Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity
The essential micronutrient Selenium (Se) is co-translationally incorporated as selenocysteine into proteins. Selenoproteins contain one or more selenocysteines and are vital for optimum immunity. Interestingly, many pathogenic bacteria utilize Se for various biological processes suggesting that Se...
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| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.701341/full |
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| author | Rachel L. Markley Rachel L. Markley Rachel L. Markley Katherine H. Restori Bhuvana Katkere Sarah E. Sumner Sarah E. Sumner McKayla J. Nicol McKayla J. Nicol Anastasia Tyryshkina Anastasia Tyryshkina Shaneice K. Nettleford Shaneice K. Nettleford David R. Williamson David E. Place David E. Place Kalyan K. Dewan Kalyan K. Dewan Ashley E. Shay Ashley E. Shay Bradley A. Carlson Santhosh Girirajan K. Sandeep Prabhu K. Sandeep Prabhu Girish S. Kirimanjeswara Girish S. Kirimanjeswara |
| author_facet | Rachel L. Markley Rachel L. Markley Rachel L. Markley Katherine H. Restori Bhuvana Katkere Sarah E. Sumner Sarah E. Sumner McKayla J. Nicol McKayla J. Nicol Anastasia Tyryshkina Anastasia Tyryshkina Shaneice K. Nettleford Shaneice K. Nettleford David R. Williamson David E. Place David E. Place Kalyan K. Dewan Kalyan K. Dewan Ashley E. Shay Ashley E. Shay Bradley A. Carlson Santhosh Girirajan K. Sandeep Prabhu K. Sandeep Prabhu Girish S. Kirimanjeswara Girish S. Kirimanjeswara |
| author_sort | Rachel L. Markley |
| collection | DOAJ |
| description | The essential micronutrient Selenium (Se) is co-translationally incorporated as selenocysteine into proteins. Selenoproteins contain one or more selenocysteines and are vital for optimum immunity. Interestingly, many pathogenic bacteria utilize Se for various biological processes suggesting that Se may play a role in bacterial pathogenesis. A previous study had speculated that Francisella tularensis, a facultative intracellular bacterium and the causative agent of tularemia, sequesters Se by upregulating Se-metabolism genes in type II alveolar epithelial cells. Therefore, we investigated the contribution of host vs. pathogen-associated selenoproteins in bacterial disease using F. tularensis as a model organism. We found that F. tularensis was devoid of any Se utilization traits, neither incorporated elemental Se, nor exhibited Se-dependent growth. However, 100% of Se-deficient mice (0.01 ppm Se), which express low levels of selenoproteins, succumbed to F. tularensis-live vaccine strain pulmonary challenge, whereas 50% of mice on Se-supplemented (0.4 ppm Se) and 25% of mice on Se-adequate (0.1 ppm Se) diet succumbed to infection. Median survival time for Se-deficient mice was 8 days post-infection while Se-supplemented and -adequate mice was 11.5 and >14 days post-infection, respectively. Se-deficient macrophages permitted significantly higher intracellular bacterial replication than Se-supplemented macrophages ex vivo, corroborating in vivo observations. Since Francisella replicates in alveolar macrophages during the acute phase of pneumonic infection, we hypothesized that macrophage-specific host selenoproteins may restrict replication and systemic spread of bacteria. F. tularensis infection led to an increased expression of several macrophage selenoproteins, suggesting their key role in limiting bacterial replication. Upon challenge with F. tularensis, mice lacking selenoproteins in macrophages (TrspM) displayed lower survival and increased bacterial burden in the lung and systemic tissues in comparison to WT littermate controls. Furthermore, macrophages from TrspM mice were unable to restrict bacterial replication ex vivo in comparison to macrophages from littermate controls. We herein describe a novel function of host macrophage-specific selenoproteins in restriction of intracellular bacterial replication. These data suggest that host selenoproteins may be considered as novel targets for modulating immune response to control a bacterial infection. |
| first_indexed | 2024-12-14T07:47:58Z |
| format | Article |
| id | doaj.art-99bbee9a907a441aa3a38efdca6ca9f1 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T07:47:58Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-99bbee9a907a441aa3a38efdca6ca9f12022-12-21T23:10:49ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-10-011210.3389/fimmu.2021.701341701341Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host ImmunityRachel L. Markley0Rachel L. Markley1Rachel L. Markley2Katherine H. Restori3Bhuvana Katkere4Sarah E. Sumner5Sarah E. Sumner6McKayla J. Nicol7McKayla J. Nicol8Anastasia Tyryshkina9Anastasia Tyryshkina10Shaneice K. Nettleford11Shaneice K. Nettleford12David R. Williamson13David E. Place14David E. Place15Kalyan K. Dewan16Kalyan K. Dewan17Ashley E. Shay18Ashley E. Shay19Bradley A. Carlson20Santhosh Girirajan21K. Sandeep Prabhu22K. Sandeep Prabhu23Girish S. Kirimanjeswara24Girish S. Kirimanjeswara25Pathobiology Graduate Program, The Pennsylvania State University, University Park, PA, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United StatesDepartment of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United StatesPathobiology Graduate Program, The Pennsylvania State University, University Park, PA, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United StatesPathobiology Graduate Program, The Pennsylvania State University, University Park, PA, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United StatesNeuroscience Graduate Program, Huck Institute of the Life Sciences, The Pennsylvania State University, University Park, PA, United StatesDepartment of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, United StatesPathobiology Graduate Program, The Pennsylvania State University, University Park, PA, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United StatesDepartment of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United StatesDepartment of Infectious Diseases, The University of Georgia, Athens, GA, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United StatesCenter for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United StatesOffice of Research Support, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesDepartment of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States0Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA, United StatesDepartment of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States0Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA, United StatesThe essential micronutrient Selenium (Se) is co-translationally incorporated as selenocysteine into proteins. Selenoproteins contain one or more selenocysteines and are vital for optimum immunity. Interestingly, many pathogenic bacteria utilize Se for various biological processes suggesting that Se may play a role in bacterial pathogenesis. A previous study had speculated that Francisella tularensis, a facultative intracellular bacterium and the causative agent of tularemia, sequesters Se by upregulating Se-metabolism genes in type II alveolar epithelial cells. Therefore, we investigated the contribution of host vs. pathogen-associated selenoproteins in bacterial disease using F. tularensis as a model organism. We found that F. tularensis was devoid of any Se utilization traits, neither incorporated elemental Se, nor exhibited Se-dependent growth. However, 100% of Se-deficient mice (0.01 ppm Se), which express low levels of selenoproteins, succumbed to F. tularensis-live vaccine strain pulmonary challenge, whereas 50% of mice on Se-supplemented (0.4 ppm Se) and 25% of mice on Se-adequate (0.1 ppm Se) diet succumbed to infection. Median survival time for Se-deficient mice was 8 days post-infection while Se-supplemented and -adequate mice was 11.5 and >14 days post-infection, respectively. Se-deficient macrophages permitted significantly higher intracellular bacterial replication than Se-supplemented macrophages ex vivo, corroborating in vivo observations. Since Francisella replicates in alveolar macrophages during the acute phase of pneumonic infection, we hypothesized that macrophage-specific host selenoproteins may restrict replication and systemic spread of bacteria. F. tularensis infection led to an increased expression of several macrophage selenoproteins, suggesting their key role in limiting bacterial replication. Upon challenge with F. tularensis, mice lacking selenoproteins in macrophages (TrspM) displayed lower survival and increased bacterial burden in the lung and systemic tissues in comparison to WT littermate controls. Furthermore, macrophages from TrspM mice were unable to restrict bacterial replication ex vivo in comparison to macrophages from littermate controls. We herein describe a novel function of host macrophage-specific selenoproteins in restriction of intracellular bacterial replication. These data suggest that host selenoproteins may be considered as novel targets for modulating immune response to control a bacterial infection.https://www.frontiersin.org/articles/10.3389/fimmu.2021.701341/fullseleniumredoxintracellular bacteriatularemiainnate immunity |
| spellingShingle | Rachel L. Markley Rachel L. Markley Rachel L. Markley Katherine H. Restori Bhuvana Katkere Sarah E. Sumner Sarah E. Sumner McKayla J. Nicol McKayla J. Nicol Anastasia Tyryshkina Anastasia Tyryshkina Shaneice K. Nettleford Shaneice K. Nettleford David R. Williamson David E. Place David E. Place Kalyan K. Dewan Kalyan K. Dewan Ashley E. Shay Ashley E. Shay Bradley A. Carlson Santhosh Girirajan K. Sandeep Prabhu K. Sandeep Prabhu Girish S. Kirimanjeswara Girish S. Kirimanjeswara Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity Frontiers in Immunology selenium redox intracellular bacteria tularemia innate immunity |
| title | Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity |
| title_full | Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity |
| title_fullStr | Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity |
| title_full_unstemmed | Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity |
| title_short | Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity |
| title_sort | macrophage selenoproteins restrict intracellular replication of francisella tularensis and are essential for host immunity |
| topic | selenium redox intracellular bacteria tularemia innate immunity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.701341/full |
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