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Characterizing the Roles for Host-Derived Lipids During Mycobacterium tuberculosis Infection- [electronic resource]
Characterizing the Roles for Host-Derived Lipids During Mycobacterium tuberculosis Infection- [electronic resource]
상세정보
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214101631
- ISBN
- 9798380314992
- DDC
- 576
- 서명/저자
- Characterizing the Roles for Host-Derived Lipids During Mycobacterium tuberculosis Infection - [electronic resource]
- 발행사항
- [S.l.]: : Cornell University., 2023
- 발행사항
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- 형태사항
- 1 online resource(119 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
- 주기사항
- Advisor: VanderVen, Brian.
- 학위논문주기
- Thesis (Ph.D.)--Cornell University, 2023.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 초록/해제
- 요약Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a proficient bacterial pathogen capable of establishing long-term infection in humans. An important factor contributing to the long-term survival of Mtb is its ability to utilize host-derived lipids both as an energy source and as precursors for biosynthesis of cell envelope lipids that act as essential virulence factors.To take advantage of host nutrients, Mtb employs importers, Mce1 and Mce4, to facilitate uptake of fatty acids and cholesterol, respectively. These multiprotein complexes are hypothesized to utilize the same ATPase, MceG, to enable translocation of lipid substrates into the cytosol. Key shared subunits have been identified as essential for stabilizing the two transporters, therefore we investigated the role of MceG in stabilizing the Mce1 and Mce4 complexes. We show enzymatic activity of MceG is required for Mce1- and Mce4-mediated transport of fatty acids and cholesterol and that loss of lipid uptake in mutants lacking MceG is due to degradation of the complexes. Lastly, we show that MceG is required for full fitness in mice indicating that MceG may be a bottleneck that could be exploited by novel therapeutics.Once imported, host lipids can be assimilated into Mtb lipid biosynthetic pathways to produce virulence factors that influence the host immune response and aid in the establishment of infection. One such immune response is dependent on prostaglandin E2 (PGE2), which regulates both cell death pathways and macrophage type I interferon (IFN) responses, yet how Mtb induces PGE2 production remains poorly understood. Here, we demonstrate that the cell wall lipid, phthiocerol dimycocerosate (PDIM), is required to stimulate PGE2 synthesis during Mtb infection in mice and in macrophages ex vivo. Additionally, PDIM-dependent stimulation of PGE2 production occurs independent of signaling through IL-1β but requires export of the ESX-1 secretory protein, ESAT-6. Overall, this work reveals a new aspect of Mtb sensing in the cytosol of macrophages and provides a more complete understanding of critical events in lipid homeostasis during Mtb infection.
- 일반주제명
- Microbiology.
- 일반주제명
- Pathology.
- 일반주제명
- Virology.
- 키워드
- Mtb infection
- 키워드
- Cholesterol
- 키워드
- Macrophages
- 기타저자
- Cornell University Microbiology
- 기본자료저록
- Dissertations Abstracts International. 85-03B.
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520240214101631
■006m o d
■007cr#unu||||||||
■020 ▼a9798380314992
■035 ▼a(MiAaPQ)AAI30631267
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a576
■1001 ▼aFieweger, Rachael Alexis.▼0(orcid)0000-0002-7696-1217
■24510▼aCharacterizing the Roles for Host-Derived Lipids During Mycobacterium tuberculosis Infection▼h[electronic resource]
■260 ▼a[S.l.]:▼bCornell University. ▼c2023
■260 1▼aAnn Arbor :▼bProQuest Dissertations & Theses, ▼c2023
■300 ▼a1 online resource(119 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-03, Section: B.
■500 ▼aAdvisor: VanderVen, Brian.
■5021 ▼aThesis (Ph.D.)--Cornell University, 2023.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aMycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a proficient bacterial pathogen capable of establishing long-term infection in humans. An important factor contributing to the long-term survival of Mtb is its ability to utilize host-derived lipids both as an energy source and as precursors for biosynthesis of cell envelope lipids that act as essential virulence factors.To take advantage of host nutrients, Mtb employs importers, Mce1 and Mce4, to facilitate uptake of fatty acids and cholesterol, respectively. These multiprotein complexes are hypothesized to utilize the same ATPase, MceG, to enable translocation of lipid substrates into the cytosol. Key shared subunits have been identified as essential for stabilizing the two transporters, therefore we investigated the role of MceG in stabilizing the Mce1 and Mce4 complexes. We show enzymatic activity of MceG is required for Mce1- and Mce4-mediated transport of fatty acids and cholesterol and that loss of lipid uptake in mutants lacking MceG is due to degradation of the complexes. Lastly, we show that MceG is required for full fitness in mice indicating that MceG may be a bottleneck that could be exploited by novel therapeutics.Once imported, host lipids can be assimilated into Mtb lipid biosynthetic pathways to produce virulence factors that influence the host immune response and aid in the establishment of infection. One such immune response is dependent on prostaglandin E2 (PGE2), which regulates both cell death pathways and macrophage type I interferon (IFN) responses, yet how Mtb induces PGE2 production remains poorly understood. Here, we demonstrate that the cell wall lipid, phthiocerol dimycocerosate (PDIM), is required to stimulate PGE2 synthesis during Mtb infection in mice and in macrophages ex vivo. Additionally, PDIM-dependent stimulation of PGE2 production occurs independent of signaling through IL-1β but requires export of the ESX-1 secretory protein, ESAT-6. Overall, this work reveals a new aspect of Mtb sensing in the cytosol of macrophages and provides a more complete understanding of critical events in lipid homeostasis during Mtb infection.
■590 ▼aSchool code: 0058.
■650 4▼aMicrobiology.
■650 4▼aPathology.
■650 4▼aVirology.
■653 ▼aMtb infection
■653 ▼aMycobacterium tuberculosis
■653 ▼aBacterial pathogen
■653 ▼aCholesterol
■653 ▼aMacrophages
■690 ▼a0410
■690 ▼a0720
■690 ▼a0571
■71020▼aCornell University▼bMicrobiology.
■7730 ▼tDissertations Abstracts International▼g85-03B.
■773 ▼tDissertation Abstract International
■790 ▼a0058
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16934605▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
