Date of Award

Winter 12-12-2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Richard K. Plemper

Second Advisor

Andrew T. Gewirtz

Third Advisor

Timothy L. Denning

Abstract

Innumerable future deaths and hospitalizations could be avoided through improved pandemic preparedness and the use of personalized medicine. Here, various animal models have been used to improve an understanding of the pathogenicity and therapeutic treatment potential of three viral pathogens that have a significant impact on public health: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV), and influenza virus.

Roborovski dwarf hamsters were developed as a novel animal model to study SARS-CoV-2-induced acute lower respiratory tract injury. Dwarf hamsters recapitulate the pathogenicity of SARS-CoV-2 variants of concern (VOC) and demonstrate that the effect size of molnupiravir and paxlovid-like nirmatrelvir/ritonavir is VOC-dependent. Additionally, the ferret model of upper respiratory disease was used to study human-to-human-like transmission of SARS-CoV-2 and define a therapeutic window and human effect-size equivalent dose (HESED) for the approved drugs molnupiravir and paxlovid. Therapeutic administration of molnupiravir successfully prevented contact transmission, whereas paxlovid-like nirmatrelvir/ritonavir only partially reduced upper respiratory viral shedding. Moreover, the oral prodrug of remdesivir parent GS-441524 was shown to be efficacious against SARS-CoV-2 in ferrets.

A broad-spectrum polymerase inhibitor, 4’-Fluorouridine (4’-FlU), was identified and characterized, revealing potent activity against influenza virus, RSV, and SARS-CoV-2. This pre-clinical candidate is orally available and was shown to block replication of RSV in mice and SARS-CoV-2 in ferrets. In the mouse and ferret model, 4’-FlU mitigated lethal infection with pandemic human and highly pathogenic avian influenza. 4’-FlU could overcome moderate resistance, making this candidate a promising first line defense broad-spectrum antiviral. In parallel, an allosteric orally efficacious AVG-inhibitor series, which targets a dynamic interface in the RSV polymerase, was further developed to proof-of-concept in vivo efficacy testing.

To explore a relationship between the gut microbiota and the host response to respiratory viral infections, the impact of the intestinal microbiome on influenza virus infection outcome was investigated. Colonization with segmented filamentous bacteria (SFB) in the gut stably and broadly altered the phenotype of alveolar macrophages (AM) enabling these cells to better protect their hosts from lethal respiratory viral infections. Moreover, gut microbiota-derived metabolites were discovered which conferred protection against SARS-CoV-2.

DOI

https://doi.org/10.57709/36279511

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