Human Recombinant Fab Fragment Neutralizes Shiga Toxin Type 2 Cytotoxic Effects  in vitro  and  in vivo

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Abstract

Shiga toxin (Stx) producing Escherichia coli (STEC) is responsible for causing hemolytic uremic syndrome (HUS), a life-threatening thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and acute renal failure after bacterially induced hemorrhagic diarrhea. Until now, there has been neither an effective treatment nor method of prevention for the deleterious effects caused by Stx intoxication. Antibodies are well recognized as affinity components of therapeutic drugs; thus, a previously obtained recombinant human FabC11:Stx2 fragment was used to neutralize Stx2 in vitro in a Vero cell viability assay. Herein, we demonstrated that this fragment neutralized, in a dose-dependent manner, the cytotoxic effects of Stx2 on human glomerular endothelial cells, on human proximal tubular epithelial cells, and prevented the morphological alterations induced by Stx2. FabC11:Stx2 protected mice from a lethal dose of Stx2 by toxin-antibody pre-incubation. Altogether, our results show the ability of a new encouraging molecule to prevent Stx-intoxication symptoms during STEC infection.

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Paradoxical glomerular filtration of carbon nanotubes.

Carlos Villa, M McDevitt, Carl Batt … (2010)

The molecular weight cutoff for glomerular filtration is thought to be 30-50 kDa. Here we report rapid and efficient filtration of molecules 10-20 times that mass and a model for the mechanism of this filtration. We conducted multimodal imaging studies in mice to investigate renal clearance of a single-walled carbon nanotube (SWCNT) construct covalently appended with ligands allowing simultaneous dynamic positron emission tomography, near-infrared fluorescence imaging, and microscopy. These SWCNTs have a length distribution ranging from 100 to 500 nm. The average length was determined to be 200-300 nm, which would yield a functionalized construct with a molecular weight of approximately 350-500 kDa. The construct was rapidly (t(1/2) approximately 6 min) renally cleared intact by glomerular filtration, with partial tubular reabsorption and transient translocation into the proximal tubular cell nuclei. Directional absorption was confirmed in vitro using polarized renal cells. Active secretion via transporters was not involved. Mathematical modeling of the rotational diffusivity showed the tendency of flow to orient SWCNTs of this size to allow clearance via the glomerular pores. Surprisingly, these results raise questions about the rules for renal filtration, given that these large molecules (with aspect ratios ranging from 100:1 to 500:1) were cleared similarly to small molecules. SWCNTs and other novel nanomaterials are being actively investigated for potential biomedical applications, and these observations-that high aspect ratio as well as large molecular size have an impact on glomerular filtration-will allow the design of novel nanoscale-based therapeutics with unusual pharmacologic characteristics.

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Shiga toxins and stx phages: highly diverse entities.

Alejandra Krüger, Paula Lucchesi (2015)

Shiga toxins are the main virulence factors of a group of Escherichia coli strains [Shiga toxin-producing E. coli (STEC)] that cause severe human diseases, such as haemorrhagic colitis and haemolytic-uraemic syndrome. The Shiga toxin family comprises several toxin subtypes, which have been differentially related to clinical manifestations. In addition, the phages that carry the Shiga toxin genes (stx phages) are also diverse. These phages play an important role not only in the dissemination of Shiga toxin genes and the emergence of new STEC strains, but also in the regulation of Shiga toxin production. Consequently, differences in stx phages may affect the dissemination of stx genes as well as the virulence of STEC strains. In addition to presenting an overview of Shiga toxins and stx phages, in this review we highlight current knowledge about the diversity of stx phages, with emphasis on its impact on STEC virulence. We consider that this diversity should be taken into account when developing STEC infection treatments and diagnostic approaches, and when conducting STEC control in reservoirs.

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Haemolytic uraemic syndrome.

Ida Arvidsson, Diana Karpman, Sebastian Loos … (2017)

Haemolytic uraemic syndrome (HUS) is defined by the simultaneous occurrence of nonimmune haemolytic anaemia, thrombocytopenia and acute renal failure. This leads to the pathological lesion termed thrombotic microangiopathy, which mainly affects the kidney, as well as other organs. HUS is associated with endothelial cell injury and platelet activation, although the underlying cause may differ. Most cases of HUS are associated with gastrointestinal infection with Shiga toxin-producing enterohaemorrhagic Escherichia coli (EHEC) strains. Atypical HUS (aHUS) is associated with complement dysregulation due to mutations or autoantibodies. In this review, we will describe the causes of HUS. In addition, we will review the clinical, pathological, haematological and biochemical features, epidemiology and pathogenetic mechanisms as well as the biochemical, microbiological, immunological and genetic investigations leading to diagnosis. Understanding the underlying mechanisms of the different subtypes of HUS enables tailoring of appropriate treatment and management. To date, there is no specific treatment for EHEC-associated HUS but patients benefit from supportive care, whereas patients with aHUS are effectively treated with anti-C5 antibody to prevent recurrences, both before and after renal transplantation.

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Journal

Journal ID (nlm-ta): Toxins (Basel)

Journal ID (iso-abbrev): Toxins (Basel)

Journal ID (publisher-id): toxins

Title: Toxins

Publisher: MDPI

ISSN (Electronic): 2072-6651

Publication date (Electronic): 02 December 2018

Publication date Collection: December 2018

Volume: 10

Issue: 12

Electronic Location Identifier: 508

Affiliations

[1 ]Laboratório de Bacteriologia, Instituto Butantan, São Paulo 05503900, Brasil

[2 ]Laboratorio de Fisiopatogenia, Departamento de Fisiología, Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121, Argentina; mmamaral74@ 123456gmail.com (M.M.A.); flasacerdoti@ 123456gmail.com (F.S.); cristinaadrianaibarra@ 123456gmail.com (C.I.)

[3 ]Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental, (IMEX)-CONICET-Academia Nacional de Medicina, Buenos Aires C1425, Argentina; alanmbernal@ 123456gmail.com (A.M.B.); marinasandrapalermo@ 123456gmail.com (M.S.P.)

[4 ]Laboratório de Biofármacos em Células Animais, Instituto Butantan, São Paulo, SP 05503-900, Brazil; wagner.quintilio@ 123456butantan.gov.br (W.Q.); ana.moro@ 123456butantan.gov.br (A.M.M.)

Author notes

[* ]Correspondence: daniedaluz@ 123456yahoo.com.br (D.L.); roxane@ 123456butantan.gov.br (R.M.F.P.); Tel.: +55-11-2627-9708 (R.M.F.P.)

[†]

These authors contributed equally to this paper.

Author information

Wagner Quintilio https://orcid.org/0000-0002-3382-8184

Ana Maria Moro https://orcid.org/0000-0002-0650-7764

Cristina Ibarra https://orcid.org/0000-0001-8182-501X

Roxane Maria Fontes Piazza https://orcid.org/0000-0003-0068-8506

Article

Publisher ID: toxins-10-00508

DOI: 10.3390/toxins10120508

PMC ID: 6315604

PubMed ID: 30513821

SO-VID: 3240c55c-a98a-4e12-9a38-61d77ac12c34

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Human Recombinant Fab Fragment Neutralizes Shiga Toxin Type 2 Cytotoxic Effects in vitro and in vivo

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Abstract

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Neuronal Signaling

Most cited references 25

Paradoxical glomerular filtration of carbon nanotubes.

Shiga toxins and stx phages: highly diverse entities.

Haemolytic uraemic syndrome.

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