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A Francisella tularensis Schu S4 Purine Auxotroph Is Highly Attenuated in Mice but Offers Limited Protection against Homologous Intranasal Challenge
BACKGROUND: Francisella tularensis is a Gram-negative coccobacillus that causes the febrile illness tularemia. Subspecies that are pathogenic for humans include those comprising the type A (subspecies tularensis) or type B (subspecies holarctica) biovars. An attenuated live vaccine strain (LVS) deve...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2008
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2429968/ https://www.ncbi.nlm.nih.gov/pubmed/18575611 http://dx.doi.org/10.1371/journal.pone.0002487 |
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author | Pechous, Roger D. McCarthy, Travis R. Mohapatra, Nrusingh P. Soni, Shilpa Penoske, Renee M. Salzman, Nita H. Frank, Dara W. Gunn, John S. Zahrt, Thomas C. |
author_facet | Pechous, Roger D. McCarthy, Travis R. Mohapatra, Nrusingh P. Soni, Shilpa Penoske, Renee M. Salzman, Nita H. Frank, Dara W. Gunn, John S. Zahrt, Thomas C. |
author_sort | Pechous, Roger D. |
collection | PubMed |
description | BACKGROUND: Francisella tularensis is a Gram-negative coccobacillus that causes the febrile illness tularemia. Subspecies that are pathogenic for humans include those comprising the type A (subspecies tularensis) or type B (subspecies holarctica) biovars. An attenuated live vaccine strain (LVS) developed from a type B isolate has previously been used to vaccinate at-risk individuals, but offers limited protection against high dose (>1000 CFUs) challenge with type A strains delivered by the respiratory route. Due to differences between type A and type B F. tularensis strains at the genetic level, it has been speculated that utilization of an attenuated type A strain as a live vaccine might offer better protection against homologous respiratory challenge compared with LVS. Here, we report the construction and characterization of an unmarked ΔpurMCD mutant in the highly virulent type A strain Schu S4. METHODOLOGY/PRINCIPAL FINDINGS: Growth of Schu S4 ΔpurMCD was severely attenuated in primary human peripheral blood monocyte-derived macrophages and in the A549 human lung epithelial cell line. The Schu S4 ΔpurMCD mutant was also highly attenuated in mice when delivered via either the intranasal or intradermal infection route. Mice vaccinated intranasally with Schu S4 ΔpurMCD were well protected against high dose intradermal challenge with virulent type A or type B strains of F. tularensis. However, intranasal vaccination with Schu S4 ΔpurMCD induced tissue damage in the lungs, and conferred only limited protection against high dose Schu S4 challenge delivered by the same route. The level of protection observed was similar to that conferred following vaccination with wild-type LVS or the analogous LVS ΔpurMCD mutant. CONCLUSIONS/SIGNIFICANCE: Collectively, these results argue that development of the next generation live attenuated vaccine for Francisella should be based on use of the less pathogenic type B biovar rather than the more reactogenic type A biovar. |
format | Text |
id | pubmed-2429968 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-24299682008-06-25 A Francisella tularensis Schu S4 Purine Auxotroph Is Highly Attenuated in Mice but Offers Limited Protection against Homologous Intranasal Challenge Pechous, Roger D. McCarthy, Travis R. Mohapatra, Nrusingh P. Soni, Shilpa Penoske, Renee M. Salzman, Nita H. Frank, Dara W. Gunn, John S. Zahrt, Thomas C. PLoS One Research Article BACKGROUND: Francisella tularensis is a Gram-negative coccobacillus that causes the febrile illness tularemia. Subspecies that are pathogenic for humans include those comprising the type A (subspecies tularensis) or type B (subspecies holarctica) biovars. An attenuated live vaccine strain (LVS) developed from a type B isolate has previously been used to vaccinate at-risk individuals, but offers limited protection against high dose (>1000 CFUs) challenge with type A strains delivered by the respiratory route. Due to differences between type A and type B F. tularensis strains at the genetic level, it has been speculated that utilization of an attenuated type A strain as a live vaccine might offer better protection against homologous respiratory challenge compared with LVS. Here, we report the construction and characterization of an unmarked ΔpurMCD mutant in the highly virulent type A strain Schu S4. METHODOLOGY/PRINCIPAL FINDINGS: Growth of Schu S4 ΔpurMCD was severely attenuated in primary human peripheral blood monocyte-derived macrophages and in the A549 human lung epithelial cell line. The Schu S4 ΔpurMCD mutant was also highly attenuated in mice when delivered via either the intranasal or intradermal infection route. Mice vaccinated intranasally with Schu S4 ΔpurMCD were well protected against high dose intradermal challenge with virulent type A or type B strains of F. tularensis. However, intranasal vaccination with Schu S4 ΔpurMCD induced tissue damage in the lungs, and conferred only limited protection against high dose Schu S4 challenge delivered by the same route. The level of protection observed was similar to that conferred following vaccination with wild-type LVS or the analogous LVS ΔpurMCD mutant. CONCLUSIONS/SIGNIFICANCE: Collectively, these results argue that development of the next generation live attenuated vaccine for Francisella should be based on use of the less pathogenic type B biovar rather than the more reactogenic type A biovar. Public Library of Science 2008-06-25 /pmc/articles/PMC2429968/ /pubmed/18575611 http://dx.doi.org/10.1371/journal.pone.0002487 Text en Pechous et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Pechous, Roger D. McCarthy, Travis R. Mohapatra, Nrusingh P. Soni, Shilpa Penoske, Renee M. Salzman, Nita H. Frank, Dara W. Gunn, John S. Zahrt, Thomas C. A Francisella tularensis Schu S4 Purine Auxotroph Is Highly Attenuated in Mice but Offers Limited Protection against Homologous Intranasal Challenge |
title | A Francisella tularensis Schu S4 Purine Auxotroph Is Highly Attenuated in Mice but Offers Limited Protection against Homologous Intranasal Challenge |
title_full | A Francisella tularensis Schu S4 Purine Auxotroph Is Highly Attenuated in Mice but Offers Limited Protection against Homologous Intranasal Challenge |
title_fullStr | A Francisella tularensis Schu S4 Purine Auxotroph Is Highly Attenuated in Mice but Offers Limited Protection against Homologous Intranasal Challenge |
title_full_unstemmed | A Francisella tularensis Schu S4 Purine Auxotroph Is Highly Attenuated in Mice but Offers Limited Protection against Homologous Intranasal Challenge |
title_short | A Francisella tularensis Schu S4 Purine Auxotroph Is Highly Attenuated in Mice but Offers Limited Protection against Homologous Intranasal Challenge |
title_sort | francisella tularensis schu s4 purine auxotroph is highly attenuated in mice but offers limited protection against homologous intranasal challenge |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2429968/ https://www.ncbi.nlm.nih.gov/pubmed/18575611 http://dx.doi.org/10.1371/journal.pone.0002487 |
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