SseJ has been shown to modify the lipid composition of the SCV by esterifying cholesterol through its glycerophospholipid:cholesterol acyltransferase activity (Kolodziejek and Miller, 2015; Ohlson et al., 2005). Cell. Salmonella, a rod-shaped gram-negative bacterium belonging to the family of Enterobacteriaceae, is the causative agent of salmonellosis.Salmonellosis in warm-blooded vertebrates is in most cases associated with serovars of Salmonella enterica.The most common type of infection is the carrier state, in which infected animals carry the pathogen for a variable period of time without showing any . 1998 May;66(5):2310-8. doi: 10.1128/IAI.66.5.2310-2318.1998. Consistent with this observation, in comparison to the parental cell line, we found a significant decrease in the levels of typhoid toxin in the infection medium of SAR1B-deficient cells (Figure 4g and h, Figure 4figure supplement 4, and Figure 4source data 2). As the reviewer would certainly understand, this makes the work of studying pathogens much harder because, although knowledge of cell biological process available is extremely useful, often we can't fit our observations into preestablished canons. Check if you have food poisoning. The authors should discuss their data in the context of this information. We found in CI-M6PR-deficient cells relative to the parental cell line a marked reduction in the number of typhoid toxin vesicle carrier intermediates that can be visualized as typhoid toxin-associated fluorescent puncta (Figure 2d and e, Figure 2figure supplement 1, Figure 2figure supplement 2, and Figure 2source data 2). We therefore hypothesized that a pair of v- and t-SNAREs must be involved in targeting typhoid toxin-containing vesicles to the plasma membrane. It is known that through its acetyl transferase activity, SseJ modifies the lipid composition of the SCV membrane. Agent: Salmonella typhi; Agent: Shiga toxin (Verocytotoxin)-Producing Escherichia coli; Agent: Shigella; Agent: Treponema pallidum; . These data are shown in several additional Supplementary Figures. You should control for the possibility that secreted toxin undergoes proteolysis in cells lacking M6PR (or other proteins). All data generated or analysed during this study are included in the manuscript and supporting files; source data files for all figures have been provided. 2022 Nov 25;13:1016438. doi: 10.3389/fmicb.2022.1016438. 2016 Apr 25;8(5):121. doi: 10.3390/toxins8050121. eCollection 2021 May 21. The three most common causative organisms of bacterial dysentery are Campylobacter, Shigella, and Salmonella. Ahn C, Yang YA, Neupane DP, Nguyen T, Richards AF, Sim JH, Mantis NJ, Song J. iScience. The toxin does the heavy lifting in the disease process, using a specific protein one-two punch technique when attacking its prey, white blood cells. Our data also contribute novel information about the function of S-CDT, as S-CDT-mediated DNA damage occurs only during certain phases of the cell cycle, and the resulting damage does not induce cell death as assessed using a propidium iodide exclusion assay. World Health Organization estimates of the global and regional disease burden of 22 foodborne bacterial, protozoal, and viral diseases, 2010: a data synthesis. This site needs JavaScript to work properly. Weinstein DL, O'Neill BL, Hone DM, Metcalf ES. The remaining fluorescence was defined as the area of typhoid toxin carrier intermediates. (a) Western blot analysis of the expression of typhoid toxin in parental HEK293T cells and derivatives deficient in SEC23B (an inner coat protein of COPII), AP4M1 (AP4 subunit Mu-1), CLTC (clathrin heavy chain), or AP3B1 (AP3 subunit Beta-1). Salmonella and e coli Toxins. We therefore investigated the contribution of Sar1 to typhoid toxin packaging into vesicle carriers by examining their presence in Sar1-deficient cells generated by CRISPR/Cas9 genome editing (Figure 4figure supplement 1c and d). The most common serotypes of S. enterica are Enteritidis and Typhi. M6PR intracellular trafficking pathways have been well characterised with information on the signalling sequences found in its cytoplasmic tail, the adaptor proteins they interact with including AP1, AP2, GGAs, PACS-1, TIP47 and Rab9 and the specific steps of trafficking pathways that they are involved in. (b) Quantification of the intensity of fluorescent puncta associated with typhoid toxin carrier intermediates in parental HEK293T and the indicated deficient cells. Molecular Insights into the Assembly and Functional Diversification of Typhoid Toxin. While S. Typhi . . This family includes Salmonella typhi (S. typhi), a strain of Salmonella that causes typhoid fever, which is a serious and sometimes life-threatening infection. Thank you for resubmitting your work entitled "Typhoid toxin sorting and exocytic transport from Salmonella Typhi infected cells" for further consideration by eLife. The Typhoid Toxin Produced by the Nontyphoidal Salmonella enterica Serotype Javiana Is Required for Induction of a DNA Damage Response In Vitro and Systemic Spread In Vivo The Typhoid Toxin Produced by the Nontyphoidal Salmonella enterica Serotype Javiana Is Required for Induction of a DNA Damage Response In Vitro and Systemic Spread In Vivo 2021 Jul 29;12:704152. doi: 10.3389/fmicb.2021.704152. The emergence of multiple-antibiotic resistant strains of these pathogens, which are becoming endemic in different parts of the world, is a major concern as it is complicating the available therapies (Chau et al., 2007). and transmitted securely. Unprocessed coomassie stain of the protein gel. Rather than one enzymatic A subunit as seen in all other AB5 toxins, typhoid toxin has two covalently linked A subunits (PltA and CdtB) linked to a pentameric B subunit alternatively composed of PltB or PltC (Fowler, 2019; Song et al., 2013). See this image and copyright information in PMC. Overall, we show that production of active S-CDT by NTS serotype S. Javiana requires different genes (cdtB, pltA, and either pltB or artB) for expression of biologically active toxin than those reported for S-CDT production by S. Typhi (cdtB, pltA, pltB, and ttsA). Salmonella enterica is a Gram-negative, food-borne pathogen, which colonizes the intestinal tract and invades enterocytes. The extracted peptides were subjected to LC-MS/MS analysis as previously described (Sun et al., 2018). Of all the effectors tested, only the expression of SseJ resulted in a significant reduction in the recruitment of CI-M6PR to the S. Typhi-containing vacuole (Figure 3c and d, Figure 3figure supplement 3, Figure 3figure supplement 4, Figure 3figure supplement 5 and Figure 3source data 1), without altering the total levels of CI-M6PR in the infected cells (Figure 3figure supplement 6). As indicated by the reviewer, the absence of AP4 resulted in a reduced level of typhoid toxin export. Some controls are missing in this version of the manuscript, which could provide strength to these findings. Salmonella Heidelberg has caused outbreaks associated with raw produce. Food is the source for most of these illnesses. The data shown are the mean SD of three independent experiments. Unable to load your collection due to an error, Unable to load your delegates due to an error. Consistent with their involvement in typhoid toxin transport, cells lacking SNAP23 or syntaxin 4 showed markedly reduced levels of typhoid toxin in the infection media. Similar to our last bacteria, shigella, the salmonella family shares about 65 percent of their DNA with E. coli. The wild-type S. enterica serovars Typhi ISP2825 (Galn and Curtiss, 1991) and Typhimurium SL1344 (Hoiseth and Stocker, 1981) have been described previously. Those severely at-risk clusters may benefit from personalized medicine and lifestyle intervention to improve their dysregulated metabolic traits, aiming to achieve healthier aging. With a size of 595 kDa, SiiE is the largest protein of the . AP4 knockdown also decreased toxin export. The luminal localization of typhoid toxin, which does not have any transmembrane domain, makes it highly unlikely that it could be involved in the recruitment of CI-M6PR or COPII to the SCV. Infection media obtained from Salmonella Typhi-infected HEK293T parental and the indicated deficient cells were serially diluted and applied to uninfected HEK293T cells. In order to convincingly establish a pathway, the proteins identified should be linked experimentally. The results of an additional independent experiment are shown in Figure 5figure supplement 2. Your article has been reviewed by 3 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and a Senior Editor. Values are the mean SD of three independent experiments (g). This observation (shown in the revised manuscript as Supplementary Figure S17) is consistent with the involvement of COPII in the packaging and trafficking of typhoid toxin to the extracellular space. S. Typhi and S. Paratyphi are common in many developing . Salmonella typhi. Rab11B has been implicated in various vesicle transport pathways to the plasma membrane including melanin exocytosis (Tarafder et al., 2014). Typhoid fever is a serious threat in many parts of the world, infecting 11-20 million and killing as many as 161,000 people each year, with many multidrug resistant strains. (b) Western blot analysis of the expression of typhoid toxin in parental HEK293T and Rab11B-deficient cells. Careers. ****: p<0.0001, unpaired two-sided t test. This work answers a long-standing question in the field, and the author conclusions are well supported by a series of complementary experiments. E. coli strains carrying the plasmids encoding the different toxins were grown at 37C in LB media to an OD600 of ~0.6, toxin expression was induced by the addition of 0.5 mM IPTG, and cultures were further incubated at 25 C overnight. feeling generally unwell - such as feeling tired or having aches and chills. Bethesda, MD 20894, Web Policies This difference is specifically due to the absence in S. Typhi of two T3SS effector proteins (SopD2 and GtgE), which effectively prevent the recruitment of these GTPases to the S. Typhimurium-containing vacuole (see for example PMID: 22042847, PMID: 23162001, PMID: 26867180, PMID: 32703879). 2021 Apr 20;24(5):102454. doi: 10.1016/j.isci.2021.102454. Interacting proteins of cation-independent mannose-6-phosphate receptor (CI-M6PR) identified by immunoprecipitation-mass spectrometry (IP-MS). Whether the involvement of AP4 is direct or indirect is not clear at this point. The toxin then binds its specific Neu5Ac-bearing receptors, and after receptor-mediated endocytosis, it is transported to its intracellular destination via a specialized retrograde transport pathway (Chang et al., 2019). The authors should also comment on the fact that the CI-M6PR normally traffics from the TGN to both endosomes and the plasma membrane, which could provide a plausible pathway. Normal, Key amino acid residues necessary for PltB binding to sugar moieties are also, S-CDT-mediated DNA damage primarily occurs, S-CDT-mediated DNA damage primarily occurs in the S and G 2 /M phases, Infection of HIEC-6 human intestinal epithelial cells with S. Javiana does not induce, Infection of C56BL/6 mice with WT S. Javiana results in a higher bacterial, MeSH While Salmonella and E. coli share some similarities, there are also significant . This observation further supports the premise that the CI-M6PR/COPII complex serves as cargo receptor for typhoid toxin. Like Salmonella, E. coli is commonly found in animals' guts and places where animals are slaughtered, in soil and water, through which they can produce food. Epub 2016 May 24. (b) Intracellular survival of Salmonella Typhi in parental HEK293T and CI-M6PR-deficient cells. stomach cramps and abdominal pain. Salmonellosis is illness caused by the bacterium Salmonella. non-typhoidal serovars) (Fowler and Galn, 2018; Fowler, 2019; Galn, 2016; Haghjoo and Galn, 2004; Song et al., 2013; Span et al., 2008). Recent genomic sequence analyses in several organisms suggest that new functions encoded by small open reading frames (sORFs) may emerge de novo from noncoding sequences. Dr. Jeongmin Song, assistant professor of microbiology and immunology, has discovered a new potential defense against this bacterial disease one of its closest relatives. For example, while the Rab-family GTPases Rab29, Rab32, and Rab38 are robustly recruited to the S. Typhi-containing vacuole, these GTPases are absent in the vacuolar compartment harboring S. Typhimurium (Span and Galn, 2012; Span et al., 2011). The sgRNA sequences for the generation of CRISPR/Cas9-edited cell lines used in this study, which are listed in the Key resources table, were cloned into plasmid pSpCas9(BB)-2A-Puro(PX459) V2.0 (Ran et al., 2013), which was a gift from Feng Zhang (Addgene plasmid # 62988; RRID:Addgene # 62988; http://n2t.net/addgene:62988). In some places in the manuscript (i.e., Abstract and Result, page 2, lines 11-13, page 7, lines 16-18), the corresponding descriptions are a bit confusing, sounding like a SPI2 effector produced by S. Typhi plays a key role in the packaging process. Symptoms may be aggressive and can last for up to 48. Epub 2014 Jul 16. Both toxins had three binding sites, but the difference in their amino-acid make up enabled typhoid toxins to attack a broader range of cellular targets and induce deadly systemic infections throughout the body, while Javiana could only attach to cells in the intestinal tract. Bookshelf We found that this step requires the activities of the coat protein complex COPII and the Sar1 small GTPase. In each case, we have analyzed at least two independently-generated mutant clones. Therefore, in an attempt to identify the v-SNARE potentially responsible for the fusion of typhoid toxin carriers with the plasma membrane, we tested the export of typhoid toxin on VAMP-7-deficient cells generated by CRISPR/Cas9 gene editing (Figure 5figure supplement 1). Here we show that by up-regulating hisB expression, de novo small proteins ( 50 amino acids in length) selected from random sequence libraries can rescue Escherichia coli cells that lack the conditionally essential SerB enzyme. This effector has been shown to be involved in regulating vesicular transport from recycling endosomes to the apical plasma membrane, and in particular, in the regulation of insulin granule exocytosis (Schonteich et al., 2008; Sugawara et al., 2009). Salmonella are a group of bacteria that can cause gastrointestinal illness and fever called salmonellosis. Food items cross-contaminated by a contaminated food or the environment . 2021 Mar 28;22(7):3499. doi: 10.3390/ijms22073499. . The recent discovery of typhoid toxin has provided unique opportunities to develop much needed preventive and therapeutic strategies. Host adaptation of a bacterial toxin from the human pathogen Salmonella Typhi. The relative toxicity of the different samples, shown in (h), was measured by determining the percentage of cells in the G2/M phase from the results of the dilution of infection media experiments (shown in f and g) fitted by nonlinear regression. Small changes in the inhibitor P1'-equivalent position led to preferential use of one pathway over the other. The animals were infected with Salmonella Typhi and then treated; during treatment, we . Both serovars are restricted to the human host and no animal reservoir for these pathogens has been identified. This is actually one of the exciting aspects of the study of pathogens because "unprecedented" often times does not mean that bugs do it "their way" but rather, that the study of the canonical systems have missed that aspect of cell biology. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). We therefore generated SNAP23-deficient cells by CRISPR/Cas9 gene editing (Figure 5figure supplement 1), infected them with S. Typhi, and examined the levels of typhoid-toxin carrier intermediates in the infected cells and the levels of typhoid toxin in the culture media. Wu B, Ed-Dra A, Pan H, Dong C, Jia C, Yue M. Front Microbiol. Pathogens. Recent Advances in the Detection of Antibiotic and Multi-Drug Resistant, NCI CPTC Antibody Characterization Program, Crump JA, Luby SP, Mintz ED. The reviewer is correct, and it remains formally possible that typhoid toxin may engage alternative receptors in different cells. Although cells deficient in Rab11B showed reduced amount of toxin in the infection media, they showed normal levels of vesicle carrier intermediates. In particular, we identified Rab11B as required for the efficient transport of typhoid toxin to the extracellular space. These results indicate that inactivation of CI-M6PR did not affect cellular processes that may grossly alter S. Typhi and/or toxin biology in a manner that may affect the interpretation of these experiments. 1) I think that it is important to complement all the CRISPR KO cell lines described in this study with a plasmid expressing the deleted gene to confirm that the phenotype is not due to a random mutation acquired during the process (either due to the technique itself or the selection of clones within the initial WT population). ***: p<0.001; **: p<0.01, unpaired two-sided t test. 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does salmonella typhi produce toxins