Deletion Mutants of <i>Francisella</i> Phagosomal Transporters FptA and FptF Are Highly Attenuated for Virulence and Are Protective Against Lethal Intranasal <i>Francisella</i> LVS Challenge in a Murine Model of Respiratory Tularemia
<i>Francisella tularensis</i> (<i>Ft</i>) is a Gram-negative, facultative intracellular bacterium that is a Tier 1 Select Agent of concern for biodefense for which there is no licensed vaccine. A subfamily of 9 <i>Francisella</i> phagosomal transporter (<i>f...
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MDPI AG
2021-06-01
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| author | Brandi E. Hobbs Courtney A. Matson Vasileios I. Theofilou Tonya J. Webb Rania H. Younis Eileen M. Barry |
| author_facet | Brandi E. Hobbs Courtney A. Matson Vasileios I. Theofilou Tonya J. Webb Rania H. Younis Eileen M. Barry |
| author_sort | Brandi E. Hobbs |
| collection | DOAJ |
| description | <i>Francisella tularensis</i> (<i>Ft</i>) is a Gram-negative, facultative intracellular bacterium that is a Tier 1 Select Agent of concern for biodefense for which there is no licensed vaccine. A subfamily of 9 <i>Francisella</i> phagosomal transporter (<i>fpt</i>) genes belonging to the Major Facilitator Superfamily of transporters was identified as critical to pathogenesis and potential targets for attenuation and vaccine development. We evaluated the attenuation and protective capacity of LVS derivatives with deletions of the <i>fptA</i> and <i>fptF</i> genes in the C57BL/6J mouse model of respiratory tularemia. LVSΔ<i>fptA</i> and LVSΔ<i>fptF</i> were highly attenuated with LD<sub>50</sub> values of >20 times that of LVS when administered intranasally and conferred 100% protection against lethal challenge. Immune responses to the <i>fpt</i> mutant strains in mouse lungs on day 6 post-infection were substantially modified compared to LVS and were associated with reduced organ burdens and reduced pathology. The immune responses to LVSΔ<i>fptA</i> and LVSΔf<i>ptF</i> were characterized by decreased levels of IL-10 and IL-1β in the BALF versus LVS, and increased numbers of B cells, αβ and γδ T cells, NK cells, and DCs versus LVS. These results support a fundamental requirement for FptA and FptF in the pathogenesis of <i>Ft</i> and the modulation of the host immune response. |
| first_indexed | 2024-03-10T10:07:01Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-10T10:07:01Z |
| publishDate | 2021-06-01 |
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| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-e73fbda3bfd344ffa0a382046fb61f612023-11-22T01:28:51ZengMDPI AGPathogens2076-08172021-06-0110779910.3390/pathogens10070799Deletion Mutants of <i>Francisella</i> Phagosomal Transporters FptA and FptF Are Highly Attenuated for Virulence and Are Protective Against Lethal Intranasal <i>Francisella</i> LVS Challenge in a Murine Model of Respiratory TularemiaBrandi E. Hobbs0Courtney A. Matson1Vasileios I. Theofilou2Tonya J. Webb3Rania H. Younis4Eileen M. Barry5Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, MD 21201, USADepartment of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, MD 21201, USACenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA<i>Francisella tularensis</i> (<i>Ft</i>) is a Gram-negative, facultative intracellular bacterium that is a Tier 1 Select Agent of concern for biodefense for which there is no licensed vaccine. A subfamily of 9 <i>Francisella</i> phagosomal transporter (<i>fpt</i>) genes belonging to the Major Facilitator Superfamily of transporters was identified as critical to pathogenesis and potential targets for attenuation and vaccine development. We evaluated the attenuation and protective capacity of LVS derivatives with deletions of the <i>fptA</i> and <i>fptF</i> genes in the C57BL/6J mouse model of respiratory tularemia. LVSΔ<i>fptA</i> and LVSΔ<i>fptF</i> were highly attenuated with LD<sub>50</sub> values of >20 times that of LVS when administered intranasally and conferred 100% protection against lethal challenge. Immune responses to the <i>fpt</i> mutant strains in mouse lungs on day 6 post-infection were substantially modified compared to LVS and were associated with reduced organ burdens and reduced pathology. The immune responses to LVSΔ<i>fptA</i> and LVSΔf<i>ptF</i> were characterized by decreased levels of IL-10 and IL-1β in the BALF versus LVS, and increased numbers of B cells, αβ and γδ T cells, NK cells, and DCs versus LVS. These results support a fundamental requirement for FptA and FptF in the pathogenesis of <i>Ft</i> and the modulation of the host immune response.https://www.mdpi.com/2076-0817/10/7/799<i>Francisella tularensis</i>Live Vaccine Strain (LVS)live attenuated vaccineMFS transporterattenuationorgan burdens |
| spellingShingle | Brandi E. Hobbs Courtney A. Matson Vasileios I. Theofilou Tonya J. Webb Rania H. Younis Eileen M. Barry Deletion Mutants of <i>Francisella</i> Phagosomal Transporters FptA and FptF Are Highly Attenuated for Virulence and Are Protective Against Lethal Intranasal <i>Francisella</i> LVS Challenge in a Murine Model of Respiratory Tularemia Pathogens <i>Francisella tularensis</i> Live Vaccine Strain (LVS) live attenuated vaccine MFS transporter attenuation organ burdens |
| title | Deletion Mutants of <i>Francisella</i> Phagosomal Transporters FptA and FptF Are Highly Attenuated for Virulence and Are Protective Against Lethal Intranasal <i>Francisella</i> LVS Challenge in a Murine Model of Respiratory Tularemia |
| title_full | Deletion Mutants of <i>Francisella</i> Phagosomal Transporters FptA and FptF Are Highly Attenuated for Virulence and Are Protective Against Lethal Intranasal <i>Francisella</i> LVS Challenge in a Murine Model of Respiratory Tularemia |
| title_fullStr | Deletion Mutants of <i>Francisella</i> Phagosomal Transporters FptA and FptF Are Highly Attenuated for Virulence and Are Protective Against Lethal Intranasal <i>Francisella</i> LVS Challenge in a Murine Model of Respiratory Tularemia |
| title_full_unstemmed | Deletion Mutants of <i>Francisella</i> Phagosomal Transporters FptA and FptF Are Highly Attenuated for Virulence and Are Protective Against Lethal Intranasal <i>Francisella</i> LVS Challenge in a Murine Model of Respiratory Tularemia |
| title_short | Deletion Mutants of <i>Francisella</i> Phagosomal Transporters FptA and FptF Are Highly Attenuated for Virulence and Are Protective Against Lethal Intranasal <i>Francisella</i> LVS Challenge in a Murine Model of Respiratory Tularemia |
| title_sort | deletion mutants of i francisella i phagosomal transporters fpta and fptf are highly attenuated for virulence and are protective against lethal intranasal i francisella i lvs challenge in a murine model of respiratory tularemia |
| topic | <i>Francisella tularensis</i> Live Vaccine Strain (LVS) live attenuated vaccine MFS transporter attenuation organ burdens |
| url | https://www.mdpi.com/2076-0817/10/7/799 |
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