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MARTX Toxin in the Zoonotic Serovar of Vibrio vulnificus Triggers an Early Cytokine Storm in Mice
Vibrio vulnificus biotype 2-serovar E is a zoonotic clonal complex that can cause death by sepsis in humans and fish. Unlike other biotypes, Bt2 produces a unique type of MARTX(Vv) (Multifunctional-Autoprocessive-Repeats-in-Toxin; RtxA1(3)), which is encoded by a gene duplicated in the pVvBt2 plasmi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517466/ https://www.ncbi.nlm.nih.gov/pubmed/28775962 http://dx.doi.org/10.3389/fcimb.2017.00332 |
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author | Murciano, Celia Lee, Chung-Te Fernández-Bravo, Ana Hsieh, Tsung-Han Fouz, Belén Hor, Lien-I Amaro, Carmen |
author_facet | Murciano, Celia Lee, Chung-Te Fernández-Bravo, Ana Hsieh, Tsung-Han Fouz, Belén Hor, Lien-I Amaro, Carmen |
author_sort | Murciano, Celia |
collection | PubMed |
description | Vibrio vulnificus biotype 2-serovar E is a zoonotic clonal complex that can cause death by sepsis in humans and fish. Unlike other biotypes, Bt2 produces a unique type of MARTX(Vv) (Multifunctional-Autoprocessive-Repeats-in-Toxin; RtxA1(3)), which is encoded by a gene duplicated in the pVvBt2 plasmid and chromosome II. In this work, we analyzed the activity of this toxin and its role in human sepsis by performing in vitro, ex vivo, and in vivo assays. First, we demonstrated that the ACD domain, present exclusively in this toxin variant, effectively has an actin-cross-linking activity. Second, we determined that the whole toxin caused death of human endotheliocytes and monocytes by lysis and apoptosis, respectively. Finally, we tested the hypothesis that RtxA1(3) contributes to human death caused by this zoonotic serovar by triggering an early cytokine storm in blood. To this end, we used a Bt2-SerE strain (R99) together with its rtxA1(3) deficient mutant, and a Bt1 strain (YJ016) producing RtxA1(1) (the most studied MARTX(Vv)) together with its rtxA1(1) deficient mutant, as controls. Our results showed that RtxA1(3) was essential for virulence, as R99ΔΔrtxA1(3) was completely avirulent in our murine model of infection, and that R99, but not strain YJ016, induced an early, strong and dysregulated immune response involving the up-regulation of a high number of genes. This dysregulated immune response was directly linked to RtxA1(3). Based on these results and those obtained ex vivo (human blood), we propose a model of infection for the zoonotic serovar of V. vulnificus, in which RtxA1(3) would act as a sepsis-inducing toxin. |
format | Online Article Text |
id | pubmed-5517466 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55174662017-08-03 MARTX Toxin in the Zoonotic Serovar of Vibrio vulnificus Triggers an Early Cytokine Storm in Mice Murciano, Celia Lee, Chung-Te Fernández-Bravo, Ana Hsieh, Tsung-Han Fouz, Belén Hor, Lien-I Amaro, Carmen Front Cell Infect Microbiol Microbiology Vibrio vulnificus biotype 2-serovar E is a zoonotic clonal complex that can cause death by sepsis in humans and fish. Unlike other biotypes, Bt2 produces a unique type of MARTX(Vv) (Multifunctional-Autoprocessive-Repeats-in-Toxin; RtxA1(3)), which is encoded by a gene duplicated in the pVvBt2 plasmid and chromosome II. In this work, we analyzed the activity of this toxin and its role in human sepsis by performing in vitro, ex vivo, and in vivo assays. First, we demonstrated that the ACD domain, present exclusively in this toxin variant, effectively has an actin-cross-linking activity. Second, we determined that the whole toxin caused death of human endotheliocytes and monocytes by lysis and apoptosis, respectively. Finally, we tested the hypothesis that RtxA1(3) contributes to human death caused by this zoonotic serovar by triggering an early cytokine storm in blood. To this end, we used a Bt2-SerE strain (R99) together with its rtxA1(3) deficient mutant, and a Bt1 strain (YJ016) producing RtxA1(1) (the most studied MARTX(Vv)) together with its rtxA1(1) deficient mutant, as controls. Our results showed that RtxA1(3) was essential for virulence, as R99ΔΔrtxA1(3) was completely avirulent in our murine model of infection, and that R99, but not strain YJ016, induced an early, strong and dysregulated immune response involving the up-regulation of a high number of genes. This dysregulated immune response was directly linked to RtxA1(3). Based on these results and those obtained ex vivo (human blood), we propose a model of infection for the zoonotic serovar of V. vulnificus, in which RtxA1(3) would act as a sepsis-inducing toxin. Frontiers Media S.A. 2017-07-20 /pmc/articles/PMC5517466/ /pubmed/28775962 http://dx.doi.org/10.3389/fcimb.2017.00332 Text en Copyright © 2017 Murciano, Lee, Fernández-Bravo, Hsieh, Fouz, Hor and Amaro. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Murciano, Celia Lee, Chung-Te Fernández-Bravo, Ana Hsieh, Tsung-Han Fouz, Belén Hor, Lien-I Amaro, Carmen MARTX Toxin in the Zoonotic Serovar of Vibrio vulnificus Triggers an Early Cytokine Storm in Mice |
title | MARTX Toxin in the Zoonotic Serovar of Vibrio vulnificus Triggers an Early Cytokine Storm in Mice |
title_full | MARTX Toxin in the Zoonotic Serovar of Vibrio vulnificus Triggers an Early Cytokine Storm in Mice |
title_fullStr | MARTX Toxin in the Zoonotic Serovar of Vibrio vulnificus Triggers an Early Cytokine Storm in Mice |
title_full_unstemmed | MARTX Toxin in the Zoonotic Serovar of Vibrio vulnificus Triggers an Early Cytokine Storm in Mice |
title_short | MARTX Toxin in the Zoonotic Serovar of Vibrio vulnificus Triggers an Early Cytokine Storm in Mice |
title_sort | martx toxin in the zoonotic serovar of vibrio vulnificus triggers an early cytokine storm in mice |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517466/ https://www.ncbi.nlm.nih.gov/pubmed/28775962 http://dx.doi.org/10.3389/fcimb.2017.00332 |
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