Models Derived from <italic toggle="yes">In Vitro</italic> Analyses of Spleen, Liver, and Lung Leukocyte Functions Predict Vaccine Efficacy against the <named-content content-type="genus-species">Francisella tularensis</named-content> Live Vaccine Strain (LVS)
ABSTRACT Currently, there are no licensed vaccines and no correlates of protection against Francisella tularensis, which causes tularemia. We recently demonstrated that measuring in vitro control of intramacrophage bacterial growth by murine F. tularensis-immune splenocytes, as well as transcription...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2014-05-01
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| Series: | mBio |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00936-13 |
| _version_ | 1818856675275177984 |
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| author | Roberto De Pascalis Alicia Y. Chou Patrik Ryden Nikki J. Kennett Anders Sjöstedt Karen L. Elkins |
| author_facet | Roberto De Pascalis Alicia Y. Chou Patrik Ryden Nikki J. Kennett Anders Sjöstedt Karen L. Elkins |
| author_sort | Roberto De Pascalis |
| collection | DOAJ |
| description | ABSTRACT Currently, there are no licensed vaccines and no correlates of protection against Francisella tularensis, which causes tularemia. We recently demonstrated that measuring in vitro control of intramacrophage bacterial growth by murine F. tularensis-immune splenocytes, as well as transcriptional analyses, discriminated Francisella vaccines of different efficacies. Further, we identified potential correlates of protection against systemic challenge. Here, we extended this approach by studying leukocytes derived from lungs and livers of mice immunized by parenteral and respiratory routes with F. tularensis vaccines. Liver and lung leukocytes derived from intradermally and intranasally vaccinated mice controlled in vitro Francisella Live Vaccine Strain (LVS) intramacrophage replication in patterns similar to those of splenocytes. Gene expression analyses of potential correlates also revealed similar patterns in liver cells and splenocytes. In some cases (e.g., tumor necrosis factor alpha [TNF-α], interleukin 22 [IL-22], and granulocyte-macrophage colony-stimulating factor [GM-CSF]), liver cells exhibited even higher relative gene expression, whereas fewer genes exhibited differential expression in lung cells. In contrast with their strong ability to control LVS replication, splenocytes from intranasally vaccinated mice expressed few genes with a hierarchy of expression similar to that of splenocytes from intradermally vaccinated mice. Thus, the relative levels of gene expression vary between cell types from different organs and by vaccination route. Most importantly, because studies comparing cell sources and routes of vaccination supported the predictive validity of this coculture and gene quantification approach, we combined in vitro LVS replication with gene expression data to develop analytical models that discriminated between vaccine groups and successfully predicted the degree of vaccine efficacy. Thus, this strategy remains a promising means of identifying and quantifying correlative T cell responses. IMPORTANCE Identifying and quantifying correlates of protection is especially challenging for intracellular bacteria, including Francisella tularensis. F. tularensis is classified as a category A bioterrorism agent, and no vaccines have been licensed in the United States, but tularemia is a rare disease. Therefore, clinical trials to test promising vaccines are impractical. In this report, we further evaluated a novel approach to developing correlates by assessing T cell immune responses in lungs and livers of differentially vaccinated mice; these nonprofessional immune tissues are colonized by Francisella. The relative degree of vaccine efficacy against systemic challenge was reflected by the ability of immune T cells, particularly liver T cells, to control the intramacrophage replication of bacteria in vitro and by relative gene expression of several immunological mediators. We therefore developed analytical models that combined bacterial replication data and gene expression data. Several resulting models provided excellent discrimination between vaccines of different efficacies. |
| first_indexed | 2024-12-19T08:28:16Z |
| format | Article |
| id | doaj.art-5765e28e0d5d4a9591b63f0287921cd5 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-19T08:28:16Z |
| publishDate | 2014-05-01 |
| publisher | American Society for Microbiology |
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| series | mBio |
| spelling | doaj.art-5765e28e0d5d4a9591b63f0287921cd52022-12-21T20:29:15ZengAmerican Society for MicrobiologymBio2150-75112014-05-015210.1128/mBio.00936-13Models Derived from <italic toggle="yes">In Vitro</italic> Analyses of Spleen, Liver, and Lung Leukocyte Functions Predict Vaccine Efficacy against the <named-content content-type="genus-species">Francisella tularensis</named-content> Live Vaccine Strain (LVS)Roberto De Pascalis0Alicia Y. Chou1Patrik Ryden2Nikki J. Kennett3Anders Sjöstedt4Karen L. Elkins5Laboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland, USALaboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland, USADepartment of Mathematics and Mathematical Statistics, Umeå University, Umeå, SwedenLaboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland, USADepartment of Clinical Microbiology, Clinical Bacteriology, and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, SwedenLaboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland, USAABSTRACT Currently, there are no licensed vaccines and no correlates of protection against Francisella tularensis, which causes tularemia. We recently demonstrated that measuring in vitro control of intramacrophage bacterial growth by murine F. tularensis-immune splenocytes, as well as transcriptional analyses, discriminated Francisella vaccines of different efficacies. Further, we identified potential correlates of protection against systemic challenge. Here, we extended this approach by studying leukocytes derived from lungs and livers of mice immunized by parenteral and respiratory routes with F. tularensis vaccines. Liver and lung leukocytes derived from intradermally and intranasally vaccinated mice controlled in vitro Francisella Live Vaccine Strain (LVS) intramacrophage replication in patterns similar to those of splenocytes. Gene expression analyses of potential correlates also revealed similar patterns in liver cells and splenocytes. In some cases (e.g., tumor necrosis factor alpha [TNF-α], interleukin 22 [IL-22], and granulocyte-macrophage colony-stimulating factor [GM-CSF]), liver cells exhibited even higher relative gene expression, whereas fewer genes exhibited differential expression in lung cells. In contrast with their strong ability to control LVS replication, splenocytes from intranasally vaccinated mice expressed few genes with a hierarchy of expression similar to that of splenocytes from intradermally vaccinated mice. Thus, the relative levels of gene expression vary between cell types from different organs and by vaccination route. Most importantly, because studies comparing cell sources and routes of vaccination supported the predictive validity of this coculture and gene quantification approach, we combined in vitro LVS replication with gene expression data to develop analytical models that discriminated between vaccine groups and successfully predicted the degree of vaccine efficacy. Thus, this strategy remains a promising means of identifying and quantifying correlative T cell responses. IMPORTANCE Identifying and quantifying correlates of protection is especially challenging for intracellular bacteria, including Francisella tularensis. F. tularensis is classified as a category A bioterrorism agent, and no vaccines have been licensed in the United States, but tularemia is a rare disease. Therefore, clinical trials to test promising vaccines are impractical. In this report, we further evaluated a novel approach to developing correlates by assessing T cell immune responses in lungs and livers of differentially vaccinated mice; these nonprofessional immune tissues are colonized by Francisella. The relative degree of vaccine efficacy against systemic challenge was reflected by the ability of immune T cells, particularly liver T cells, to control the intramacrophage replication of bacteria in vitro and by relative gene expression of several immunological mediators. We therefore developed analytical models that combined bacterial replication data and gene expression data. Several resulting models provided excellent discrimination between vaccines of different efficacies.https://journals.asm.org/doi/10.1128/mBio.00936-13 |
| spellingShingle | Roberto De Pascalis Alicia Y. Chou Patrik Ryden Nikki J. Kennett Anders Sjöstedt Karen L. Elkins Models Derived from <italic toggle="yes">In Vitro</italic> Analyses of Spleen, Liver, and Lung Leukocyte Functions Predict Vaccine Efficacy against the <named-content content-type="genus-species">Francisella tularensis</named-content> Live Vaccine Strain (LVS) mBio |
| title | Models Derived from <italic toggle="yes">In Vitro</italic> Analyses of Spleen, Liver, and Lung Leukocyte Functions Predict Vaccine Efficacy against the <named-content content-type="genus-species">Francisella tularensis</named-content> Live Vaccine Strain (LVS) |
| title_full | Models Derived from <italic toggle="yes">In Vitro</italic> Analyses of Spleen, Liver, and Lung Leukocyte Functions Predict Vaccine Efficacy against the <named-content content-type="genus-species">Francisella tularensis</named-content> Live Vaccine Strain (LVS) |
| title_fullStr | Models Derived from <italic toggle="yes">In Vitro</italic> Analyses of Spleen, Liver, and Lung Leukocyte Functions Predict Vaccine Efficacy against the <named-content content-type="genus-species">Francisella tularensis</named-content> Live Vaccine Strain (LVS) |
| title_full_unstemmed | Models Derived from <italic toggle="yes">In Vitro</italic> Analyses of Spleen, Liver, and Lung Leukocyte Functions Predict Vaccine Efficacy against the <named-content content-type="genus-species">Francisella tularensis</named-content> Live Vaccine Strain (LVS) |
| title_short | Models Derived from <italic toggle="yes">In Vitro</italic> Analyses of Spleen, Liver, and Lung Leukocyte Functions Predict Vaccine Efficacy against the <named-content content-type="genus-species">Francisella tularensis</named-content> Live Vaccine Strain (LVS) |
| title_sort | models derived from italic toggle yes in vitro italic analyses of spleen liver and lung leukocyte functions predict vaccine efficacy against the named content content type genus species francisella tularensis named content live vaccine strain lvs |
| url | https://journals.asm.org/doi/10.1128/mBio.00936-13 |
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