The Experts below are selected from a list of 15783 Experts worldwide ranked by ideXlab platform
Nicholas J Mantis - One of the best experts on this subject based on the ideXlab platform.
-
Antibody-mediated inhibition of ricin Toxin retrograde transport
mBio, 2014Co-Authors: A. Yermakova, Tove Irene Klokk, Richard Cole, Kirsten Sandvig, Nicholas J MantisAbstract:ABSTRACT Ricin is a member of the ubiquitous family of plant and bacterial AB Toxins that gain entry into the cytosol of host cells through receptor-mediated endocytosis and retrograde traffic through the trans-Golgi network (TGN) and endoplasmic reticulum (ER). While a few ricin Toxin-specific neutralizing monoclonal antibodies (MAbs) have been identified, the mechanisms by which these antibodies prevent Toxin-induced cell death are largely unknown. Using immunofluorescence confocal microscopy and a TGN-specific sulfation assay, we demonstrate that 24B11, a MAb against ricin's binding subunit (RTB), associates with ricin in solution or when prebound to cell surfaces and then markedly enhances Toxin uptake into host cells. Following endocytosis, however, Toxin-Antibody complexes failed to reach the TGN; instead, they were shunted to Rab7-positive late endosomes and LAMP-1-positive lysosomes. Monovalent 24B11 Fab fragments also interfered with Toxin retrograde transport, indicating that neither cross-linking of membrane glycoproteins/glycolipids nor the recently identified intracellular Fc receptor is required to derail ricin en route to the TGN. Identification of the mechanism(s) by which antibodies like 24B11 neutralize ricin will advance our fundamental understanding of protein trafficking in mammalian cells and may lead to the discovery of new classes of Toxin inhibitors and therapeutics for biodefense and emerging infectious diseases. IMPORTANCE Ricin is the prototypic member of the AB family of medically important plant and bacterial Toxins that includes cholera and Shiga Toxins. Ricin is also a category B biothreat agent. Despite ongoing efforts to develop vaccines and Antibody-based therapeutics against ricin, very little is known about the mechanisms by which antibodies neutralize this Toxin. In general, it is thought that antibodies simply prevent Toxins from attaching to cell surface receptors or promote their clearance through Fc receptor (FcR)-mediated uptake. In this report, however, we describe a neutralizing monoclonal Antibody (MAb) against ricin's binding subunit (RTB) that not only associates with ricin after the Toxin has bound to the cell's surface but actually enhances Toxin uptake into host cells. Following endocytosis, the Antibody-Toxin complexes are then routed for degradation. The results of this study are important because they reveal a previously unappreciated role for B-subunit-specific antibodies in intracellular neutralization of ricin Toxin.
-
Immunity to Ricin: Fundamental Insights into Toxin–Antibody Interactions
Current topics in microbiology and immunology, 2011Co-Authors: Joanne M. O’hara, A. Yermakova, Nicholas J MantisAbstract:Ricin Toxin is an extraordinarily potent inducer of cell death and inflammation. Ricin is also a potent provocateur of the humoral immune system, eliciting a mixture of neutralizing, non-neutralizing and even Toxin-enhancing antibodies. The characterization of dozens of monoclonal antibodies (mAbs) against the Toxin’s enzymatic (RTA) and binding (RTB) subunits has begun to reveal fundamental insights into the underlying mechanisms by which antibodies neutralize (or fail to neutralize) ricin in systemic and mucosal compartments. This information has had immediate applications in the design, development and evaluation of ricin subunit vaccines and immunotherapeutics.
-
immunity to ricin fundamental insights into Toxin Antibody interactions
Current Topics in Microbiology and Immunology, 2011Co-Authors: A. Yermakova, Nicholas J Mantis, Joanne M OharaAbstract:Ricin Toxin is an extraordinarily potent inducer of cell death and inflammation. Ricin is also a potent provocateur of the humoral immune system, eliciting a mixture of neutralizing, non-neutralizing and even Toxin-enhancing antibodies. The characterization of dozens of monoclonal antibodies (mAbs) against the Toxin’s enzymatic (RTA) and binding (RTB) subunits has begun to reveal fundamental insights into the underlying mechanisms by which antibodies neutralize (or fail to neutralize) ricin in systemic and mucosal compartments. This information has had immediate applications in the design, development and evaluation of ricin subunit vaccines and immunotherapeutics.
A. Yermakova - One of the best experts on this subject based on the ideXlab platform.
-
Antibody-mediated inhibition of ricin Toxin retrograde transport
mBio, 2014Co-Authors: A. Yermakova, Tove Irene Klokk, Richard Cole, Kirsten Sandvig, Nicholas J MantisAbstract:ABSTRACT Ricin is a member of the ubiquitous family of plant and bacterial AB Toxins that gain entry into the cytosol of host cells through receptor-mediated endocytosis and retrograde traffic through the trans-Golgi network (TGN) and endoplasmic reticulum (ER). While a few ricin Toxin-specific neutralizing monoclonal antibodies (MAbs) have been identified, the mechanisms by which these antibodies prevent Toxin-induced cell death are largely unknown. Using immunofluorescence confocal microscopy and a TGN-specific sulfation assay, we demonstrate that 24B11, a MAb against ricin's binding subunit (RTB), associates with ricin in solution or when prebound to cell surfaces and then markedly enhances Toxin uptake into host cells. Following endocytosis, however, Toxin-Antibody complexes failed to reach the TGN; instead, they were shunted to Rab7-positive late endosomes and LAMP-1-positive lysosomes. Monovalent 24B11 Fab fragments also interfered with Toxin retrograde transport, indicating that neither cross-linking of membrane glycoproteins/glycolipids nor the recently identified intracellular Fc receptor is required to derail ricin en route to the TGN. Identification of the mechanism(s) by which antibodies like 24B11 neutralize ricin will advance our fundamental understanding of protein trafficking in mammalian cells and may lead to the discovery of new classes of Toxin inhibitors and therapeutics for biodefense and emerging infectious diseases. IMPORTANCE Ricin is the prototypic member of the AB family of medically important plant and bacterial Toxins that includes cholera and Shiga Toxins. Ricin is also a category B biothreat agent. Despite ongoing efforts to develop vaccines and Antibody-based therapeutics against ricin, very little is known about the mechanisms by which antibodies neutralize this Toxin. In general, it is thought that antibodies simply prevent Toxins from attaching to cell surface receptors or promote their clearance through Fc receptor (FcR)-mediated uptake. In this report, however, we describe a neutralizing monoclonal Antibody (MAb) against ricin's binding subunit (RTB) that not only associates with ricin after the Toxin has bound to the cell's surface but actually enhances Toxin uptake into host cells. Following endocytosis, the Antibody-Toxin complexes are then routed for degradation. The results of this study are important because they reveal a previously unappreciated role for B-subunit-specific antibodies in intracellular neutralization of ricin Toxin.
-
Immunity to Ricin: Fundamental Insights into Toxin–Antibody Interactions
Current topics in microbiology and immunology, 2011Co-Authors: Joanne M. O’hara, A. Yermakova, Nicholas J MantisAbstract:Ricin Toxin is an extraordinarily potent inducer of cell death and inflammation. Ricin is also a potent provocateur of the humoral immune system, eliciting a mixture of neutralizing, non-neutralizing and even Toxin-enhancing antibodies. The characterization of dozens of monoclonal antibodies (mAbs) against the Toxin’s enzymatic (RTA) and binding (RTB) subunits has begun to reveal fundamental insights into the underlying mechanisms by which antibodies neutralize (or fail to neutralize) ricin in systemic and mucosal compartments. This information has had immediate applications in the design, development and evaluation of ricin subunit vaccines and immunotherapeutics.
-
immunity to ricin fundamental insights into Toxin Antibody interactions
Current Topics in Microbiology and Immunology, 2011Co-Authors: A. Yermakova, Nicholas J Mantis, Joanne M OharaAbstract:Ricin Toxin is an extraordinarily potent inducer of cell death and inflammation. Ricin is also a potent provocateur of the humoral immune system, eliciting a mixture of neutralizing, non-neutralizing and even Toxin-enhancing antibodies. The characterization of dozens of monoclonal antibodies (mAbs) against the Toxin’s enzymatic (RTA) and binding (RTB) subunits has begun to reveal fundamental insights into the underlying mechanisms by which antibodies neutralize (or fail to neutralize) ricin in systemic and mucosal compartments. This information has had immediate applications in the design, development and evaluation of ricin subunit vaccines and immunotherapeutics.
Tracy Hussell - One of the best experts on this subject based on the ideXlab platform.
-
protection against tetanus Toxin using a plant based vaccine
European Journal of Immunology, 2005Co-Authors: John S Tregoning, Simon Clare, Frances Bowe, Lorna Edwards, Neil F Fairweather, Omar I Qazi, Peter J Nixon, Pal Maliga, Gordon Dougan, Tracy HussellAbstract:Plant-expressed vaccines may provide a unique opportunity for generating anti-pathogen immunity, especially in countries where cold storage is lacking. In the following study, we show that soluble protein from tobacco leaves expressing fragment C of tetanus Toxin protected mice against a lethal tetanus Toxin challenge. More importantly, we show that a single intranasal (i.n.) vaccination was as efficient as oral delivery, inducing high levels of activated CD4(+) T cells and anti-Toxin Antibody. Unlike the oral route, i.n. delivery did not require the presence of adjuvant (cholera Toxin). Indeed, addition of cholera Toxin induced bystander immune responses to plant proteins as well. This is the first study documenting protective immunity by a single i.n. dose of plant vaccine. Plant-based vaccines are promising because they are more heat stable, are easy to produce, cheap and do not require needles.
Joanne M Ohara - One of the best experts on this subject based on the ideXlab platform.
-
immunity to ricin fundamental insights into Toxin Antibody interactions
Current Topics in Microbiology and Immunology, 2011Co-Authors: A. Yermakova, Nicholas J Mantis, Joanne M OharaAbstract:Ricin Toxin is an extraordinarily potent inducer of cell death and inflammation. Ricin is also a potent provocateur of the humoral immune system, eliciting a mixture of neutralizing, non-neutralizing and even Toxin-enhancing antibodies. The characterization of dozens of monoclonal antibodies (mAbs) against the Toxin’s enzymatic (RTA) and binding (RTB) subunits has begun to reveal fundamental insights into the underlying mechanisms by which antibodies neutralize (or fail to neutralize) ricin in systemic and mucosal compartments. This information has had immediate applications in the design, development and evaluation of ricin subunit vaccines and immunotherapeutics.
John S Tregoning - One of the best experts on this subject based on the ideXlab platform.
-
protection against tetanus Toxin using a plant based vaccine
European Journal of Immunology, 2005Co-Authors: John S Tregoning, Simon Clare, Frances Bowe, Lorna Edwards, Neil F Fairweather, Omar I Qazi, Peter J Nixon, Pal Maliga, Gordon Dougan, Tracy HussellAbstract:Plant-expressed vaccines may provide a unique opportunity for generating anti-pathogen immunity, especially in countries where cold storage is lacking. In the following study, we show that soluble protein from tobacco leaves expressing fragment C of tetanus Toxin protected mice against a lethal tetanus Toxin challenge. More importantly, we show that a single intranasal (i.n.) vaccination was as efficient as oral delivery, inducing high levels of activated CD4(+) T cells and anti-Toxin Antibody. Unlike the oral route, i.n. delivery did not require the presence of adjuvant (cholera Toxin). Indeed, addition of cholera Toxin induced bystander immune responses to plant proteins as well. This is the first study documenting protective immunity by a single i.n. dose of plant vaccine. Plant-based vaccines are promising because they are more heat stable, are easy to produce, cheap and do not require needles.