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Modeling Epstein-Barr Virus Germinal Center Infection with Tonsil Organoids

Award Number: K99DE035580
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Modeling Epstein-Barr Virus Germinal Center Infection with Tonsil Organoids - Project Summary Epstein-Barr virus (EBV) infects over 90% of United States adults through salivary transmission. Much of the EBV lifecycle takes place within the tonsils, where it establishes lifelong persistence in tonsillar B lymphocytes and transforms them by expressing a series of viral latency oncogenes. This strategy enables EBV to periodically secrete virions into the saliva for transmission to new hosts, but is also associated with a range of diseases that arise from chronic EBV infection. Acute EBV infection can cause infectious mononucleosis, which can result in life-threatening tonsil and adenoid tissue enlargement and airway compromise. Chronic EBV infection is associated with >200,000 cancer cases per year, many of which arise in the oral cavity, nasopharynx, head and neck. These include Burkitt lymphoma which can present in the face or jaw, Hodgkin lymphoma and nasopharyngeal carcinoma. Much remains to be learned about the EBV lifecycle and about EBV pathogenesis in the context of the tonsil microenvironment. However, available models do not adequately capture this important context of EBV infection. Infection of peripheral blood B lymphocytes results in immortalization into lymphoblastoid cell lines by the fully transforming viral latency III program, but do not model infection states present in tonsil and other secondary lymphoid tissues. Yet, studies of tonsil tissues highlight additional EBV-infected B cell states, including within specialized lymphoid germinal center structures, where immunoglobulin gene editing takes place and from which memory B cells arise. Memory cells are the reservoir for lifelong EBV infection, but much remains to be learned about EBV+ memory cells, as there has not been a tractable model system available with which to study them. During the initial post-doctoral fellowship, the applicant developed a novel tonsil organoid infection model of EBV infection. The model captures key elements of the tonsil EBV lifecycle, including germinal center and memory B cell EBV infection states. Our central hypothesis is that EBV infection reprograms both B cells and the tonsillar microenvironment to support latent infection and immune escape. We will test this with the following three aims: 1) Define how EBV infection programs B cell differentiation in tonsil organoids; 2) Define EBV oncogene and microenvironmental immune cell roles in tonsil B cell differentiation; 3) Elucidate latently EBV infected B cell immunoevasion mechanisms in tonsil organoids. Completion of these aims will provide key insights into how EBV navigates the tonsillar B cell compartment to establish persistent infection, with relevance to a range of diseases that arise from chronic oropharyngeal EBV infection. Collectively, these studies aim to open new avenues in EBV biology and oral immunology, potentially leading to novel therapeutic strategies. The career development plan will prepare the applicant for transitioning to an independent investigator role, employing a multidisciplinary approach to unravel the mechanisms of virus-host interactions and their implications for tonsillar and oral pathogenesis.


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 = $136,093 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	1	8/10/2026	NEW	$136,093
														Subtotal = $136,093

Grand Total All Awards = $136,093

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Modeling Epstein-Barr Virus Germinal Center Infection with Tonsil Organoids

Award Number: K99DE035580

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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