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Escherichia coli (EHEC) and Shigella dysenteriae serotype 1 are enterohemorrhagic bacteria that induce hemorrhagic colitis. This, in turn, may result in potentially lethal complications, such as hemolytic uremic syndrome (HUS), which is characterized by thrombocytopenia, acute renal failure, and neurological abnormalities. Both species of bacteria produce Shiga toxins (Stxs), a phage-encoded exotoxin inhibiting protein synthesis in host cells that are primarily responsible for bacterial virulence. Although most studies have focused on the pathogenic roles of Stxs as harmful substances capable of inducing cell death and as proinflammatory factors that sensitize the host target organs to damage, less is known about the interface between the commensalism of bacterial communities and the pathogenicity of the toxins. The gut contains more species of bacteria than any other organ, providing pathogenic bacteria that colonize the gut with a greater number of opportunities to encounter other bacterial species. Notably, the presence in the intestines of pathogenic EHEC producing Stxs associated with severe illness may have compounding effects on the diversity of the indigenous bacteria and bacterial communities in the gut. The present review focuses on studies describing the roles of Stxs in the complex interactions between pathogenic Shiga toxin-producing E. coli, the resident microbiome, and host tissues. The determination of these interactions may provide insights into the unresolved issues regarding these pathogens.
Kyung-Soo Lee; Yu-Jin Jeong; Moo-Seung Lee. Escherichia coli Shiga Toxins and Gut Microbiota Interactions. Toxins 2021, 13, 416 .
AMA StyleKyung-Soo Lee, Yu-Jin Jeong, Moo-Seung Lee. Escherichia coli Shiga Toxins and Gut Microbiota Interactions. Toxins. 2021; 13 (6):416.
Chicago/Turabian StyleKyung-Soo Lee; Yu-Jin Jeong; Moo-Seung Lee. 2021. "Escherichia coli Shiga Toxins and Gut Microbiota Interactions." Toxins 13, no. 6: 416.
O-linked β-N-acetylglucosamine (O-GlcNAc) modification regulates the activity of hundreds of nucleocytoplasmic proteins involved in a wide variety of cellular processes, such as gene expression, signaling, and cell growth; however, the mechanism underlying the regulation of B cell development and function by O-GlcNAcylation remains largely unknown. Here, we demonstrate that changes in cellular O-GlcNAc levels significantly affected the growth of pre-B cells, which rapidly proliferate to allow expansion of functional clones that express successfully rearranged heavy chains at the pro-B stage during early B cell development. In our study, the overall O-GlcNAc levels in these proliferative pre-B cells, which are linked to the glucose uptake rate, were highly induced when compared with those in pro-B cells. Thus, pharmacologically, genetically, or nutritionally, inhibition of O-GlcNAcylation in pre-B cells markedly downregulated c-Myc expression, resulting in cell cycle arrest via blockade of cyclin expression. Importantly, the population of B cells after the pro-B cell stage in mouse bone marrow was severely impaired by the administration of an O-GlcNAc inhibitor. These results strongly suggest that O-GlcNAcylation-dependent expression of c-Myc represents a new regulatory component of pre-B cell proliferation, as well as a potential therapeutic target for the treatment of pre-B cell-derived leukemia.
Da Hee Lee; Na Eun Kwon; Won-Ji Lee; Moo-Seung Lee; Doo-Jin Kim; Ji Hyung Kim; Sung-Kyun Park; Lee; Kim. Increased O-GlcNAcylation of c-Myc Promotes Pre-B Cell Proliferation. Cells 2020, 9, 158 .
AMA StyleDa Hee Lee, Na Eun Kwon, Won-Ji Lee, Moo-Seung Lee, Doo-Jin Kim, Ji Hyung Kim, Sung-Kyun Park, Lee, Kim. Increased O-GlcNAcylation of c-Myc Promotes Pre-B Cell Proliferation. Cells. 2020; 9 (1):158.
Chicago/Turabian StyleDa Hee Lee; Na Eun Kwon; Won-Ji Lee; Moo-Seung Lee; Doo-Jin Kim; Ji Hyung Kim; Sung-Kyun Park; Lee; Kim. 2020. "Increased O-GlcNAcylation of c-Myc Promotes Pre-B Cell Proliferation." Cells 9, no. 1: 158.
The emergence and spread of antibiotic-resistant Aeromonas spp. is a serious public and animal health concern. Wild animals serve as reservoirs, vectors, and sentinels of these bacteria and can facilitate their transmission to humans and livestock. The nutria (Myocastor coypus), a semi-aquatic rodent, currently is globally considered an invasive alien species that has harmful impacts on natural ecosystems and carries various zoonotic aquatic pathogens. This study aimed to determine the prevalence of antibiotic-resistant zoonotic Aeromonas spp. in wild invasive nutrias captured in Korea during governmental eradication program. Three potential zoonotic Aeromonas spp. (A. hydrophila, A. caviae, and A. dhakensis) were identified among isolates from nutria. Some strains showed unexpected resistance to fluoroquinolones, third-generation cephalosporins, and carbapenems. In carbapenem-resistant isolates, the cphA gene, which is related to intrinsic resistance of Aeromonas to carbapenems, was identified, and phylogenetic analysis based on this gene revealed the presence of two major groups represented by A. hydrophila (including A. dhakensis) and other Aeromonas spp. These results indicate that wild nutrias in Korea are a potential reservoir of zoonotic and antibiotic-resistant Aeromonas spp. that can cause infection and treatment failure in humans. Thus, measures to prevent contact of wild nutrias with livestock and humans are needed.
Se Ra Lim; Do-Hun Lee; Seon Young Park; Seungki Lee; Hyo Yeon Kim; Moo-Seung Lee; Jung Ro Lee; Jee Eun Han; Hye Kwon Kim; Ji Hyung Kim. Wild Nutria (Myocastor coypus) Is a Potential Reservoir of Carbapenem-Resistant and Zoonotic Aeromonas spp. in Korea. Microorganisms 2019, 7, 224 .
AMA StyleSe Ra Lim, Do-Hun Lee, Seon Young Park, Seungki Lee, Hyo Yeon Kim, Moo-Seung Lee, Jung Ro Lee, Jee Eun Han, Hye Kwon Kim, Ji Hyung Kim. Wild Nutria (Myocastor coypus) Is a Potential Reservoir of Carbapenem-Resistant and Zoonotic Aeromonas spp. in Korea. Microorganisms. 2019; 7 (8):224.
Chicago/Turabian StyleSe Ra Lim; Do-Hun Lee; Seon Young Park; Seungki Lee; Hyo Yeon Kim; Moo-Seung Lee; Jung Ro Lee; Jee Eun Han; Hye Kwon Kim; Ji Hyung Kim. 2019. "Wild Nutria (Myocastor coypus) Is a Potential Reservoir of Carbapenem-Resistant and Zoonotic Aeromonas spp. in Korea." Microorganisms 7, no. 8: 224.
Shigella species and Shiga toxin-producing Escherichia coli (STEC) are agents of bloody diarrhea that may progress to potentially lethal complications such as diarrhea-associated hemolytic uremic syndrome (D+HUS) and neurological disorders. The bacteria share the ability to produce virulence factors called Shiga toxins (Stxs). Research over the past two decades has identified Stxs as multifunctional toxins capable of inducing cell stress responses in addition to their canonical ribotoxic function inhibiting protein synthesis. Notably, Stxs are not only potent inducers of cell death, but also activate innate immune responses that may lead to inflammation, and these effects may increase the severity of organ injury in patients infected with Stx-producing bacteria. In the intestines, kidneys, and central nervous system, excessive or uncontrolled host innate and cellular immune responses triggered by Stxs may result in sensitization of cells to toxin mediated damage, leading to immunopathology and increased morbidity and mortality in animal models (including primates) and human patients. Here, we review studies describing Stx-induced innate immune responses that may be associated with tissue damage, inflammation, and complement activation. We speculate on how these processes may contribute to immunopathological responses to the toxins.
Moo-Seung Lee; Vernon L. Tesh. Roles of Shiga Toxins in Immunopathology. Toxins 2019, 11, 212 .
AMA StyleMoo-Seung Lee, Vernon L. Tesh. Roles of Shiga Toxins in Immunopathology. Toxins. 2019; 11 (4):212.
Chicago/Turabian StyleMoo-Seung Lee; Vernon L. Tesh. 2019. "Roles of Shiga Toxins in Immunopathology." Toxins 11, no. 4: 212.
Shiga toxins (Stxs) produced by Shiga toxin-producing bacteria Shigella dysenteriae serotype 1 and select serotypes of Escherichia coli are the most potent known virulence factors in the pathogenesis of hemorrhagic colitis progressing to potentially fatal systemic complications such as acute renal failure, blindness and neurological abnormalities. Although numerous studies have defined apoptotic responses to Shiga toxin type 1 (Stx1) or Shiga toxin type 2 (Stx2) in a variety of cell types, the potential significance of Stx-induced apoptosis of photoreceptor and pigmented cells of the eye following intoxication is unknown. We explored the use of immortalized human retinal pigment epithelial (RPE) cells as an in vitro model of Stx-induced retinal damage. To the best of our knowledge, this study is the first report that intoxication of RPE cells with Stxs activates both apoptotic cell death signaling and the endoplasmic reticulum (ER) stress response. Using live-cell imaging analysis, fluorescently labeled Stx1 or Stx2 were internalized and routed to the RPE cell endoplasmic reticulum. RPE cells were significantly sensitive to wild type Stxs by 72 h, while the cells survived challenge with enzymatically deficient mutant toxins (Stx1A− or Stx2A−). Upon exposure to purified Stxs, RPE cells showed activation of a caspase-dependent apoptotic program involving a reduction of mitochondrial transmembrane potential (Δψm), increased activation of ER stress sensors IRE1, PERK and ATF6, and overexpression CHOP and DR5. Finally, we demonstrated that treatment of RPE cells with Stxs resulted in the activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), suggesting that the ribotoxic stress response may be triggered. Collectively, these data support the involvement of Stx-induced apoptosis in ocular complications of intoxication. The evaluation of apoptotic responses to Stxs by cells isolated from multiple organs may reveal unique functional patterns of the cytotoxic actions of these toxins in the systemic complications that follow ingestion of toxin-producing bacteria.
Jun-Young Park; Yu-Jin Jeong; Sung-Kyun Park; Sung-Jin Yoon; Song Choi; Dae Gwin Jeong; Su Wol Chung; Byung Joo Lee; Jeong Hun Kim; Vernon L. Tesh; Moo-Seung Lee; Young-Jun Park. Shiga Toxins Induce Apoptosis and ER Stress in Human Retinal Pigment Epithelial Cells. Toxins 2017, 9, 319 .
AMA StyleJun-Young Park, Yu-Jin Jeong, Sung-Kyun Park, Sung-Jin Yoon, Song Choi, Dae Gwin Jeong, Su Wol Chung, Byung Joo Lee, Jeong Hun Kim, Vernon L. Tesh, Moo-Seung Lee, Young-Jun Park. Shiga Toxins Induce Apoptosis and ER Stress in Human Retinal Pigment Epithelial Cells. Toxins. 2017; 9 (10):319.
Chicago/Turabian StyleJun-Young Park; Yu-Jin Jeong; Sung-Kyun Park; Sung-Jin Yoon; Song Choi; Dae Gwin Jeong; Su Wol Chung; Byung Joo Lee; Jeong Hun Kim; Vernon L. Tesh; Moo-Seung Lee; Young-Jun Park. 2017. "Shiga Toxins Induce Apoptosis and ER Stress in Human Retinal Pigment Epithelial Cells." Toxins 9, no. 10: 319.
Shiga toxins (Stxs) produced by Shiga toxin-producing bacteria Shigella dysenteriae serotype 1 and select serotypes of Escherichia coli are primary virulence factors in the pathogenesis of hemorrhagic colitis progressing to potentially fatal systemic complications, such as hemolytic uremic syndrome and central nervous system abnormalities. Current therapeutic options to treat patients infected with toxin-producing bacteria are limited. The structures of Stxs, toxin-receptor binding, intracellular transport and the mode of action of the toxins have been well defined. However, in the last decade, numerous studies have demonstrated that in addition to being potent protein synthesis inhibitors, Stxs are also multifunctional proteins capable of activating multiple cell stress signaling pathways, which may result in apoptosis, autophagy or activation of the innate immune response. Here, we briefly present the current understanding of Stx-activated signaling pathways and provide a concise review of therapeutic applications to target tumors by engineering the toxins.
Moo-Seung Lee; Sunwoo Koo; Dae Gwin Jeong; Vernon L. Tesh. Shiga Toxins as Multi-Functional Proteins: Induction of Host Cellular Stress Responses, Role in Pathogenesis and Therapeutic Applications. Toxins 2016, 8, 77 .
AMA StyleMoo-Seung Lee, Sunwoo Koo, Dae Gwin Jeong, Vernon L. Tesh. Shiga Toxins as Multi-Functional Proteins: Induction of Host Cellular Stress Responses, Role in Pathogenesis and Therapeutic Applications. Toxins. 2016; 8 (3):77.
Chicago/Turabian StyleMoo-Seung Lee; Sunwoo Koo; Dae Gwin Jeong; Vernon L. Tesh. 2016. "Shiga Toxins as Multi-Functional Proteins: Induction of Host Cellular Stress Responses, Role in Pathogenesis and Therapeutic Applications." Toxins 8, no. 3: 77.
Shiga toxins are a family of genetically and structurally related toxins that are the primary virulence factors produced by the bacterial pathogens Shigella dysenteriae serotype 1 and certain Escherichia coli strains. The toxins are multifunctional proteins inducing protein biosynthesis inhibition, ribotoxic and ER stress responses, apoptosis, autophagy, and inflammatory cytokine and chemokine production. The regulated induction of inflammatory responses is key to minimizing damage upon injury or pathogen-mediated infections, requiring the concerted activation of multiple signaling pathways to control cytokine/chemokine expression. Activation of host cell signaling cascades is essential for Shiga toxin-mediated proinflammatory responses and the contribution of the toxins to virulence. Many studies have been reported defining the inflammatory response to Shiga toxins in vivo and in vitro, including production and secretion of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), macrophage inflammatory protein-1α/β (MIP-1α/β), macrophage chemoattractant monocyte chemoattractant protein 1 (MCP-1), interleukin 8 (IL-8), interleukin 6 (IL-6), and Groβ. These cytokines and chemokines may contribute to damage in the colon and development of life threatening conditions such as acute renal failure (hemolytic uremic syndrome) and neurological abnormalities. In this review, we summarize recent findings in Shiga toxin-mediated inflammatory responses by different types of cells in vitro and in animal models. Signaling pathways involved in the inflammatory responses are briefly reviewed.
Moo-Seung Lee; Myunghee Kim; Vernon L. Tesh. Shiga toxins expressed by human pathogenic bacteria induce immune responses in host cells. Journal of Microbiology 2013, 51, 724 -730.
AMA StyleMoo-Seung Lee, Myunghee Kim, Vernon L. Tesh. Shiga toxins expressed by human pathogenic bacteria induce immune responses in host cells. Journal of Microbiology. 2013; 51 (6):724-730.
Chicago/Turabian StyleMoo-Seung Lee; Myunghee Kim; Vernon L. Tesh. 2013. "Shiga toxins expressed by human pathogenic bacteria induce immune responses in host cells." Journal of Microbiology 51, no. 6: 724-730.