Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity.

Autor:	Markley RL; Pathobiology Graduate Program, The Pennsylvania State University, University Park, PA, United States.; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States.; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States., Restori KH; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States., Katkere B; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States., Sumner SE; Pathobiology Graduate Program, The Pennsylvania State University, University Park, PA, United States.; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States., Nicol MJ; Pathobiology Graduate Program, The Pennsylvania State University, University Park, PA, United States.; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States., Tyryshkina A; Neuroscience Graduate Program, Huck Institute of the Life Sciences, The Pennsylvania State University, University Park, PA, United States.; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, United States., Nettleford SK; Pathobiology Graduate Program, The Pennsylvania State University, University Park, PA, United States.; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States., Williamson DR; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States., Place DE; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States.; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, United States., Dewan KK; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States.; Department of Infectious Diseases, The University of Georgia, Athens, GA, United States., Shay AE; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States.; Center 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 States., Carlson BA; Office of Research Support, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States., Girirajan S; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, United States., Prabhu KS; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States.; Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA, United States., Kirimanjeswara GS; Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, United States.; Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Oct 29; Vol. 12, pp. 701341. Date of Electronic Publication: 2021 Oct 29 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.701341
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Markley, Restori, Katkere, Sumner, Nicol, Tyryshkina, Nettleford, Williamson, Place, Dewan, Shay, Carlson, Girirajan, Prabhu and Kirimanjeswara.)
Databáze:	MEDLINE
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