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Defining Host Factors Uniquely Required for Antibody-Dependent Enhancement of Dengue Virus Infection
Defining Host Factors Uniquely Required for Antibody-Dependent Enhancement of Dengue Virus Infection
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152803
- ISBN
- 9798384099352
- DDC
- 576.6
- 저자명
- Belmont, Laura.
- 서명/저자
- Defining Host Factors Uniquely Required for Antibody-Dependent Enhancement of Dengue Virus Infection
- 발행사항
- [Sl] : University of Washington, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 105 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-03, Section: B.
- 주기사항
- Includes supplementary digital materials.
- 주기사항
- Advisor: Goo, Leslie.
- 학위논문주기
- Thesis (Ph.D.)--University of Washington, 2024.
- 초록/해제
- 요약Dengue virus (DENV) causes 100 million symptomatic cases annually and represents a growing public health threat as the geographic range of its vector mosquitoes expands. However, there are no treatments for dengue disease and limited vaccine options. The antibody response to DENV represents a major barrier in developing safe and effective clinical interventions; intermediate IgG antibody titers are correlated with more severe dengue disease. The prevailing theory behind this observation is a phenomenon known as antibody-dependent enhancement (ADE) of DENV, where DENV uses non-neutralizing IgG antibodies to enter target cells expressing Fc gamma receptors (FcgR). Beyond the requirement of Fc-FcgR interactions, functional requirements of ADE of DENV infection are unknown because existing studies are unable to establish cause and effect. However, functional requirements of DENV in the absence of antibodies infection have been robustly identified via genome-wide CRISPR knockout screens. Therefore, I used genome-wide CRISPR knockout screening in a model amenable to efficient infection only via ADE to investigate the functional requirements of ADE.By performing genome-wide and follow-up targeted CRISPR screens, I identified and validated novel candidate host factors specifically required for ADE. Specifically, I found that knockout of SV2B or TBC1D24, genes typically involved in vesicle trafficking and regulated secretion in the nervous system, reduced the level of infection via ADE, but not direct infection, and trans-complementation of these genes restored ADE efficiency to wild-type levels. Knockout of these genes reduced ADE efficiency in various contexts, including in assays using sera from DENV-experienced donors, fully infectious virus of each serotype, and multiple cell lines. Finally, knockout of these genes reduced binding of antibody-virion complexes to cells without affecting FcgR expression levels. Overall, these studies show SV2B and TBC1D24 are required for ADE of DENV infection and suggest a role for endocytic pathways typically involved in synaptic vesicle trafficking in this non-canonical viral uptake pathway. The findings described in this thesis are a first step toward increasing fundamental knowledge of the biology of this alternative infection route implicated in disease, which eventually could be exploited to inform therapeutic approaches.
- 일반주제명
- Virology
- 일반주제명
- Immunology
- 일반주제명
- Cellular biology
- 일반주제명
- Molecular biology
- 일반주제명
- Genetics
- 키워드
- Dengue virus
- 키워드
- Host factors
- 키워드
- Virus infection
- 기타저자
- University of Washington Molecular and Cellular Biology
- 기본자료저록
- Dissertations Abstracts International. 86-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798384099352
■035 ▼a(MiAaPQ)AAI31556891
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a576.6
■1001 ▼aBelmont, Laura.
■24510▼aDefining Host Factors Uniquely Required for Antibody-Dependent Enhancement of Dengue Virus Infection
■260 ▼a[Sl]▼bUniversity of Washington▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a105 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-03, Section: B.
■500 ▼aIncludes supplementary digital materials.
■500 ▼aAdvisor: Goo, Leslie.
■5021 ▼aThesis (Ph.D.)--University of Washington, 2024.
■520 ▼aDengue virus (DENV) causes 100 million symptomatic cases annually and represents a growing public health threat as the geographic range of its vector mosquitoes expands. However, there are no treatments for dengue disease and limited vaccine options. The antibody response to DENV represents a major barrier in developing safe and effective clinical interventions; intermediate IgG antibody titers are correlated with more severe dengue disease. The prevailing theory behind this observation is a phenomenon known as antibody-dependent enhancement (ADE) of DENV, where DENV uses non-neutralizing IgG antibodies to enter target cells expressing Fc gamma receptors (FcgR). Beyond the requirement of Fc-FcgR interactions, functional requirements of ADE of DENV infection are unknown because existing studies are unable to establish cause and effect. However, functional requirements of DENV in the absence of antibodies infection have been robustly identified via genome-wide CRISPR knockout screens. Therefore, I used genome-wide CRISPR knockout screening in a model amenable to efficient infection only via ADE to investigate the functional requirements of ADE.By performing genome-wide and follow-up targeted CRISPR screens, I identified and validated novel candidate host factors specifically required for ADE. Specifically, I found that knockout of SV2B or TBC1D24, genes typically involved in vesicle trafficking and regulated secretion in the nervous system, reduced the level of infection via ADE, but not direct infection, and trans-complementation of these genes restored ADE efficiency to wild-type levels. Knockout of these genes reduced ADE efficiency in various contexts, including in assays using sera from DENV-experienced donors, fully infectious virus of each serotype, and multiple cell lines. Finally, knockout of these genes reduced binding of antibody-virion complexes to cells without affecting FcgR expression levels. Overall, these studies show SV2B and TBC1D24 are required for ADE of DENV infection and suggest a role for endocytic pathways typically involved in synaptic vesicle trafficking in this non-canonical viral uptake pathway. The findings described in this thesis are a first step toward increasing fundamental knowledge of the biology of this alternative infection route implicated in disease, which eventually could be exploited to inform therapeutic approaches.
■590 ▼aSchool code: 0250.
■650 4▼aVirology
■650 4▼aImmunology
■650 4▼aCellular biology
■650 4▼aMolecular biology
■650 4▼aGenetics
■653 ▼aDengue virus
■653 ▼aAntibody-dependent enhancement
■653 ▼aHost factors
■653 ▼aVirus infection
■653 ▼aAntibodies infection
■690 ▼a0720
■690 ▼a0982
■690 ▼a0379
■690 ▼a0369
■690 ▼a0307
■71020▼aUniversity of Washington▼bMolecular and Cellular Biology.
■7730 ▼tDissertations Abstracts International▼g86-03B.
■790 ▼a0250
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17163870▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
