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

Award Number: R01GM138696
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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-a, 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $331,497 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	000	4	3/6/2024	NON-COMPETING CONTINUATION	$331,497
														Subtotal = $331,497

Issue Date FY: 2023 ( Subtotal = $368,329 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	000	3	12/16/2022	NON-COMPETING CONTINUATION	$331,497
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	001	3	3/30/2023	NON-COMPETING CONTINUATION	$36,832
														Subtotal = $368,329

Issue Date FY: 2022 ( Subtotal = $368,329 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	000	2	1/11/2022	NON-COMPETING CONTINUATION	$331,497
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	001	2	8/3/2022	NON-COMPETING CONTINUATION	$36,832
														Subtotal = $368,329

Issue Date FY: 2021 ( Subtotal = $368,329 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	000	1	3/9/2021	NEW	$368,329
														Subtotal = $368,329

Grand Total All Awards = $1,436,484

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

Award Number: R01GM138696

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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