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Autotransporter-Mediated Display of Complement Receptor Ligands by Gram-Negative Bacteria Increases Antibody Responses and Limits Disease Severity

The targeting of immunogens/vaccines to specific immune cells is a promising approach for amplifying immune responses in the absence of exogenous adjuvants. However, the targeting approaches reported thus far require novel, labor-intensive reagents for each vaccine and have primarily been shown as p...

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Autores principales: Holland-Tummillo, Kristen M, Shoudy, Lauren E, Steiner, Donald, Kumar, Sudeep, Rosa, Sarah J, Namjoshi, Prachi, Singh, Anju, Sellati, Timothy J, Gosselin, Edmund J, Hazlett, Karsten RO
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281241/
https://www.ncbi.nlm.nih.gov/pubmed/32422907
http://dx.doi.org/10.3390/pathogens9050375
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author Holland-Tummillo, Kristen M
Shoudy, Lauren E
Steiner, Donald
Kumar, Sudeep
Rosa, Sarah J
Namjoshi, Prachi
Singh, Anju
Sellati, Timothy J
Gosselin, Edmund J
Hazlett, Karsten RO
author_facet Holland-Tummillo, Kristen M
Shoudy, Lauren E
Steiner, Donald
Kumar, Sudeep
Rosa, Sarah J
Namjoshi, Prachi
Singh, Anju
Sellati, Timothy J
Gosselin, Edmund J
Hazlett, Karsten RO
author_sort Holland-Tummillo, Kristen M
collection PubMed
description The targeting of immunogens/vaccines to specific immune cells is a promising approach for amplifying immune responses in the absence of exogenous adjuvants. However, the targeting approaches reported thus far require novel, labor-intensive reagents for each vaccine and have primarily been shown as proof-of-concept with isolated proteins and/or inactivated bacteria. We have engineered a plasmid-based, complement receptor-targeting platform that is readily applicable to live forms of multiple gram-negative bacteria, including, but not limited to, Escherichia coli, Klebsiella pneumoniae, and Francisella tularensis. Using F. tularensis as a model, we find that targeted bacteria show increased binding and uptake by macrophages, which coincides with increased p38 and p65 phosphorylation. Mice vaccinated with targeted bacteria produce higher titers of specific antibody that recognizes a greater diversity of bacterial antigens. Following challenge with homologous or heterologous isolates, these mice exhibited less weight loss and/or accelerated weight recovery as compared to counterparts vaccinated with non-targeted immunogens. Collectively, these findings provide proof-of-concept for plasmid-based, complement receptor-targeting of live gram-negative bacteria.
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spelling pubmed-72812412020-06-15 Autotransporter-Mediated Display of Complement Receptor Ligands by Gram-Negative Bacteria Increases Antibody Responses and Limits Disease Severity Holland-Tummillo, Kristen M Shoudy, Lauren E Steiner, Donald Kumar, Sudeep Rosa, Sarah J Namjoshi, Prachi Singh, Anju Sellati, Timothy J Gosselin, Edmund J Hazlett, Karsten RO Pathogens Article The targeting of immunogens/vaccines to specific immune cells is a promising approach for amplifying immune responses in the absence of exogenous adjuvants. However, the targeting approaches reported thus far require novel, labor-intensive reagents for each vaccine and have primarily been shown as proof-of-concept with isolated proteins and/or inactivated bacteria. We have engineered a plasmid-based, complement receptor-targeting platform that is readily applicable to live forms of multiple gram-negative bacteria, including, but not limited to, Escherichia coli, Klebsiella pneumoniae, and Francisella tularensis. Using F. tularensis as a model, we find that targeted bacteria show increased binding and uptake by macrophages, which coincides with increased p38 and p65 phosphorylation. Mice vaccinated with targeted bacteria produce higher titers of specific antibody that recognizes a greater diversity of bacterial antigens. Following challenge with homologous or heterologous isolates, these mice exhibited less weight loss and/or accelerated weight recovery as compared to counterparts vaccinated with non-targeted immunogens. Collectively, these findings provide proof-of-concept for plasmid-based, complement receptor-targeting of live gram-negative bacteria. MDPI 2020-05-14 /pmc/articles/PMC7281241/ /pubmed/32422907 http://dx.doi.org/10.3390/pathogens9050375 Text en © 2020 by the authors. 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/).
spellingShingle Article
Holland-Tummillo, Kristen M
Shoudy, Lauren E
Steiner, Donald
Kumar, Sudeep
Rosa, Sarah J
Namjoshi, Prachi
Singh, Anju
Sellati, Timothy J
Gosselin, Edmund J
Hazlett, Karsten RO
Autotransporter-Mediated Display of Complement Receptor Ligands by Gram-Negative Bacteria Increases Antibody Responses and Limits Disease Severity
title Autotransporter-Mediated Display of Complement Receptor Ligands by Gram-Negative Bacteria Increases Antibody Responses and Limits Disease Severity
title_full Autotransporter-Mediated Display of Complement Receptor Ligands by Gram-Negative Bacteria Increases Antibody Responses and Limits Disease Severity
title_fullStr Autotransporter-Mediated Display of Complement Receptor Ligands by Gram-Negative Bacteria Increases Antibody Responses and Limits Disease Severity
title_full_unstemmed Autotransporter-Mediated Display of Complement Receptor Ligands by Gram-Negative Bacteria Increases Antibody Responses and Limits Disease Severity
title_short Autotransporter-Mediated Display of Complement Receptor Ligands by Gram-Negative Bacteria Increases Antibody Responses and Limits Disease Severity
title_sort autotransporter-mediated display of complement receptor ligands by gram-negative bacteria increases antibody responses and limits disease severity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281241/
https://www.ncbi.nlm.nih.gov/pubmed/32422907
http://dx.doi.org/10.3390/pathogens9050375
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