The Functional Role of the Tetraspanin CD82/Kai1 in Fungal Innate Immunity

四跨膜蛋白 CD82/Kai1 在真菌先天免疫中的功能作用

基本信息

  • 批准号:
    10090557
  • 负责人:
  • 金额:
    $ 52.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-01-11 至 2022-12-31
  • 项目状态:
    已结题

项目摘要

Project Summary: Invasive fungal infections (IFIs) represent a major threat to critically ill and immunocompromised patients and are associated with significant morbidity and mortality. Aspergillus and Candida are opportunistic fungi that cause the majority of these life-threatening infections. In order to exert their deleterious effects, pathogens including viruses, bacteria, parasites, and fungi can hijack tetraspanins for cell invasion or intracellular trafficking. Tetraspanins comprise a family of proteins that are expressed on the plasma membrane, intracellular membranes, and exosomes from nearly all cell types. As their name implies, tetraspanins span the membrane four times and have short intracellular amino and carboxyl-termini and two extracellular loops. Tetraspanins regulate diverse biological processes including cell migration, adhesion, and signaling events by serving as organizers of multimolecular complexes; they form promiscuous associations with one another and other membrane proteins and lipids to generate tetraspanin-enriched microdomains. Elucidating the precise function of tetraspanins has been difficult due to molecular redundancy, a lack of catalytic activity, and insufficient specific antibodies. Despite these challenges, several tetraspanins have been implicated as key regulators of cancer progression and immunity. In particular, CD82 acts as a potent suppressor of tumor metastasis. Tetraspanins including CD82 are also widely expressed in immune cells, but their exact role in undefined. We have made several key observations that begin to define the role of CD82 in fungal immunity. Following phagocytosis by macrophages, CD82 is specifically recruited to phagosomes containing fungal pathogens prior to lysosomal fusion. Remarkably, LysM-Cre CD82 knockout mice infected with Candida albicans have significantly reduced survival compared to wild-type controls, indicating that CD82 plays an important functional role in myeloid cells in response to systemic fungal infection. We developed fungal-like particles to probe directly the immune response to carbohydrates expressed on the fungal cell wall, such as β- 1,3 glucan which is recognized by the pathogen recognition receptor, Dectin-1. We demonstrated that Dectin-1 is critical for phagolysosomal maturation and controls recruitment of the autophagy-related protein, LC3, to fungal containing phagosomes through Syk activation. We also found that CD82 associates with Dectin-1 in macrophages and is important for downstream signaling events in response to fungal infection including Syk activation and ROS generation. To determine the molecular mechanism of CD82 in fungal innate immunity in macrophages, we propose the following two specific aims: (1) Determine the role of CD82 in Dectin-1 signaling by macrophages stimulated with β-1,3 glucan, and (2) Define the role of CD82 in LC3 associated phagocytosis in macrophages challenged by C. albicans.
项目总结:

项目成果

期刊论文数量(0)
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Jatin M Vyas其他文献

Jatin M Vyas的其他文献

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{{ truncateString('Jatin M Vyas', 18)}}的其他基金

2023 Immunology of Fungal Infections GRC/GRS
2023年真菌感染免疫学GRC/GRS
  • 批准号:
    10608737
  • 财政年份:
    2022
  • 资助金额:
    $ 52.94万
  • 项目类别:
Host Responses to Coccidioides by Human Airway Epithelium
人体气道上皮对球孢子菌的宿主反应
  • 批准号:
    10373208
  • 财政年份:
    2022
  • 资助金额:
    $ 52.94万
  • 项目类别:
Host Responses to Coccidioides by Human Airway Epithelium
人体气道上皮对球孢子菌的宿主反应
  • 批准号:
    10616716
  • 财政年份:
    2022
  • 资助金额:
    $ 52.94万
  • 项目类别:
MGH Next Generation Physician-Scientist Through Stimulating Access to Research in Residency Program (MGH-Next Gen StARR)
MGH 下一代医师科学家通过促进住院医师研究项目 (MGH-Next Gen StARR)
  • 批准号:
    10115797
  • 财政年份:
    2020
  • 资助金额:
    $ 52.94万
  • 项目类别:
Control of Type I Interferon Production in Response to Candida albicans
控制白色念珠菌产生的 I 型干扰素的产生
  • 批准号:
    10375410
  • 财政年份:
    2020
  • 资助金额:
    $ 52.94万
  • 项目类别:
MGH Next Generation Physician-Scientist Through Stimulating Access to Research in Residency Program (MGH-Next Gen StARR)
MGH 下一代医师科学家通过促进住院医师研究项目 (MGH-Next Gen StARR)
  • 批准号:
    10441143
  • 财政年份:
    2020
  • 资助金额:
    $ 52.94万
  • 项目类别:
Control of Type I Interferon Production in Response to Candida albicans
控制白色念珠菌产生的 I 型干扰素的产生
  • 批准号:
    10591418
  • 财政年份:
    2020
  • 资助金额:
    $ 52.94万
  • 项目类别:
MGH Next Generation Physician-Scientist Through Stimulating Access to Research in Residency Program (MGH-Next Gen StARR)
MGH 下一代医师科学家通过促进住院医师研究项目 (MGH-Next Gen StARR)
  • 批准号:
    10655348
  • 财政年份:
    2020
  • 资助金额:
    $ 52.94万
  • 项目类别:
Pathways to Mentorship and Research: Training the Next Generation Physician-Scientists
指导和研究途径:培训下一代医生科学家
  • 批准号:
    10226306
  • 财政年份:
    2019
  • 资助金额:
    $ 52.94万
  • 项目类别:
Pathways to Mentorship and Research: Training the Next Generation Physician-Scientists
指导和研究途径:培训下一代医生科学家
  • 批准号:
    10672162
  • 财政年份:
    2019
  • 资助金额:
    $ 52.94万
  • 项目类别:

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