상세정보
Export to Refworks부가기능
Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis
상세 프로파일
| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis. |
| 개인저자 | Markley, Rachel L. |
| 단체저자명 | The Pennsylvania State University. Immunology and Infectious Diseases. |
| 발행사항 | [S.l.]: The Pennsylvania State University., 2017. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2017. |
| 형태사항 | 120 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-01B. Dissertation Abstract International |
| ISBN | 9781392335390 |
| 학위논문주기 | Thesis (Ph.D.)--The Pennsylvania State University, 2017. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-01, Section: B.
Publisher info.: Dissertation/Thesis. Advisor: Kirimanjeswara, Girish S. |
| 요약 | The micronutrient selenium (Se) has been suggested as a promising adjuvant for pharmaconutrient intervention in clinical applications. Use of Se in cancer research and for viral infections has been well documented. It has been less well defined in bacterial infections. The application of the micronutrient as a novel therapeutic is rooted in the fact that adequate and supplemental levels of Se are required to maintain optimal expression of selenoproteins. Selenoproteins are a particular class of proteins which contain Se in the form of the amino acid, selenocysteine. It has been well established that deficiency of Se is deleterious to human health, and in the last two decades a large body of work has been published correlating deficiency with individuals suffering from chronic and in a small number of cases acute bacterial infections. Moreover, the increased interest of pharmaconutrient intervention using Se supplementation to improve patient outcome has been supported by evidence that selenoproteins are important mediators of inflammation. Of the 25 selenoproteins expressed in humans and 24 expressed in mice over half perform antioxidant or redox function. In addition to maintaining redox homeostasis, selenoproteins have also been attributed to a wide array of other bimolecular functions vital to immune response. Some that have been more clearly defined then others.I was particularly interested in addressing the role of selenoproteins during acute infection, specifically understanding how these proteins influenced macrophages a subset cells that are part of the innate immune response. Macrophages are important mediators of immune defenses against bacteria and have the capacity for bactericidal activity. Therefore, I investigated the effect of Se and selenoproteins on macrophages function during an acute intracellular bacterial infection. Francisella tularensis, the causative agent of tularemia, is an intracellular bacterium that preferentially infects phagocytes. I have determined that F. tularensis lacks the metabolic machinery to specifically incorporate Se into its proteome and the inability to accumulate elemental selenium in its biomass, which indicates the bacteria, is unable to utilize Se. Furthermore, empirical data I have collected shows that Se supplementation does not affect the physiology of the bacteria. For these reasons, F. tularensis is ideally suited to investigate the effects of Se on macrophages during acute bacterial infection. Upon entry into a host cell, F. tularensis is able to escape the phagosomal compartment, and initiate replication, multiplying approximately 50 to 100 fold within 24 hours.To determine the effect of Se on F. tularensis infection, groups of mice were maintained on Se-deficient (<0.01 ppm of Na2SO3) or Se-supplemented (0.4 ppm Na2SO3) defined diets. While 50% of Se-supplemented mice died following infection with F. tularensis, 100% of Sedeficient mice succumbed suggesting that Se plays a significant role in protection from infection. Since, F. tularensis infects and replicates primarily in macrophages, I investigated the bacterial replication in Se-deficient (treated with 0 nM of Na2SO3) and Se-supplemented (200 nM of Na2SO3) macrophages. Interestingly, Se-supplemented macrophages restricted bacterial growth by about 20 fold compared to Se-deficient cells. Next, the role of selenoproteins in restricting bacterial growth was tested by using the macrophages derived from TrspM mice, which are unable to synthesize selenoproteins in macrophages. TrspM macrophages were unable to control the replication of F. tularensis compared to wild-type (WT) macrophages. Consistent with these results, TrspM mice were significantly more susceptible to F. tularensis infection than WT mice. Furthermore, bacterial burden in the livers and spleens of TrspM mice were significantly higher than WT mice indicating that macrophage selenoproteins are essential for restricting bacterial replication and promoting host survival.Given that F. tularensis temporally activates the host's autophagy pathway to meet its nutrients and energy requirements during the proliferative phase, and aid in host immune evasion. I examined the expression of autophagy markers in the Se-deficient and Sesupplemented macrophages. The data indicated that Se supplementation suppressed autophagy in a selenoprotein dependent manner. I hypothesize that Se via specific selenoprotein(s) suppresses autophagy limiting available nutrients thereby restricting bacterial replication. This restriction in bacterial replication may lead to a less sever systemic infection and reduces Ft. pathogenesis. These date provide insight into the influence of micronutrients on infectious disease pathogenesis and suggest novel strategies to manage infectious diseasesThe work presented here focuses on 4 goals: 1.) To assess the potential for Se adjuvant intervention as a therapeutic approach in the treatment of acute bacterial infections. 2.) To validate the F. tularensis pathogen model. 3.) To address the role of selenium via selenoproteins on the restriction of intracellular F. tularensis replication. 4.) To examine the underlying mechanisms driving the phenotypic restriction of bacterial replication that we have observed under selenium supplemented conditions. |
| 일반주제명 | Microbiology. Animal Diseases. Immunology. |
| 언어 | 영어 |
| 바로가기 | 
: 이 자료의 원문은 한국교육학술정보원에서 제공합니다. |
