Host-virus harmony alto at the interplay between merkel cell polyomavirus and host innate immunity Taylor Senay

Format:

Book

Thesis/Dissertation

Author/Creator:

Senay, Taylor, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology., degree granting institution.

Language:

English

Subjects (All):

Virology.

Immunology.

Cellular biology.

Pathology.

Molecular biology.

0720.

0982.

0379.

0307.

0571.

Local Subjects:

Virology.

Immunology.

Cellular biology.

Pathology.

Molecular biology.

0720.

0982.

0379.

0307.

0571.

Genre:

Academic theses

Physical Description:

1 online resource (157 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

Merkel cell polyomavirus (MCPyV) latently and asymptomatically infects the majority of adults throughout their lives. In rare instances, particularly when patients become immune-compromised, the virus can give rise to Merkel cell carcinoma (MCC), an aggressive neuroendocrine skin cancer for which there are few durable and effective therapeutic treatments available. Understanding how host cell innate immunity controls MCPyV to maintain balance with the virus, and what causes the loss of this balance prior to the development of cancer, can improve approaches to screening and prevention, particularly in the most at-risk populations. Through preliminary screening experiments, we identified the MCPyV protein ALTO as a robust stimulator of host cell STING signaling, an antiviral and antitumor pathway with significant roles in MCC. This protein was only loosely characterized, so we combined in silico analytical platforms and traditional molecular biology techniques to identify many of its fundamental characteristics, including phosphorylation status, candidate kinase interactions, and intrinsically disordered regions (IDRs). We also found that ALTO interacts with STING, Src, and TBK1 to stimulate TBK1 autophosphorylation; however, the subsequent canonical pathway steps, phosphorylation of STING and IRF3, do not occur in this scenario, indicating a TBK1-targeted effect. We next leveraged progressive N-terminal truncation of ALTO's IDR to identify a functional domain without which the protein failed to interact with and stimulate TBK1. This previously undescribed domain, which we term the Lost in Tau (LIT) domain, also acted as a dominant negative competitor for wildtype ALTO. Furthermore, an ALTO mutant with the LIT domain excluded (ALTOdelLIT) failed to interact with and stimulate TBK1 despite normal interactions with STING and Src. Finally, we found that both ALTO and ALTOdelLIT traffic through and colocalize substantially with the Golgi, the structure of which appears to be necessary for early events in ALTO-mediated TBK1 autophosphorylation, but dispensable once initial autophosphorylation is established. Taken together, these experiments shed new light on a previously under-explored viral protein with an essential role in promoting persistent viral infection by modulating host innate immunity. This work is foundational to future studies of MCPyV host innate immune modulation and understanding how host and virus promote persistent infection

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: You, Jianxin Committee members: Diab, Ahmed; Miner, Jonathan J.; Rhoades, Elizabeth; Weiss, Susan R.

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247982333

Access Restriction:

Restricted for use by site license