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Epstein-Barr virus molecular pathogenesis in the nasopharynx and the role of LMP1 in lytic infection

Award Number: R01AI168022
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Epstein-Barr virus molecular pathogenesis in the nasopharynx and the role of LMP1 in lytic infection - Epstein-Barr virus (EBV) infection in the nasopharynx can be latent or lytic but EBV-associated nasopharyngeal carcinomas (NPC) are latently-infected. Lytic infection, and the failure to replicate, in response to epithelial differentiation is important to EBV pathogenesis in the nasopharynx for several reasons. EBV lytic genes promote cancer mechanisms including genome instability and the production of inflammatory cytokines. Furthermore, virus shed from lytic infection replenishes the local reservoir. Intriguingly, IgA antibodies to EBV lytic proteins are elevated in NPC patients sometimes rising years prior to the onset of NPC. The nasopharyngeal epithelium is composed of many cell types which are broadly divided into stratified epithelia and pseudostratified respiratory epithelia. The assortment of cell types in these epithelial tissues cannot be studied in 2-D culture. This gap has made it challenging to elucidate EBV molecular pathogenesis in the nasopharyngeal epithelium with any clarity. One transformative approach is the use of 3-D cell culture models. In this proposal, we demonstrate with different types of nasopharyngeal air-liquid interface (ALI) 3-D cell culture models that the EBV protein, latent membrane protein 1 (LMP1), is required for lytic induction through induced expression of the immediate-early gene (BZLF1) encoding Zebra. In this application, we will use a HK1 EBV-infected cell line reactivated in ALI culture (known as HK1-EBV ALI), and a second [de novo EBV infection] model in which primary nasopharyngeal cells are seeded in organotypic rafts (referred as nasal-rafts). Both these 3-D culture models are highly permissive in terms of lytic potential. We focus on redefining LMP1 as a virulence factor required for lytic induction, which revises the current paradigm acknowledging LMP1 as an EBV oncoprotein. The removal or inhibition of LMP1 in HK1-EBV ALI or in nasal-rafts, blunts Zebra induction. Conversely, the introduced expression of LMP1 in HK1-EBV cells produces a differentiation-dependent superlytic phenotype. Strikingly, LMP1 is one of the most divergent EBV- encoded genes but is highly conserved in NPC tumors, yet the functional significance of LMP1 sequence variation in relation to lytic infection is completely unknown. We show evidence that the LMP1 interactome is completely rewired during lytic infection. We hypothesize that LMP1 sequence variation impacts Zebra induction and this response would be dependent on the differential activation of differentiation-dependent transcription factors (TF). In this proposal, we seek to define LMP1’s mechanisms involved in the induction of Zebra through activation or induced expression of TFs in three Aims. In one Aim, we will study how LMP1 sequence variation impacts LMP1 functional genomics in relation to Zebra induction. In the other two Aims, we will use a combination of protein array and single cell RNA-sequencing methods to elucidate differentiation-dependent and LMP1-induced TFs that activate Zebra expression. This proposal is expected to shed light on the significance of LMP1 sequence evolution in regard to lytic potential and to define how rewiring of LMP1 mechanisms during lytic infection redefines LMP1 as a virulence factor.


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: 2026 ( Subtotal = $405,033 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	5	12/24/2025	NON-COMPETING CONTINUATION	$405,033
														Subtotal = $405,033

Issue Date FY: 2025 ( Subtotal = $388,255 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	4	2/13/2025	NON-COMPETING CONTINUATION	$388,255
														Subtotal = $388,255

Issue Date FY: 2024 ( Subtotal = $405,033 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	3	5/23/2024	NON-COMPETING CONTINUATION	$40,503
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	3	1/10/2024	NON-COMPETING CONTINUATION	$364,530
														Subtotal = $405,033

Issue Date FY: 2023 ( Subtotal = $478,528 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	1/17/2023	NON-COMPETING CONTINUATION	$478,528
														Subtotal = $478,528

Issue Date FY: 2022 ( Subtotal = $544,137 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	1/26/2022	NEW	$544,137
														Subtotal = $544,137

Grand Total All Awards = $2,220,986

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Epstein-Barr virus molecular pathogenesis in the nasopharynx and the role of LMP1 in lytic infection

Award Number: R01AI168022

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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