Antivirals and mechanisms of sars-cov-2 entry in the respiratory epithelium Jorge Alberto Acuña Alzamora

Format:

Book

Thesis/Dissertation

Author/Creator:

Acuña Alzamora, Jorge Alberto, author.

Contributor:

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

Language:

English

Subjects (All):

Virology.

Molecular biology.

Pharmacology.

0720.

0307.

0419.

Local Subjects:

Virology.

Molecular biology.

Pharmacology.

0720.

0307.

0419.

Genre:

Academic theses

Physical Description:

1 online resource (158 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third and most recent pathogenic member of the Coronaviridae family to emerge in the past quarter-century. Its outbreak resulted in a global pandemic and although effective vaccines and current therapeutics can mitigate disease progression, SARS-CoV-2 continues to evolve. SARS-CoV-2 initiates infection of respiratory cells by binding to the host receptor angiotensin converting enzyme 2 (ACE2) through its Spike glycoprotein and subsequently enters cells through viral-host membrane fusion facilitated by host proteases. In cells expressing the transmembrane serine protease 2 (TMPRSS2) viral entry occurs at the plasma membrane, whereas in cells lacking TMPRSS2, viral entry occurs inside endosomal compartments. In parallel, innate immune sensors detect viral components and activate signaling pathways to mount an antiviral response. As SARS-CoV-2 continues to circulate, concerns remain for emerging resistance to therapeutics as variants develop properties of altered cell-entry mechanisms and enhanced immune evasion. Therefore, we sought to identify antivirals targeting conserved mechanisms of SARS-CoV-2 entry and determine differences in variant sensitivities to innate immune agonists. We utilized high-throughput automated microscopy coupled with genetic, pharmacological, and mechanistic assays to identify three inhibitors of SARS-CoV-2 entry in respiratory epithelial cells. Using a two-tiered approach, we screened compounds against live virus where active candidates were then tested for activity against recombinant vesicular stomatitis virus expressing SARS-CoV-2 Spike (VSV-S). We identified Staurosporine and Retro-2.1 as inhibitors targeting conserved mechanisms across both routes of viral entry. We found that PKCη and NF1 are host factors required for distinct steps of infection. Screening a diverse panel of innate immune agonists, we compared the sensitivities of ancestral SARS-CoV-2 to the Omicron BA.1 variant. Although we found similar sensitivities between both viruses, we identified short oligodeoxynucleotides (ODNs) as unique inhibitors of SARS-CoV-2 Omicron entry. We demonstrate that ODNs specifically target Omicron Spike and pretreatment in mice can reduce viral loads following infection. Altogether, these studies identify inhibitors of SARS-CoV-2 entry and uncover proviral host factors that elucidate additional mechanisms of infection. This work advances our understanding of host-pathogen interactions that may be leveraged against current and emerging coronaviruses

Notes:

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

Advisors: Cherry, Sara Committee members: Bates, Paul F.; Weiss, Susan R.; Weitzman, Matthew D.; Jurado, Kellie A.

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247979098

Access Restriction:

Restricted for use by site license