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Endotoxemia in Primate Models
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Heinz Redl, Günther Schlag, Soheyl Bahrami
Among the possibilities of intervention, binding and inactivating bacterial toxins is the most attractive because it occurs at the top of the inflammatory network such that it avoids downstream multiple mediator induction and does not directly interfere with the immune system, minimizing unpredictable side effects and blockade of favorable host responses. Due to the physiological similarity with humans as well as the cross-reactivity with human reagents, primates are (and should be) used as ultimate models before going into clinical trials. For this review of studies in primate models, the concept was used to separate according to the source of endotoxin: (1) translocation from the endogenous sources, (2) endotoxin from bacterial infections, and (3) exogenously applied endotoxin.
Neuropathogenesis of viral infections
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Avindra Nath, Joseph R. Berger
Most microorganisms are known to produce toxic substances. For example, bacterial toxins include cholera toxin, botulinum toxin, tetanus toxoid, etc. Prion proteins have been studied extensively with regards to their neurotoxic properties. Similarly, viral products may also be toxic. Although virotoxins have been best characterized for HIV gene products, it is increasingly clear that several other viruses also produce toxic gene products (Table 2.5). For example, the rabies virus [53] envelope glycoprotein and the measles virus hemagglutinin glycoprotein [54] have sequence homology to snake venom neurotoxins and the fusion domain of influenza virus has a striking similarity to the neurotoxic domain of amyloid beta peptide [55]. A common theme emerges in these viruses, in that often it is the envelope and the transactivating viral genes that are toxic. These viral proteins may interact with neurons and glial cells to disrupt their function.
Immune Response to Microbial Toxins in Inflammatory and Neurodegenerative Disorders
Published in David Perlmutter, The Microbiome and the Brain, 2019
Bacterial toxins are a group of proteins, lipoproteins, and LPS that are produced by bacteria. Although they are an important component of the healthy immune system—as microbe-associated molecular patterns (MAMPs), they are recognized by pattern recognition receptors on epithelial and immune cells—overproduction of these toxins can damage the host at the site of a bacterial infection or at locations far from the source [Medzhitov 2007]. In this review, major emphasis will be placed on the BCdTs and LPS that are produced by enterobacters and other bacteria.
GRP75 as a functional element of cholix transcytosis
Published in Tissue Barriers, 2023
Keyi Liu, Tom Hunter, Alistair Taverner, Kevin Yin, Julia MacKay, Kate Colebrook, Morgan Correia, Amandine Rapp, Randall J. Mrsny
Bacterial toxins use a variety of pathways to reach the cytosol of target cells where they demonstrate a plethora of actions.1 Once internalized, often by receptor-mediated endocytosis, these agents modify host component activities that lead to physiological changes to alter cell properties, often resulting in cell death.2,3 Some toxins incite intestinal pathologies by directly damaging the polarized epithelial cells that line the lumen, altering the robust barrier that functions to restrict the nonspecific uptake of intestinal contents into the body.4,5 In doing so, a variety of innate and adaptive immune system pathways are triggered that target the pathogen and its associated virulence factors.6 There are, however, a group of bacterial toxins that appear to first cross the epithelium without damaging these polarized cells and then target underlying cells of the innate and/or adaptive immune systems. This clandestine epithelial transcytosis with targeted death of selected cells within the lamina propria theoretically benefits the establishment of a durable infection at the intestinal lumen. Non-pandemic strains of Vibrio cholerae secrete an exotoxin, cholix (Chx), that is capable of translocating through the intestinal barrier to reach the lamina propria and which provides an example of this pathophysiological strategy.7
Membrane protective role of autophagic machinery during infection of epithelial cells by Candida albicans
Published in Gut Microbes, 2022
Pierre Lapaquette, Amandine Ducreux, Louise Basmaciyan, Tracy Paradis, Fabienne Bon, Amandine Bataille, Pascale Winckler, Bernhard Hube, Christophe d’Enfert, Audrey Esclatine, Elisabeth Dubus, Marie-Agnès Bringer, Etienne Morel, Frédéric Dalle
Contribution of some autophagy-related proteins (ATG16L1, ATG5, and ATG12) in lysosomal exocytosis was recently highlighted in the context of host cell infection by the Gram-positive pathogenic bacterium Listeria monocytogenes.46 Cells lacking these ATG proteins were unable to trigger lysosomal membrane exocytosis for the repair of membrane damage induced by bacterial pore-forming toxins (LLO and PLY). As a result, an increase in sensitivity of cells to bacterial toxins was observed.46 Interestingly, we report herein similar observations showing that plasma membrane damage induced by C. albicans correlates with (i) a strong decrease in lysosomal membrane exocytosis as observed in ATG16L1- and Atg5-deficient cells and (ii) an increase sensitivity of these deficient cells to C. albicans-mediated cell death. This plasma membrane damage might result from the mechanical stress applied by the fungal active penetration in association with secreted factors (including Saps) already reported to alter the host plasma membrane.1
GSDMD-dependent pyroptotic induction by a multivalent CXCR4-targeted nanotoxin blocks colorectal cancer metastases
Published in Drug Delivery, 2022
Rita Sala, Elisa Rioja-Blanco, Naroa Serna, Laura Sánchez-García, Patricia Álamo, Lorena Alba-Castellón, Isolda Casanova, Antonio López-Pousa, Ugutz Unzueta, María Virtudes Céspedes, Esther Vázquez, Antonio Villaverde, Ramon Mangues
Among all cytotoxic domains found in organisms, bacterial toxins are already being used in new strategies for cancer therapy, exhibiting a highly potent anticancer effect (Weldon & Pastan, 2011). On this basis, we previously developed protein-only nanoparticles, incorporating the de-immunized version of the catalytic domain of the exotoxin A from Pseudomonas aeruginosa together with a polypeptide containing the T22 peptide and a His-tag; thus, generating the self-assembling multivalent T22-PE24-H6 nanotoxin (Sánchez-García et al., 2018). This novel protein-only nanoparticle approach allowed us to achieve a faster production process by skipping the conjugation step needed for the therapeutic nanoconjugates synthesis (Sharma et al., 2012) while reducing its immunogenicity due to the replacement of the exogenous GFP protein, found in our previously developed nanoconjugates (Céspedes et al., 2018; Pallarès et al., 2020).