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21.
A tripartite cytolytic toxin formed by Vibrio cholerae proteins with flagellum-facilitated secretion
Aftab Nadeem Raghavendra Nagampalli Eric Toh Athar Alam Si Lhyam Myint Thomas V. Heidler Mitesh Dongre Nikola Zlatkov Hudson Pace Fouzia Bano Anders Sjstedt Marta Bally Bernt Eric Uhlin Sun Nyunt Wai Karina Persson 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(47)
The protein MakA was discovered as a motility-associated secreted toxin from Vibrio cholerae. Here, we show that MakA is part of a gene cluster encoding four additional proteins: MakB, MakC, MakD, and MakE. MakA, MakB, and MakE were readily detected in culture supernatants of wild-type V. cholerae, whereas secretion was very much reduced from a flagellum-deficient mutant. Crystal structures of MakA, MakB, and MakE revealed a structural relationship to a superfamily of bacterial pore-forming toxins. Expression of MakA/B/E in Escherichia coli resulted in toxicity toward Caenorhabditis elegans used as a predatory model organism. None of these Mak proteins alone or in pairwise combinations were cytolytic, but an equimolar mixture of MakA, MakB, and MakE acted as a tripartite cytolytic toxin in vitro, causing lysis of erythrocytes and cytotoxicity on cultured human colon carcinoma cells. Formation of oligomeric complexes on liposomes was observed by electron microscopy. Oligomer interaction with membranes was initiated by MakA membrane binding followed by MakB and MakE joining the assembly of a pore structure. A predicted membrane insertion domain of MakA was shown by site-directed mutagenesis to be essential for toxicity toward C. elegans. Bioinformatic analyses revealed that the makCDBAE gene cluster is present as a genomic island in the vast majority of sequenced genomes of V. cholerae and the fish pathogen Vibrio anguillarum. We suggest that the hitherto-unrecognized cytolytic MakA/B/E toxin can contribute to Vibrionaceae fitness and virulence potential in different host environments and organisms.Vibrio cholerae is known as the cause of cholera, a disease that can lead to fatal dehydration (1). The disease is caused by a few serogroups, and the main factor behind the symptoms is the cholera toxin (CT) encoded by genes located on a prophage mobile genetic element (CTX-φ) that induce severe disruption of intestinal cell function, leading to watery, secretory diarrhea (2). Most serogroups do not cause cholera, as they do not possess the genes for CT, but they cause other diseases [e.g., skin, wound, and gastrointestinal infections as well as bacteremia (3)]. The natural reservoirs of V. cholerae are aquatic sources such as rivers, brackish waters, and estuaries and are often associated with copepods, aquatic plants, and shellfish (4). The factors and mechanisms allowing V. cholerae and other Vibrionaceae to survive and thrive in harsh natural environments are of major interest to researchers (5).V. cholerae is motile by virtue of a single polar flagellum. The flagellum export machinery and the virulence-associated type-III secretion system (fT3SS and vT3SS, respectively) are suggested to share a common ancestor (6), explaining their similar structure and molecular organization. The vT3SS allows the delivery of effector proteins through a hollow channel directly to the eukaryotic host cell (7), and flagellar proteins are delivered via the fT3SS channel during flagellum assembly. In the bacterial cytoplasm, effectors secreted by the vT3SS are stabilized by chaperones to prevent aggregation. These chaperones are often encoded by genes adjacent to those encoding the effectors (8). Flagellar proteins are similarly protected by chaperones before they are transported to the growing distal end of the flagellum (9).We use Caenorhabditis elegans as a predatory organism model for identifying and assessing V. cholerae factors, other than CT, that may contribute to bacterial survival and persistence (10). With this model, we discovered a cytotoxin, MakA (motility-associated killing factor A), which we demonstrated to be an essential factor for the cytotoxic activity of V. cholerae in both C. elegans and Danio rerio (zebrafish) (11). We also demonstrated that secretion of MakA occurs via the flagellum in a manner that is undocumented in V. cholerae. Our crystal structure of MakA revealed similarities to ClyA (11), the pore-forming toxin first identified in nonpathogenic Escherichia coli (12, 13) and, subsequently, also in Salmonella enterica (14). ClyA from E. coli is expressed from a monocistronic operon and oligomerizes into a dodecameric pore upon release via membrane vesicles (13, 15, 16). MakA is also structurally related to two proteins from Bacillus cereus, the hemolysin BL binding component B (HBL-B) and the NheA component of the Nhe nonhemolytic enterotoxin. Both of these are considered components of tripartite toxins (17). Recently, a tripartite toxin, AhlABC, was identified and structurally characterized as a pore-forming toxin in Aeromonas hydrophila, and the structure of soluble AhlB shares the general structure described for MakA (18). A similar toxin complex of three proteins, SmhABC from Serratia marcescens, was also reported (19). However, if and how the Ahl and Smh proteins are released during normal growth, or if there is a dedicated secretion system, remain unclear.Here, we identify the proteins from the five V. cholerae genes, vca0880 through vca0884, that are coexpressed from the operon makDCBAE and analyze the crystal structures of MakA, MakB, and MakE. Our in vitro studies revealed that an equimolar combination of the MakA/B/E proteins acted as a tripartite cytotoxin causing lysis of red blood cells and cytotoxicity to epithelial cells. Examination of a large number of bacterial genomes revealed that the mak operon is present in many V. cholerae and other Vibrionaceae strains. These include Vibrio (Listonella) anguillarum, an inhabitant of estuarine and marine coastal ecosystems worldwide and the etiological agent of vibriosis in warm- and cold-water fish (20). The identification and structural characterization of the Mak proteins in V. cholerae presented here reveals a hitherto-unrecognized potential of many pathogenic Vibrionaceae strains to produce the tripartite Mak cytolytic toxin. 相似文献
22.
Sonja Pleininger Alexander Indra Daniel Golparian Florian Heger Stefanie Schindler Susanne Jacobsson Stefan Heidler Magnus Unemo 《Euro surveillance : bulletin européen sur les maladies transmissibles = European communicable disease bulletin》2022,27(24)
We describe a gonorrhoea case with ceftriaxone plus high-level azithromycin resistance. In April 2022, an Austrian heterosexual male was diagnosed with gonorrhoea after sexual intercourse with a female sex worker in Cambodia. Recommended treatment with ceftriaxone (1 g) plus azithromycin (1.5 g) possibly failed. Worryingly, this is the second strain in an Asian Neisseria gonorrhoeae genomic sublineage including high-level azithromycin-resistant strains that developed ceftriaxone resistance by acquisition of mosaic penA-60.001. Enhanced resistance surveillance and actions are imperative to prevent spread. 相似文献
23.
Vitray Dittrich H. Vollmer Hüssy G. Popoviciu G. Strassmann Krause P. Werner Einar Sjövall Büttner Waldeyer L. Kraul Elbel Dittrich H. Langen v. Neureiter Schönberg Stephan Sommer Wilcke Heidler 《International journal of legal medicine》1935,25(5-6):205-211
Ohne Zusammenfassung 相似文献
24.
25.
Valeska Helfinger Florian Freiherr von Gall Nina Henke Michael M. Kunze Tobias Schmid Flavia Rezende Juliana Heidler Ilka Wittig Heinfried H. Radeke Viola Marschall Karen Anderson Ajay M. Shah Simone Fulda Bernhard Brüne Ralf P. Brandes Katrin Schrder 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(11)
Reactive oxygen species (ROS) can cause cellular damage and promote cancer development. Besides such harmful consequences of overproduction of ROS, all cells utilize ROS for signaling purposes and stabilization of cell homeostasis. In particular, the latter is supported by the NADPH oxidase 4 (Nox4) that constitutively produces low amounts of H2O2. By that mechanism, Nox4 forces differentiation of cells and prevents inflammation. We hypothesize a constitutive low level of H2O2 maintains basal activity of cellular surveillance systems and is unlikely to be cancerogenic. Utilizing two different murine models of cancerogen-induced solid tumors, we found that deletion of Nox4 promotes tumor formation and lowers recognition of DNA damage. Nox4 supports phosphorylation of H2AX (γH2AX), a prerequisite of DNA damage recognition, by retaining a sufficiently low abundance of the phosphatase PP2A in the nucleus. The underlying mechanism is continuous oxidation of AKT by Nox4. Interaction of oxidized AKT and PP2A captures the phosphatase in the cytosol. Absence of Nox4 facilitates nuclear PP2A translocation and dephosphorylation of γH2AX. Simultaneously AKT is left phosphorylated. Thus, in the absence of Nox4, DNA damage is not recognized and the increased activity of AKT supports proliferation. The combination of both events results in genomic instability and promotes tumor formation. By identifying Nox4 as a protective source of ROS in cancerogen-induced cancer, we provide a piece of knowledge for understanding the role of moderate production of ROS in preventing the initiation of malignancies.Reactive oxygen species (ROS) cause aging, detrimental alterations of cell homeostasis, and are a precaution of cancer. Nevertheless, prospective randomized clinical trials on antioxidant supplementation have failed to provide protection from cancer and in some studies antioxidants even increased the risk of a negative outcome (1, 2). More than 25 y ago, the ATBC trial of dietary supplementation of male smokers with the antioxidants alpha-tocopherol or beta-carotene for several years revealed no reduction in the incidence of lung cancer. Instead those supplements may have harmful effects (3). Later, in 2011, the SELECT trial even suggested that dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men (4). Animal experiments demonstrated that some major antioxidants of clinical use, such as N-acetylcysteine and vitamin E, accelerate progression of lung cancer in mice carrying mutations in K-Ras and B-Raf (5) and therefore may not serve as appropriate therapeutics for existing cancers.A potential explanation for these findings is that ROS are not just a representation of environmental stress or inflammation. Rather all cells produce ROS for signaling purposes. ROS for signaling purposes have to be generated in a highly controlled manner, as facilitated by the Nox family of NADPH oxidases (6). Nox-dependent ROS production in general occurs in response to cellular stimulation and subsequent increases in intracellular calcium or activation of Rac and protein kinase C (7). There is however one exception, the NADPH oxidase Nox4. This enzyme constitutively produces low amounts of H2O2 and thus its output is controlled by its expression level.The microenvironment of solid tumors is often characterized by hypoxic conditions and increased abundance of cytokines such as TGFβ, both potent inducers of Nox4 expression (8, 9). As a consequence of cellular stress and increased ROS formation, expression of tumor suppressor genes, such as Nrf2, are induced for facilitating antioxidative responses and cellular protection (10). Indeed, Nox4 maintains the expression of Nrf2 (11). Absence of Nox4 in mice results in a hyperinflammatory phenotype (11–15). Further, Nox4 expression is induced in the course of differentiation and is essentially involved in differentiation of mesenchymal cells (16–18). Cell stress, dedifferentiation, and inflammation are well-established prerequisites for malignant transformation and accordingly, we hypothesized that knockout of Nox4 increases the risk of cancer development. 相似文献
26.
Heidler S Temml C Broessner C Mock K Rauchenwald M Madersbacher S Ponholzer A 《The Journal of urology》2007,177(2):651-654
PURPOSE: We determined the role of the metabolic syndrome as an independent risk factor for erectile dysfunction. MATERIALS AND METHODS: Men participating in a health screening project completed the International Index of Erectile Function-5. The metabolic syndrome was defined according to the 2005 International Diabetes Federation consensus definition. Multiple linear regression, ANOVA and chi-square tests were used to investigate the impact of the metabolic syndrome on erectile dysfunction. RESULTS: A total of 2,371 men with a mean age of 46.1 years (SD 9.9, range 30 to 69) were analyzed. Of the men 33.4% (652) had no erectile dysfunction (International Index of Erectile Function-5 score 22 to 25), 59.7% (1,166) had mild erectile dysfunction (International Index of Erectile Function-5 score 17 to 21) and 6.9% (134) had moderate to severe erectile dysfunction (International Index of Erectile Function-5 score 5 to 16). The metabolic syndrome was present in 33.8% (794). In a multiple linear regression analysis an increased waist-to-hip ratio (p = 0.01) and metabolic syndrome (p = 0.01) turned out to be independently associated with a decreased International Index of Erectile Function-5 score. When stratified according to age, the metabolic syndrome was correlated to erectile dysfunction only in men 50 years old or older with an increase of severe erectile dysfunction by 48% (p = 0.01). CONCLUSIONS: The metabolic syndrome and an increased waist-to-hip ratio are independently associated with a decreased International Index of Erectile Function-5 score. The metabolic syndrome in men older than 50 years is significantly associated with a higher proportion of moderate to severe erectile dysfunction. 相似文献
27.
28.
Heidler MD 《Die Rehabilitation》2008,47(1):23-30
Classical multisensory stimulation (MSS) programmes comprises modules for visual, acoustical, olfactorial and vestibularic stimulation. Therapeutic goal is a near-optimally structured and supporting environment adapted to the reduced abilities in perception and cognition of patients in a coma, with dementia, or with a learning disability. A critical review (based on the EMBASE and PubMed databases) shows that there is a shortage of studies as well as poor evidence of the effectiveness of multisensory stimulation approaches in general. A few studies show positive short-term effects concerning behavioural changes in patients in a coma, with dementia or with a learning disability but no evident long-term effects. Verifiable short-term effects, however, legitimate multisensory interventions in brain-damaged patients. 相似文献
29.
BACKGROUND: Intercellular adhesion molecule (ICAM)-1 expressed on accessory cells has a key role in antigen presentation. The histology and immunology of lung allograft rejection is postulated to result from donor lung accessory cells presenting alloantigens to recipient lymphocytes, and, therefore, ICAM-1 may have a crucial role in the rejection process. We have previously reported that the instillation of allogeneic (C57BL/6, I-a(b)) bronchoalveolar lavage (BAL) cells (96% macrophages, 2% dendritic cells) into the lungs of recipient BALB/c mice (I-a(d)) induced the histology and immunology of acute lung allograft rejection. Using this model, the purpose of the current study was to determine the role of ICAM-1 on donor lung cells in lung allograft rejection. METHODS: BALB/c mice received allogeneic BAL cells from wild-type or ICAM-1 mutant (lacking ICAM-1 expression) C57BL/6 mice by nasal insufflation weekly for 4 weeks. Recipient mice underwent BAL and serum collection for the determination of T helper 1/T helper 2 cytokines and IgG subtypes. Lung histology was graded using standard criteria for allograft rejection. RESULTS: Although wild-type cells induced a lymphocytic vasculitis and bronchitis, ICAM-1 mutant allogeneic BAL cells only induced a lymphocytic vasculitis in recipient lungs. Both wild-type and ICAM-1 mutant cells induced up-regulated local interferon-gamma and IgG2a production, and deposition of IgG2a in recipient lungs. CONCLUSIONS: These data show that ICAM-1 on donor lung accessory cells mediates differential effects on the histology and immunology of acute lung allograft rejection. 相似文献
30.
Swanson KA Zheng Y Heidler KM Mizobuchi T Wilkes DS 《American journal of respiratory cell and molecular biology》2004,30(3):311-318
Interactions between antigen-presenting cells and T cells can result in T cell activation or suppression. With the use of RNA analysis, high-performance liquid chromatography, mixed leukocyte reactions (MLRs), and animal models, the current study reports that lung interstitial antigen-presenting cells (iAPCs, CDllc+) suppress T cell responses in vitro and in vivo by production of indoleamine 2,3-dioxygenase (IDO), an enzyme that catabolizes tryptophan to its byproduct, kynurenine. IDO mRNA expression was unique to lung iAPCs, as cells similarly isolated from the liver and spleen did not express IDO constitutively, or in response to interferon-gamma. Lung iAPCs suppressed proliferation of allogeneic T cells, correlating with increased kynurenine levels; and blockade of IDO activity with 1-methyl-DL-tryptohan (1-MT) or addition of exogenous tryptophan recovered T cell proliferation in MLRs. In contrast, liver and splenic iAPCs were potent stimulators of T cells in MLRs, and IDO inhibition had no effect on T cell responses. In vivo studies showed that systemic blockade of IDO resulted in spontaneous proliferation in lung T cells and pulmonary inflammation. Finally, overexpressing IDO in lung transplants abrogated acute allograft rejection, a T cell-mediated disease. Collectively these data show that lung iAPCs contribute to local regulation of cellular immune responses by production of IDO. 相似文献