Citation
Viloria Winnett, Alexander (2025) Quantitative Nucleic Acid Measurements Inform Strategies to Mitigate Viral Outbreaks. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/qe3a-a670. https://resolver.caltech.edu/CaltechTHESIS:12092024-223834150
Abstract
Humans have always been and continue to be at risk of infection by pathogens that surround us. However, recent advancements in quantitative nucleic acid technologies have allowed for more detailed study of these pathogens, how they spread among individuals, and how our immune systems respond to infection. In this thesis, I describe the design and execution of the Caltech COVID-19 Study, which used quantitative nucleic acid measurements to investigate the natural history of SARS-CoV-2 infection and inform strategies for diagnostics and vaccine development to reduce viral transmission. The Caltech COVID-19 Study enrolled participants in the Los Angeles area between September 2020 and April 2022 who were at risk of SARS-CoV-2 infection due to recent exposure to a household contact with acute infection. Participants collected paired upper respiratory specimens (saliva, nasal swabs, and throat swabs) daily or twice daily for approximately two weeks. These specimens underwent SARS-CoV-2 viral load quantification to assess transmission risk and determine whether to extend or terminate study enrollment. For participants who initially tested negative for SARS-CoV-2 RNA but later developed sustained infection, we tracked viral load from the very start of infection. These measurements were then used to evaluate the performance of various COVID-19 diagnostic tests. Our findings revealed a significant advantage of high-analytical-sensitivity tests over those with lower sensitivity, as well as the benefit of testing both the throat and nose rather than just the nose. In addition to viral load quantification, we sequenced human mRNA from these specimens to assess gene expression. Analyzing these changes allowed us to study how the mucosal immune system responds to acute viral infection across multiple anatomical sites over time, providing insights that could improve mucosal vaccine design. Notably, our data showed that, contrary to current models of localized paracrine interferon signaling, distinct compartments of the upper respiratory mucosa exhibited synchronized interferon stimulation during early infection—even in the absence of detectable local viral replication. Mucosal vaccines capable of triggering this coordinated interferon response, maintaining CD8+ T memory cells to rapidly execute effector functions upon viral exposure, may be key to achieving sterilizing immunity. Findings from quantitative nucleic acid measurements in this thesis inform strategies to more effectively mitigate viral outbreaks.
| Item Type: | Thesis (Dissertation (Ph.D.)) | ||||||||||||||||||||||||||||||||||||||||||||||||
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| Subject Keywords: | COVID-19, diagnostics, viral, load, mucosal, vaccines, antigen, outbreak, pandemic, public health, SARS-CoV-2, respiratory, infection, infectious, disease, nucleic acid, titer, | ||||||||||||||||||||||||||||||||||||||||||||||||
| Degree Grantor: | California Institute of Technology | ||||||||||||||||||||||||||||||||||||||||||||||||
| Division: | Biology and Biological Engineering | ||||||||||||||||||||||||||||||||||||||||||||||||
| Major Option: | Biology | ||||||||||||||||||||||||||||||||||||||||||||||||
| Awards: | Caltech Three Minute Thesis (3MT) competition, 2024, 2nd Place. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Thesis Availability: | Not set | ||||||||||||||||||||||||||||||||||||||||||||||||
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| Group: | 3MT Competition (Caltech) | ||||||||||||||||||||||||||||||||||||||||||||||||
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| Defense Date: | 17 September 2024 | ||||||||||||||||||||||||||||||||||||||||||||||||
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| Record Number: | CaltechTHESIS:12092024-223834150 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechTHESIS:12092024-223834150 | ||||||||||||||||||||||||||||||||||||||||||||||||
| DOI: | 10.7907/qe3a-a670 | ||||||||||||||||||||||||||||||||||||||||||||||||
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| Default Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||||||||||||||||||||||||||||||||||||||||
| ID Code: | 16912 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Collection: | CaltechTHESIS | ||||||||||||||||||||||||||||||||||||||||||||||||
| Deposited By: | Alexander Viloria Winnett | ||||||||||||||||||||||||||||||||||||||||||||||||
| Deposited On: | 16 Dec 2024 23:09 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Last Modified: | 18 Dec 2024 18:04 |
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