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  1. Article ; Online: Alternate atxA and acpA dependent response of Bacillus anthracis to serum, HCO3- and CO2.

    Itai Glinert / Elad Bar-David / Amir Ben-Shmuel / Assa Sittner / Reut Puni / Shira Laredo / David Kobiler / Shay Weiss / Haim Levy

    PLoS ONE, Vol 18, Iss 2, p e

    2023  Volume 0281879

    Abstract: Bacillus anthracis overcomes host immune responses by producing capsule and secreting toxins. Production of these virulence factors in response to entering the host environment was shown to be regulated by atxA, the major virulence regulator, known to be ...

    Abstract Bacillus anthracis overcomes host immune responses by producing capsule and secreting toxins. Production of these virulence factors in response to entering the host environment was shown to be regulated by atxA, the major virulence regulator, known to be activated by HCO3- and CO2. While toxin production is regulated directly by atxA, capsule production is independently mediated by two regulators; acpA and acpB. In addition, it was demonstrated that acpA has at least two promotors, one of them shared with atxA. We used a genetic approach to study capsule and toxin production under different conditions. Unlike previous works utilizing NBY, CA or R-HCO3- medium under CO2 enriched conditions, we used a sDMEM-based medium. Thus, toxin and capsule production can be induced in ambient or CO2 enriched atmosphere. Using this system, we could differentiate between induction by 10% NRS, 10% CO2 or 0.75% HCO3-. In response to high CO2, capsule production is induced by acpA based response in an atxA-independent manner, with little to no toxin (protective antigen PA) production. atxA based response is activated in response to serum independently of CO2, inducing toxin and capsule production in an acpA or acpB dependent manner. HCO3- was also found to activate atxA based response, but in non-physiological concentrations. Our findings may help explain the first stages of inhalational infection, in which spores germinating in dendritic cells require protection (by encapsulation) without affecting cell migration to the draining lymph-node by toxin secretion.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Specific and Rapid SARS-CoV‑2 Identification Based on LC-MS/MS Analysis

    Ofir Schuster / Anat Zvi / Osnat Rosen / Hagit Achdout / Amir Ben-Shmuel / Ohad Shifman / Shmuel Yitzhaki / Orly Laskar / Liron Feldberg

    ACS Omega, Vol 6, Iss 5, Pp 3525-

    2021  Volume 3534

    Keywords Chemistry ; QD1-999
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher American Chemical Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Book ; Online: Specific and Rapid SARS-CoV-2 Identification Based on LC-MS/MS Analysis

    Ofir Schuster / Anat Zvi / Osnat Rosen / Hagit Achdout / Amir Ben-Shmuel / Ohad Shifman / Shmuel Yitzhaki / Orly Laskar / Liron Feldberg

    2020  

    Abstract: This study describes the development of a novel assay for SARS-CoV-2 identification using LC-MS/MS analysis. A multi-step procedure for the rational down-selection of a set of markers has leaded to the discovery of six SARS-CoV-2 specific and sensitive ... ...

    Abstract This study describes the development of a novel assay for SARS-CoV-2 identification using LC-MS/MS analysis. A multi-step procedure for the rational down-selection of a set of markers has leaded to the discovery of six SARS-CoV-2 specific and sensitive markers, enabling the reliable identification of the virus. A rapid and simple assay was developed, successfully applied to clinical nasopharyngeal samples. The assay may potentially serve as a complementary approach for SARS-CoV-2 identification.
    Keywords Microbiology ; SARS-CoV-2 ; identification method ; LC-MS/MS ; Spike ; Nucleoprotein ; marker ; covid19
    Publishing date 2020-10-07T05:12:05Z
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Using old antibiotics to treat ancient bacterium-β-lactams for Bacillus anthracis meningitis.

    Assa Sittner / Amir Ben-Shmuel / Itai Glinert / Elad Bar-David / Josef Schlomovitz / David Kobiler / Shay Weiss / Haim Levy

    PLoS ONE, Vol 15, Iss 2, p e

    2020  Volume 0228917

    Abstract: As Bacillus anthracis spores pose a proven bio-terror risk, the treatment focus has shifted from exposed populations to anthrax patients and the need for effective antibiotic treatment protocols increases. The CDC recommends carbapenems and Linezolid ( ... ...

    Abstract As Bacillus anthracis spores pose a proven bio-terror risk, the treatment focus has shifted from exposed populations to anthrax patients and the need for effective antibiotic treatment protocols increases. The CDC recommends carbapenems and Linezolid (oxazolidinone), for the treatment of anthrax, particularly for the late, meningeal stages of the disease. Previously we demonstrated that treatment with Meropenem or Linezolid, either as a single treatment or in combination with Ciprofloxacin, fails to protect rabbits from anthrax-meningitis. In addition, we showed that the failure of Meropenem was due to slow BBB penetration rather than low antibacterial activity. Herein, we tested the effect of increasing the dose of the antibiotic on treatment efficacy. We found that for full protection (88% cure rate) the dose should be increased four-fold from 40 mg/kg to 150 mg/kg. In addition, B. anthracis is a genetically stable bacterium and naturally occurring multidrug resistant B. anthracis strains have not been reported. In this manuscript, we report the efficacy of classical β-lactams as a single treatment or in combination with β-lactamase inhibitors in treating anthrax meningitis. We demonstrate that Ampicillin based treatment of anthrax meningitis is largely efficient (66%). The high efficacy (88-100%) of Augmentin (Amoxicillin and Clavulonic acid) and Unasyn (Ampicillin and Sulbactam) makes them a favorable choice due to reports of β-lactam resistant B. anthracis strains. Tazocin (Piperacillin and Tazobactam) proved inefficient compared to the highly efficient Augmentin and Unasyn.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Infection with a Nonencapsulated Bacillus anthracis Strain in Rabbits—The Role of Bacterial Adhesion and the Potential for a Safe Live Attenuated Vaccine

    Itai Glinert / Shay Weiss / Assa Sittner / Elad Bar-David / Amir Ben-Shmuel / Josef Schlomovitz / David Kobiler / Haim Levy

    Toxins, Vol 10, Iss 12, p

    2018  Volume 506

    Abstract: Nonencapsulated (∆pXO2) Bacillus anthracis strains are commonly used as vaccines and for anthrax research, mainly in the mouse model. Previously, we demonstrated that the infection of rabbits, intranasally or subcutaneously, with the spores of a fully ... ...

    Abstract Nonencapsulated (∆pXO2) Bacillus anthracis strains are commonly used as vaccines and for anthrax research, mainly in the mouse model. Previously, we demonstrated that the infection of rabbits, intranasally or subcutaneously, with the spores of a fully virulent strain results in the systemic dissemination of the bacteria, meningitis, and death, whereas ∆pXO2 strains are fully attenuated in this animal model. We used the intravenous inoculation of rabbits to study the pathogenicity of the ∆pXO2 strain infection. Bacteremia, brain bacterial burden, and pathology were used as criteria to compare the Vollum∆pXO2 disease to the wild type Vollum infection. To test the role of adhesion in the virulence of Vollum∆pXO2, we deleted the major adhesion protein BslA and tested the virulence and immunogenicity of this mutant. We found that 50% of the rabbits succumb to Vollum∆pXO2 strain following i.v. infection, a death that was accompanied with significant neurological symptoms. Pathology revealed severe brain infection coupled with an atypical massive bacterial growth into the parenchyma. Contrary to the Vollum strain, deletion of the bslA gene fully attenuated the ∆pXO2 strain. Though the Vollum∆pXO2 cannot serve as a model for B. anthracis pathogenicity in rabbits, deletion of the bslA gene prevents central nervous system (CNS) infections, possibly leading to the generation of a safer vaccine.
    Keywords Bacillus anthacis ; vaccine strain ; BslA ; cell adherence ; encephalitis ; CNS infection ; Medicine ; R
    Subject code 572
    Language English
    Publishing date 2018-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Pathology of wild-type and toxin-independent Bacillus anthracis meningitis in rabbits.

    Assa Sittner / Elad Bar-David / Itai Glinert / Amir Ben-Shmuel / Shay Weiss / Josef Schlomovitz / David Kobiler / Haim Levy

    PLoS ONE, Vol 12, Iss 10, p e

    2017  Volume 0186613

    Abstract: Hemorrhagic meningitis is considered a complication of anthrax and was reported in about 50% of deadly cases in humans and non-human primates (NHP). Recently we demonstrated in Guinea pigs and rabbits that 100% of the B. anthracis-infected animals ... ...

    Abstract Hemorrhagic meningitis is considered a complication of anthrax and was reported in about 50% of deadly cases in humans and non-human primates (NHP). Recently we demonstrated in Guinea pigs and rabbits that 100% of the B. anthracis-infected animals presented histopathology of meningitis at the time of death, some without any sign of hemorrhage. A similar pathology was observed in animals that succumbed following infection with the toxin deficient mutant, thus indicating that anthrax meningitis is a toxin-independent phenomenon. In this manuscript we describe a histopathological study of the B. anthracis infection of the central nervous system (CNS). Though we could find sporadic growth of the bacteria around blood vessels in the cortex, we report that the main infiltration route is the choroid plexus. We found massive destruction of entire sections of the choroid plexus coupled with massive aggregation of bacilli in the ventricles, in close proximity to the parenchyma. The choroid plexus also contained significant amounts of intravascular bacterial aggregates, often enclosed in what appear to be fibrin-like clots. The high concentration of these aggregates in areas of significant tissue destruction combined with the fact that capsular B. anthracis bacteria have a low tendency to adhere to endothelial cells, might suggest that these clots are used as an adherence mechanism by the bacteria. The major histopathological finding is meningitis. We find massive bacterial growth in the meninges without evidence of encephalitis, even when the bacteria emerge from a parenchymal blood vessel. Erythrocytes were present within the meningeal space but no clear vasculitis could be detected. Histology of the brain stem indicates meningitis, edema and hemorrhages that might explain death from suffocation due to direct damage to the respiratory center. All of these processes are toxin-independent, since they were observed following infection with either the wild type strain or the toxin-deficient mutant. Herein, we propose that the first step of anthrax-meningitis is bacterial adhesion to the blood vessels by manipulating coagulation, mainly in the choroid plexus. The trapped bacteria then destroy sections of the choroid plexus, resulting in penetration into the CSF, leading to meningitis and hemorrhage. Death could be the result of increased intracranial pressure and/or damage to the brain stem.
    Keywords Medicine ; R ; Science ; Q
    Subject code 630
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis

    Nour Ershaid / Yoray Sharon / Hila Doron / Yael Raz / Ophir Shani / Noam Cohen / Lea Monteran / Leonor Leider-Trejo / Amir Ben-Shmuel / Muhammad Yassin / Motti Gerlic / Adit Ben-Baruch / Metsada Pasmanik-Chor / Roni Apte / Neta Erez

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 15

    Abstract: Cancer associated fibroblasts (CAFs) are known to promote pro-tumorigenic inflammation. Here, the authors show that CAFs sense tissue damage and activate NLRP3 inflammasome and pro-inflammatory IL-1β secretion, and CAF-derived inflammasome signalling ... ...

    Abstract Cancer associated fibroblasts (CAFs) are known to promote pro-tumorigenic inflammation. Here, the authors show that CAFs sense tissue damage and activate NLRP3 inflammasome and pro-inflammatory IL-1β secretion, and CAF-derived inflammasome signalling promotes breast tumour growth and metastasis.
    Keywords Science ; Q
    Language English
    Publishing date 2019-09-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis

    Nour Ershaid / Yoray Sharon / Hila Doron / Yael Raz / Ophir Shani / Noam Cohen / Lea Monteran / Leonor Leider-Trejo / Amir Ben-Shmuel / Muhammad Yassin / Motti Gerlic / Adit Ben-Baruch / Metsada Pasmanik-Chor / Roni Apte / Neta Erez

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 15

    Abstract: Cancer associated fibroblasts (CAFs) are known to promote pro-tumorigenic inflammation. Here, the authors show that CAFs sense tissue damage and activate NLRP3 inflammasome and pro-inflammatory IL-1β secretion, and CAF-derived inflammasome signalling ... ...

    Abstract Cancer associated fibroblasts (CAFs) are known to promote pro-tumorigenic inflammation. Here, the authors show that CAFs sense tissue damage and activate NLRP3 inflammasome and pro-inflammatory IL-1β secretion, and CAF-derived inflammasome signalling promotes breast tumour growth and metastasis.
    Keywords Science ; Q
    Language English
    Publishing date 2019-09-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Mice with induced pulmonary morbidities display severe lung inflammation and mortality following exposure to SARS-CoV-2

    Reut Falach / Liat Bar-On / Shlomi Lazar / Tamar Kadar / Ohad Mazor / Moshe Aftalion / David Gur / Yentl Evgy / Ohad Shifman / Tamar Aminov / Ofir Israeli / Inbar Cohen-Gihon / Galia Zaide / Hila Gutman / Yaron Vagima / Efi Makdasi / Dana Stein / Ronit Rosenfeld / Ron Alcalay /
    Eran Zahavy / Haim Levy / Itai Glinert / Amir Ben-Shmuel / Tomer Israely / Sharon Melamed / Boaz Politi / Hagit Achdout / Shmuel Yitzhaki / Chanoch Kronman / Tamar Sabo

    JCI Insight, Vol 6, Iss

    2021  Volume 12

    Abstract: Mice are normally unaffected by SARS coronavirus 2 (SARS-CoV-2) infection since the virus does not bind effectively to the murine version of the angiotensin-converting enzyme 2 (ACE2) receptor molecule. Here, we report that induced mild pulmonary ... ...

    Abstract Mice are normally unaffected by SARS coronavirus 2 (SARS-CoV-2) infection since the virus does not bind effectively to the murine version of the angiotensin-converting enzyme 2 (ACE2) receptor molecule. Here, we report that induced mild pulmonary morbidities rendered SARS-CoV-2–refractive CD-1 mice susceptible to this virus. Specifically, SARS-CoV-2 infection after application of low doses of the acute lung injury stimulants bleomycin or ricin caused severe disease in CD-1 mice, manifested by sustained body weight loss and mortality rates greater than 50%. Further studies revealed markedly higher levels of viral RNA in the lungs, heart, and serum of low-dose ricin–pretreated mice compared with non-pretreated mice. Furthermore, lung extracts prepared 2–3 days after viral infection contained subgenomic mRNA and virus particles capable of replication only when derived from the pretreated mice. The deleterious effects of SARS-CoV-2 infection were effectively alleviated by passive transfer of polyclonal or monoclonal antibodies generated against the SARS-CoV-2 receptor binding domain (RBD). Thus, viral cell entry in the sensitized mice seems to depend on viral RBD binding, albeit by a mechanism other than the canonical ACE2-mediated uptake route. This unique mode of viral entry, observed over a mildly injured tissue background, may contribute to the exacerbation of coronavirus disease 2019 (COVID-19) pathologies in patients with preexisting morbidities.
    Keywords COVID-19 ; Medicine ; R
    Subject code 570
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Differential, positional-dependent transcriptional response of antigenic variation (var) genes to biological stress in Plasmodium falciparum.

    Elli Rosenberg / Amir Ben-Shmuel / Oshrit Shalev / Rosa Sinay / Alan Cowman / Yaakov Pollack

    PLoS ONE, Vol 4, Iss 9, p e

    2009  Volume 6991

    Abstract: 1% of the genes of the human malaria causing agent Plasmodium falciparum belong to the heterogeneous var gene family which encodes P. falciparum erythrocyte membrane protein 1 (PFEMP1). This protein mediates part of the pathogenesis of the disease by ... ...

    Abstract 1% of the genes of the human malaria causing agent Plasmodium falciparum belong to the heterogeneous var gene family which encodes P. falciparum erythrocyte membrane protein 1 (PFEMP1). This protein mediates part of the pathogenesis of the disease by causing adherence of infected erythrocytes (IE) to the host endothelium. At any given time, only one copy of the family is expressed on the IE surface. The cues which regulate the allelic exclusion of these genes are not known. We show the existence of a differential expression pattern of these genes upon exposure to biological stress in relation to their positional placement on the chromosome - expression of centrally located var genes is induced while sub-telomeric copies of the family are repressed - this phenomenon orchestrated by the histone deacetylase pfsir2. Moreover, stress was found to cause a switch in the pattern of the expressed var genes thus acting as a regulatory cue. By using pharmacological compounds which putatively affect pfsir2 activity, distinct changes of var gene expression patterns were achieved which may have therapeutic ramifications. As disease severity is partly associated with expression of particular var gene subtypes, manipulation of the IE environment may serve as a mechanism to direct transcription towards less virulent genes.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2009-09-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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