Role of epithelial cell intracellular trafficking in the innate immune response to adenovirus infection

上皮细胞胞内运输在腺病毒感染先天免疫反应中的作用

基本信息

  • 批准号:
    10549310
  • 负责人:
  • 金额:
    $ 36.83万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-03-10 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT The apical surface of polarized epithelium constitutes one of the first points of contact between the host and pathogens such as human adenoviruses (HAdVs) that invade the lumen of the respiratory tract. In recent years, it has become clear that respiratory epithelial cells not only serve as functional and physical barriers, but actively contribute to the innate immune system providing initial protection against external pathogens. The EGF receptor (EGFR), which typically exhibits basolateral polarity, has emerged as a key player in the innate immunity of respiratory epithelium to a variety of infectious and noninfectious noxious stimuli. In contrast to the canonical ligand-stimulated EGFR pathway, a number of cellular stresses including HAdV infection (our studies) trigger an alternative mode of EGFR trafficking associated with sustained EGFR activity in non- degradative endosomes. However, molecular mechanisms regulating this pathway remain poorly understood. In addition, despite significant progress in understanding the pathological and therapeutic stresses that activate it, relatively little is known about EGFR function in the context of cellular stress. We have recently found that stress-induced EGFR signaling is involved in innate immune responses triggered by HAdV cell entry, as well as following exposure to the pro-inflammatory cytokine TNF-α, in respiratory epithelial cells. Moreover, HAdV encodes an early gene product that suppresses this pathway by promoting EGFR degradation, and which could provide new insights to potential targets for future anti-viral therapies. Interestingly, our preliminary studies have revealed that EGFR stress responses were tightly regulated by epithelial cell polarity, with robust stress-induced EGFR responses only observed when receptors were mistargeted to apical membranes. In addition, HAdV co-opted cellular pathways contributing to innate immune signaling by enabling dynamic EGFR membrane remodeling associated with enhanced stress-induced EGFR signaling from apical membranes. The newly described EGFR innate immune system is likely to have a central role in protecting the lung from infection with HAdVs and perhaps other pathogens. Conversely, failure to curb this signaling network may lead to tissue damage, respiratory compromise, and potentially systemic HAdV infections. Our research plan will identify novel mechanisms regulating dynamic EGFR membrane remodeling in polarized epithelial cells (Aim 1), and stress-induced EGFR innate immune signaling from endosomes (Aim 2); and analyze EGFR innate immune signaling pathways that are activated as a consequence of HAdV infection in primary human respiratory epithelial cells and new physiological cells models with enhanced apical EGFR expression (Aim 3). Although our studies will be carried out in the context of HAdVs, successful completion of this project will have a broad impact on a variety of respiratory conditions in need of new therapies.
摘要

项目成果

期刊论文数量(0)
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CATHLEEN R CARLIN其他文献

CATHLEEN R CARLIN的其他文献

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{{ truncateString('CATHLEEN R CARLIN', 18)}}的其他基金

Role of epithelial cell intracellular trafficking in the innate immune response to adenovirus infection
上皮细胞胞内运输在腺病毒感染先天免疫反应中的作用
  • 批准号:
    10209611
  • 财政年份:
    2021
  • 资助金额:
    $ 36.83万
  • 项目类别:
Role of epithelial cell intracellular trafficking in the innate immune response to adenovirus infection
上皮细胞胞内运输在腺病毒感染先天免疫反应中的作用
  • 批准号:
    10368996
  • 财政年份:
    2021
  • 资助金额:
    $ 36.83万
  • 项目类别:
Modulation of Rab7-Dependent Degradative Pathways by Novel Adenovirus Protein
新型腺病毒蛋白对 Rab7 依赖性降解途径的调节
  • 批准号:
    7995957
  • 财政年份:
    2008
  • 资助金额:
    $ 36.83万
  • 项目类别:
Modulation of Rab7-Dependent Degradative Pathways by Novel Adenovirus Protein
新型腺病毒蛋白对 Rab7 依赖性降解途径的调节
  • 批准号:
    8197511
  • 财政年份:
    2008
  • 资助金额:
    $ 36.83万
  • 项目类别:
Modulation of Rab7-Dependent Degradative Pathways by Novel Adenovirus Protein
新型腺病毒蛋白对 Rab7 依赖性降解途径的调节
  • 批准号:
    7741208
  • 财政年份:
    2008
  • 资助金额:
    $ 36.83万
  • 项目类别:
Control of ErbB Receptor Sorting in Endosomes
内体中 ErbB 受体分选的控制
  • 批准号:
    6654464
  • 财政年份:
    2002
  • 资助金额:
    $ 36.83万
  • 项目类别:
Control of ErbB Receptor Sorting in Endosomes
内体中 ErbB 受体分选的控制
  • 批准号:
    6544872
  • 财政年份:
    2002
  • 资助金额:
    $ 36.83万
  • 项目类别:
Control of ErbB Receptor Sorting in Endosomes
内体中 ErbB 受体分选的控制
  • 批准号:
    6945125
  • 财政年份:
    2002
  • 资助金额:
    $ 36.83万
  • 项目类别:
MECHANISMS OF ABERRANT EGF RECEPTOR SORTING IN POLYCYSTIC KIDNEY DISEASE
多囊肾疾病中异常 EGF 受体分选的机制
  • 批准号:
    6651773
  • 财政年份:
    2002
  • 资助金额:
    $ 36.83万
  • 项目类别:
Control of ErbB Receptor Sorting in Endosomes
内体中 ErbB 受体分选的控制
  • 批准号:
    6794606
  • 财政年份:
    2002
  • 资助金额:
    $ 36.83万
  • 项目类别:

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