Identifying Host Genetic Targets for Limiting Susceptibility to Respiratory Viral Infections

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2026-06-06

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2024

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Abstract

Viral diseases present unique and severe threats to global health. Our current approach to combatting these infections is two-pronged and includes prophylactic prevention of infection by vaccination and therapeutic treatment with direct-acting antivirals. A major limitation of these approaches, however, is that highly dynamic viral populations can escape these artificial pressures. There is therefore an urgent need for durable, broadly acting solutions for managing a diverse viral reservoir. The hijacking of host machinery is fundamental to viral replication. In theory, removing critical host factors would limit the susceptibility of the host cell to viral infections. It has long been hypothesized that this type of antiviral strategy would (1) offer a high barrier of resistance against viral escape and (2) have broad-spectrum activity against highly divergent viruses of the same strain. Despite these advantages, a practical path forward for the development of host-directed antivirals has yet to be paved. Therefore, the goal of this dissertation was to identify host factors which could most readily serve as genetic targets for the development of broad-spectrum antiviral strategies. Using clinically significant respiratory viral pathogens as models, I leveraged high-throughput whole-genome CRISPR screening as a tool to identify host factors strongly required for or restrictive of viral replication. In chapter 2, I used CRISPR knockout screening to identify TMEM41B as an essential host factor for the replication of diverse human coronaviruses. I further demonstrated that TMEM41B is crucial for coronavirus-mediated membrane remodeling and the establishment of viral RNA replication. In chapter 3, I used CRISPR activation screening to identify B3GAT1 as a potent restriction factor of viruses that require sialic acid for entry. I found that overexpressing B3GAT1 efficiently restructures host cell glycosylation pathways to deplete the cell surface of sialic acid. Prophylactic delivery of B3GAT1 to the respiratory tract was ultimately sufficient to prevent lethal influenza disease in a mouse model. In chapter 4, I used parallel CRISPR knockout screening to rank host factor essentiality across diverse strains of influenza virus. I further identified conserved and strain-specific factors to inform the development of future antiviral strategies. Finally, chapter 5 discusses previous work in the field to identify consensus influenza virus host factors and presents modern tools for modulating the expression of host machinery in a clinical setting.

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Trimarco, Joseph Daniel (2024). Identifying Host Genetic Targets for Limiting Susceptibility to Respiratory Viral Infections. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/30875.

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