis of Gb3 [56]. Furthermore, butyrate produced by components of the microbiota were also reported to increase the expression of Gb3 [57].

Intracellular trafficking of Shiga toxins

i) Endocytosis of Shiga toxins

After binding of the Shiga toxin B subunit to Gb3, clathrin-coated pits promote the internalization of Shiga toxins into target cells [58]. Shiga toxins themselves have been reported to mediate clathrin phosphorylation, promoting their own uptake via clathrin-dependent endocytosis [59]. Furthermore, A subunits, bound with the host plasma membrane, stimulate clathrin-dependent uptake of the toxin by inducing toxin-receptor complex recruitment [60]. Butyric acid also increases the internalization of Shiga toxins via clathrin-dependent mechanisms leading to cytotoxicity [61]. Inhibition of clathrin function reduces uptake of Shiga toxins by up to 35%, but does not completely abolish it, suggesting that clathrinindependent pathways for toxin internalization also exist [61, 62]. For example, Shiga toxins stimulate activity of the soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins VAMP2, VAMP3, and VAMP8 localized on the plasma membrane leading to clathrin-independent endocytosis [63]. Interestingly, human intestinal epithelial cells, which express no Gb3, uptake Shiga toxins by micropinocytosis, confirming the presence of various routes for toxin internalization suggesting uptake mechanisms of Shiga toxins are various [64]. After endocytosis, Shiga toxins undergo retrograde transport from the endosome to the Golgi apparatus and the ER in order to bypass degradation in late endosomes and lysosomes.

ii) Transport of Shiga toxins from the endosome to the Golgi apparatus

Shiga toxins must translocate from endosomes to the trans-Golgi network (TGN) to induce cytotoxicity. The Rab9-dependent transport pathway, used by the mannose-6-phosphate receptor (M6PR), is a major route for translocation of proteins from endosomes to the Golgi [65-68]. By contrast, Shiga toxins translocate to the TGN directly from endosomes in a Rab9-independent and calciumdependent manner [69−71]. It has also been reported that endosomal Shiga toxins are transported to the TGN in a Rab11- and clathrin-dependent manner [72, 73]. Interestingly, mutations in dynamin (dynK44A) reduce transport of Shiga toxin B subunits from endosomes to the TGN [61]. An additional host protein that contributes to the transportation of Shiga toxins from endosomes to TGN is vesicle SNARE (v-SNARE), a transmembrane protein essential for membrane fusion [63]. Recently, phosphoinositide binding proteins Sorting nexin 1 (SNX1) and Sorting nexin 2 (SNX2) were implicated in the transport of Shiga toxins to the TGN. Vero cells, which are sensitive to Shiga toxin stimulation, show a 40% decrease in toxin translocation to the TGN after SNX1,2 depletion by siRNA [74]. In addition to the role of host proteins, bacterial products have also been reported to increase Shiga toxin transportation to the TGN. Butyric acid, a byproduct of human commensal bacteria, is reported to increase the transportation of Shiga toxins to the TGN, leading to cytotoxicity of target cells [61].

iii) Shiga toxin transport from the trans-Golgi network to the endoplasmic reticulum

Upon accessing the TGN, Shiga toxins translocate to the ER using the host retrograde transport system. Retrograde transport occurs when proteins are recycled or require localization to specific cellular compartments. For instance, the cellular adhesion protein P-selectin is transported to the TGN for repacking and recycling. The copper transporter protein Menkes is also transported by the retrograde transport system for functional localization to cellular compartments [75]. Furthermore, Lys-Asp-Glu-Leu (KDEL) motif-bearing proteins are retro-translocated to the ER by KDEL receptors in the Golgi. Interestingly, certain pathogens hijack the host KDEL retrograde transport system to induce cytotoxicity. Pseudomonas exotoxin A, which contains a KDEL-like sequence, transports retrogradely to the ER before promoting cytotoxicity [76]. However, Shiga toxins that have no KDEL sequence can also be retrogradely transported to ER using the Rab6a’-dependent route [77, 78]. Interestingly, deletion of Rab33b, which redistributes enzymes from the Golgi, reduces transportation of Shiga toxins to the ER, showing that Rab33b sequentially acts after Rab6 in Shiga toxin transportation [79].

iv) Release of Shiga toxins from ER to cytosol

To inhibit protein synthesis, the A1 fragment of the Shiga toxin must be released from the holotoxin. As described above, the A subunit consists of an A1 fragment with N-glycosidase activity and an A2 fragment linked with B subunits. After endocytosis, the host endoprotease furin cleaves the A subunit into separate A1 and A2 fragments that are still linked by disulfide bonds [80]. After reaching the ER, these disulfide bonds are reduced, promoting release of A1 fragments into the ER lumen (Fig. 2) [81]. These fragments then translocate to the cytosol through the ER-associated protein degradation pathway (ERAD). ERAD is an important cellular regulatory system that targets the misfolded protein for degradation using molecular chaperones such as binding immunoglobulin protein (BiP), glucose-related protein (Grp), and heat-shock protein (Hsp) [82]. In contrast to other bacterial toxins such as ricin, cytotoxicity induced by Shiga toxin depends on the expression level of BiP, suggesting that the toxin A subunit directly interacts with BiP in the ER lumen [83]. In addition, HEDJ (ERdj3) was shown to interact with the A subunit promoting its association with Sec61 and release of the toxin A subunit to the cytosol [83].

Figure 2.Intracellular trafficking of EHEC Shiga toxins. After binding to the Stxs-specific host receptor Gb3 on the cell surface, the toxins are internalized and trafficked in a retrograde manner through the trans-Golgi network to the ER before entering cytosol as a final destination. The N-glycosidase activity of the A1 fragment inhibits protein synthesis through cleavage of 28S rRNA in the 60S ribosome.

The host cellular responses to Shiga toxin exposure

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Apoptosis

Apoptosis is a ‘programmed cell death’ that plays a key role in the development of pathogenesis induced by Shiga toxins. Apoptosis is mediated by the sequential activation of caspases, leading to membrane blebbing, chromatin condensation, DNA fragmentation, and the subsequent formation of apoptotic bodies [84]. Numerous studies have shown that Shiga toxins induce apoptosis in epithelial cells, endothelial cells, astrocytoma cells, monocytes, and amniotic cells by inducing ER stress leading to caspase activation. For example, Shiga toxin treatment activates caspases 6 and 9 and cleaves Bid and poly ADP-ribose polymerase (PARP), leading to apoptosis in the HEp-2 epithelial cell line [85]. Furthermore, human proximal tubular cells (HK-2) and human leukemia monocytic cells (THP-1) also activate caspases 3 and 7 after Shiga toxin stimulation leading to apoptosis [3]. Interestingly, the pan-caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl] fluoromethylketone (Z-VAD-FMK) inhibits Shiga toxin-induced cytotoxicity, suggesting that caspases are the main regulator of Shiga toxin-induced cell death [86]. Although the precise mechanisms of Shiga toxin-induced apoptosis remain unclear, it is well known that mitogen-activated protein kinase (MAPK) signaling contributes to the induction of apoptosis. MAPK is a serine/threoninespecific protein kinase that is activated by extracellular growth factors, mitogens, and cellular stress [87]. MAPK signaling is composed of three major constituents including c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinases (ERK), and p38 MAPK. JNK, ERK, and p38 MAPK activation are regulated by phosphorylation, leading to the activation of transcription factors that promote apoptosis and inflammation [88, 89]. Like other ribotoxins such as α-sarcin, Shiga toxins activate JNK, ERK, and p38 MAPK in epithelial and myeloid cells resulting in apoptosis and inflammation [3, 90, 91]. However, inhibition of zipper sterile-α-motif kinase (ZAK), a transduction protein in the MAPK pathway, did not block apoptotic DNA fragmentation caused by Shiga toxins, suggesting that Shiga toxins can also induce apoptosis independent of MAPK pathways [92].

Pyroptosis and necrosis

In addition to apoptosis, Shiga toxins have been shown to induce the programmed cell death pathways of pyroptosis and necrosis. Like apoptosis, pyroptosis is regulated by caspases. Pyroptosis is activated by caspases 1, 4, 5, and 11 rather than caspases 3 and 7 in apoptosis. Pyroptosis is characterized by the formation of membrane pores by gasdermin D (GSDMD) [93]. GSDMD pores induce cell lysis and release pro-inflammatory intracellular contents, leading to inflammation of the surrounding cells. The NLR family pyrin domaincontaining protein 3 (NLRP3) is activated in pyroptosis, which accelerates the activity of caspase 1, IL-1β secretion, and cleavage of GSDMD [94]. Interestingly, Shiga toxins were shown to induce NLRP3 oligomerization and caspase 1 and 4 activity, leading to the cleavage of GSDMD to its active form (p30) and subsequently the induction of pyroptosis [95]. GSDMD also localizes to the mitochondrial membrane to form pores leading to the production of reactive oxygen species (ROS) and the release of cytochrome C, which subsequently induces apoptosis and pyroptosis [95]. Necrosis, unlike apoptosis and pyroptosis, is a caspase- and ATP-independent form of cell death. Necrosis differs from apoptosis in that there is no cell swelling or chromatin condensation, and the process induces robust inflammation. Shiga toxins were reported to induce necrosis in the breast cancer cell line T47D, indicating that multiple types of cell death can be induced by Shiga toxin exposure and that this process is likely cell type-specific [96].

The unfolded protein response and ER stress

As described above, the A subunit of Shiga toxin inhibits protein synthesis by depurinating eukaryotic ribosomes, leading to the induction of the unfolded protein response (UPR) and ER stress. The UPR is activated when misfolded and/or unfolded proteins accumulate in the ER [97]. The UPR is an adaptive response against ER stress that reduces unfolded protein load to maintain cellular homeostasis. The UPR signal is activated by three major UPR stress sensors, inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). When UPR is initiated, cellular membrane resident IRE1 forms a homodimer promoting auto-phosphorylation and removal of introns of the X box-binding protein 1 (XBP1u) to make spliced XBP1 (XBP1s). XBP1s is a transcription factor for UPR target genes that regulate autophagy, apoptosis, quality control, and folding [98, 99]. PERK is an additional UPR sensor located on the cellular membrane, which is released from the BiP complex by UPR before homo-dimerizing. Dimerized phosphorylated PERK subsequently activates eukaryotic initiation factor 2α (eIF2α) by phosphorylation. Phosphorylated eIF2α directly inhibits global translation to recover from ER stress [100]. In addition, phosphorylated eIF2α induces activating transcription factor 4 (ATF4), which promotes UPR gene expression including BiP and C/EBP homologous protein (CHOP). BiP and CHOP play a key role in inducing ER stress-induced apoptosis. Shiga toxins, as an inducer of ER stress, are also reported to activate all three major UPR stress sensors, IRE1, PERK, and ATF6. For instance, monocyte-like THP-1 cells induce IRE1, PERK, and ATF6 in response to type 1 Shiga toxin exposure [101]. Consequently, the expression levels of CHOP, XBP1s, and death receptor 5 (DR5) were increased by type 1 Shiga toxin stimulation, leading to activation of caspase 3 and 8. Shiga toxin type 2 activates the UPR response, which may induce CHOP and DR5 expression, leading to apoptosis [3, 102]. Interestingly, the individual A and B subunits of Shiga toxin and a catalytically deficient toxin (Stxmut) cannot induce UPR responses, suggesting a key role for the enzymatic activity of the A subunit [101]. However, cytoprotective activated protein C (APC), which reduces CHOP expression and increases anti-apoptotic B-cell lymphoma (Bcl-2) expression, did not alter Shiga toxin-induced cytotoxicity, suggesting that ER stress alone may not be responsible for Shiga toxin-induced cell death [103].

Calcium influx

Calcium (Ca2+) influx is a crucial regulator of cell survival and death mediated by ER stress [104]. Intracellular Ca2+ is mainly stored in the ER lumen to re-fold proteins using Ca2+-binding chaperones [105]. Ca2+ is also involved in the induction of apoptosis [106]. Bcl-2-associated X protein (Bax), which is upregulated by ER stress, leads to the release of Ca2+ from the ER lumen and subsequently increases Ca2+ level in the mitochondria. Increased Ca2+ levels in the mitochondria subsequently promote release of cytochrome C, inducing apoptosis. Shiga toxins, as an ER stress inducer, are also reported to induce calcium influx in HeLa cells and platelets [107]. Interestingly, an antagonist of the P2X1 receptor – a known calcium channel – reduces Ca2+ influx in the ER lumen, leading to increased cell survival following Shiga toxin stimulation of HeLa cells [107]. Furthermore, the P2X1 antagonist reduced the release of Shiga toxin-induced pathogenic microvesicles, suggesting that Ca2+ influx is also associated with the pathogenicity of Shiga toxins [107].

Extracellular vesicles: microvesicles and exosomes

Membrane-derived extracellular vesicles (EVs) are essential for maintaining cellular homeostasis and communicating with other cells. Initially, EVs were shown to discard excess cell membrane and unnecessary membrane receptors such as transferrin [108]. Over time, additional biological functions of EVs have been identified. For instance, transferrin receptor families carried by EVs are transferred to recipient cells, leading to phenotypic changes in the target cell [109−111]. EVs derived from dendritic cells containing MHC complexes were also shown to amplify T cell activation and immune responses, suggesting that EVs play a key role in immune regulation [112]. EVs are subdivided into two major groups, exosomes and microvesicles. Exosomes are ~30−200 nm in size and contain cellular components including proteins, receptors, and/or RNAs [113, 114]. Microvesicles are ~200−1000 nm in size and contain cellular components [115−117]. The biogenesis of microvesicles and exosomes display marked differences in that microvesicles are generated from cellular membrane budding while exosomes are derived from endosomes. More recently, a pathogenic role of microvesicles in Shiga toxin-induced diseases was reported. The quantity of circulating microvesicles in the blood is increased in late-phase HUS patients. Furthermore, Shiga toxins were detected in blood-borne microvesicles originating from neutrophils, platelets, and red blood cells, suggesting that Shiga toxins transfer to target organs from blood via microvesicles [47, 118−120]. Furthermore, Shiga toxins were reported to induce the release of complement-coated microvesicles derived from red blood cells leading to acute disease progression, suggesting that complement activation contributes to the Shiga toxin-mediated pathogenesis via microvesicles [119]. Similarly, it is reported that exosomes derived from Stx2a-intoxicated human macrophages also contain Stx2a. Not only Stx2a but also pro-inflammatory exosomal mRNAs were detected in the exosomes suggesting the pathogenic role of exosomes in HUS development. Interestingly, blockade of exosomal biogenesis by GW4869 ameliorates cytotoxicity in target cells suggesting new therapy for HUS development [3]. The role of exosomes in HUS development however, remains unclear. Thus, the regulated release of exosomes and the function of exosomes in HUS development should be considered in major Stx target cells including human macrophage and various renal cells.

Ribotoxic stress and inflammation

Ribotoxic stress was first discovered by site-specific modification of ribosomal peptidyl transferase. The plant toxin ricin A and fungal ribotoxin α-sacrin act on eukaryotic 28S ribosomal RNA, targeting the peptidyl transferase in the center of ribosomes, leading to ribosome inactivation and activation of JNK [121]. Like other ribosome-inactivating proteins (RIPs), Shiga toxins inactivate eukaryotic ribosomes by cleaving the N-glycosidic bond at A-4324 in 28S ribosomal RNA, leading to the induction of ribotoxic stress [45]. For instance, Shiga toxin-susceptible cells including human macrophagelike differentiated THP-1 cells, kidney tubular cells, and retinal pigment epithelial cells induce acute activation of ribotoxic stress markers including PERK, p38 MAPK, JNK, ERK, CHOP, and DR5α after toxin stimulation [2, 3, 91, 122]. Ribotoxic stress markers such as p38 MAPK, JNK, and ERK are also involved in pro-inflammatory signaling pathways. For instance, cellular stress such as ROS induces phosphorylation of p38 MAPK, JNK, and ERK to increase the production of pro-inflammatory cytokines including TNF-α and IL-1β [123]. Similarly, phosphorylation of p38 MAPK, JNK, and ERK by Shiga toxin exposure enhances the production of pro-inflammatory cytokines. Inhibition of p38 MAPK, JNK, and ERK extensively reduce the production of pro-inflammatory cytokines including IL-1β and IL-8 [91]. Furthermore, inhibition of p38 MAPK signaling by PKR inhibitors also reduces cytokine production including TNF-α and GM-CSF, suggesting a key role of ribotoxic stress markers in Shiga toxin-induced inflammation [124].

Strategies to treat Shiga toxin-mediated diseases

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Antibiotics

Antibiotics are not recommended for the treatment of Shiga toxin-mediated diseases. Bactericidal antibiotics activate the lytic cycle of STEC. This enhances the production of Shiga toxins through the activation of the lysogenic cycle promoter. For instance, the quinolone antibiotic ciprofloxacin induces robust expression of the stx gene in STEC by inducing bacterial lysis and oxidative stress [125, 126]. Though antibiotics are not recommended for the treatment of HUS patients, several antibiotics including fosfomycin, panipenem, ceftazidime, and aztreonam display efficacy without inducing robust expression of the stx gene [127]. It is therefore important to consider the different modes of action of antibiotics when prescribing them for the treatment of HUS.

Neutralizing antibody

Antibodies against Shiga toxins are produced in STEC-infected patients, suggesting that the adaptive immune system could play a role in HUS treatment [128, 129]. Natural antibody-production in humans is typically longer than the disease course of HUS. There is therefore a need to generate humanized antibodies for the treatment of HUS in vitro [130]. For instance, Shiga toxin-specific antibody treatment reduces cytotoxicity in human cells in vitro and in an in vivo mouse model [131]. Furthermore, a specific antibody against subunit A of Shiga toxin type 2 successfully inhibits retrograde transport of the toxin and causes them to accumulate within endosomes, reducing Shiga toxin-induced cytotoxicity [132]. Another interesting concept for HUS treatment using Shiga toxin-specific antibodies is transgenic plants that express recombinant antibodies. For instance, transgenic plants such as Arabidopsis thaliana are developed that produce Shiga toxin-specific antibodies, suggesting the possibility of an edible therapy [133]. This technology can be extended to other contexts. TD4, a camelid single-domain antibody specific for Tir that overlaps with the binding site of the adhesion intimin, reduces attachment and colonization of bacteria on the human colonic mucosa [134].

Gb3 analogs blocking Stx binding to the host receptor

Since the major receptor of the Shiga toxin is Gb3, there are several trials aimed at the treatment of HUS with Gb3 analogs to inhibit the internalization of toxin by target cells expressing Gb3. SYNSORB Pk, which consists of silicon dioxide particles with covalently linked trisaccharides, was the first Gb3 analog used to treat HUS. SYNSORB Pk was tested in 145 HUSdiagnosed children, resulting in no significant difference in the number of deaths [135]. The reasons for treatment failure are likely that (i) SYNSORB Pk was administrated after HUS development, (ii) Shiga toxins are not free floating but more likely cell- and/or exosomes/microvesicles associated, and (iii) the binding affinity of Shiga toxins with Gb3 is higher than SYNSORB Pk. Thus, SUPER TWIG Gb3 analogs that show higher affinity with Gb3 than SYNSORB Pk were developed [136, 137]. Interestingly, SUPER TWIG successfully bound to Shiga toxin with a higher affinity and prevented the uptake of Shiga toxins by target cells. In addition, phagocytosis of Shiga toxin by macrophages is increased, leading to the survival of mice after toxin exposure. Acrylamide polymers of Gb3, which have a higher affinity to Gb3 than SUPER TWIG, also reduced Shiga toxin-mediated lethality in a mouse model [138]. Interestingly, orally administrated polymers reduced lethality even after colonization of the bacteria in the gut, suggesting a new therapeutic agent to treat HUS.

Shiga toxins for cancer therapy

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Since Shiga toxins bind Gb3, there are several trials aimed at delivering molecules to Gb3 expressing cells using B subunits of Shiga toxin. For instance, human cancer cells including breast cancer cells [139], ovarian cancer cells [140], prostate cancer cells [141], and testicular cancer cells [142], which express high levels of Gb3, are natural targets for Shiga toxin B subunits. Cytotoxic compounds such as topoisomerase I inhibitor SN38 and benzodiazepine RO5 linked with toxin B subunits are reported to inhibit the cancer cells described above [143], [144]. Indeed, natural holotoxins have emerged as a novel cancer therapy. For instance, intratumoral or intraperitoneal injection of Shiga toxin inhibited tumor growth in a murine metastatic fibrosarcoma model [145], human malignant meningiomas [146], human bladder carcinoma [147], human renal carcinoma [148], and human astrocytoma [149]. Interestingly, no side effects were observed in Shiga toxin-treated murine models for more than 50 days [149]. Due to the lack of other virulence factors including LPS, adhesins, and bacterial proteases, purified Shiga toxins may not be sufficient to induce HUS. Therefore, purified toxins alone may not be able to induce side effects such as bloody diarrhea [150]. Although murine models successfully show the potent anti-cancer effects of Shiga toxins, several problems remain. For instance, not only cancer cells express a high level of Gb3. Other cell types including human renal cells express Gb3, which may promote off-target effects of anti-cancer therapies using B subunits of Shiga toxins. However, the Shiga toxins or Bsubunit of the holotoxin might be exploited in immunotherapy or cancer patient treatment.

Discussion

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Finally, in the review, we discussed our current knowledge about the Shiga toxin-mediated signaling pathways in host cells and provide a concise review of therapeutic applications demonstrated by targeting identified host-directed factors to mitigate the pathological conditions in the infected human body. STEC are food-borne bacteria that are distributed among mammals, invertebrates, fish, birds, and amphibians. Recently, many more people have been at increased risk for developing life-threatening extraintestinal complications such as HUS following infection with Shiga toxin-producing bacteria. Even though many virulence factors of STEC are revealed, it is hard to reduce the pathogenesis of HUS by targeting virulence factors of STEC due to the lack of specificity and bacterial host immune evasion. As seen in the German outbreak, STEC including hybrid strain EHEC/EAEC evolves through the recombination of various STEC genes resulting in new virulence factors. Thus, it is essential to understand more precisely the interaction between the Shiga toxins and the host immune system to reduce the pathogenesis of STEC. Besides therapeutic options that target Shiga toxins themselves including neutralizing antibodies and Gb3 analogs, emerging interventions to inhibit Shiga toxins and/or STEC have been recently developed focusing on the host cellular responses. For instance, targeting exosomes induced by Shiga toxins is one of the candidates for neutralizing the toxins. Lee et al. have demonstrated that inhibiting the biogenesis of exosomes induced by Shiga toxins ameliorates the cytotoxicity of the Shiga toxins target cells by blocking the exosomemediated transport of Shiga toxins [3]. More importantly, the inhibition of the aberrant levels of host cellular O-GlcNAcylation, a type of post-translational modification (PTM) in the host, is also reported to be a promising approach to protect from the Shiga toxinsmediated renal damage. Acutely elevated O-GlcNAcylation level in the host by Shiga toxins induced host apoptosis by regulating Akt. Consequently, inhibition of O-GlcNAcylation significantly reduced Shiga toxinsinduced cytotoxicity and lethality in mice and human organoid models, suggesting new emerging therapy against Shiga toxins-mediated pathogenesis [102]. In addition to apoptosis, it is reported that Shiga toxins activate caspase-1 mediated NLRP3 inflammasome leading to pro-inflammatory cytokine production including IL-1β [151]. Furthermore, Stx2 induces pyroptosis mediated by caspase-4, activating gasdermin D by increasing ROS and IL-1β production as described above [95]. Therefore, not only apoptosis inhibitors but also pyroptosis inhibitors may be innovative therapeutic targets against Shiga toxins.

Furthermore, the microbiome that modulates the host cellular responses is reported to reduce STEC-mediated pathogenesis. For instance, Lactobacillus rhamnosus HN001-fed mice show up-regulated host blood leukocyte activity against STEC, resulting in the inhibition of the pathogenesis of STEC [152]. In addition, Bifidobacterium lactis-fed mice also show reduced lethality induced by STEC via increasing the proportion of phagocytically active cells in the blood and peritoneum [153]. However, the microbiota reducing the pathogenesis of the STEC lacks tissue specificity that further studies are warranted.

Acknowledgments

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This work was supported by the KRIBB Research Initiative Program (KGS1352221, KGM5322214) and a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2018M3A9H3023077, 2021M3A9H3016046) and and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) (2022R1A2C1003699) and also the "Cooperative Research Program for Agriculture Science and Technology Development (Project No. PJ015001022022)" Rural Development Administration, Republic of Korea.

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