Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

Coronaviruses infect a diverse range of animals from birds to pigs and cats to humans. Coronaviruses employ RNA-based replicative processes and as such are genetically adaptable to acquire novel host ranges. A coronavirus from one species can jump to another by shifting its entry requirements. As we learned from the Severe Acute Respiratory Syndrome (SARS) pandemic, this shift in species can have detrimental consequences. Thus, it is imperative that we understand the virus-host interaction during the entry process.

This dissertation focuses on host entry factors that influence human coronavirus entry. Recently, a new class of proteases, the type II transmembrane serine proteases, was shown to cleave the spike glycoprotein on human coronaviruses, readying the virus for entry into the target cell. I explored the role of this protein in a cell culture mimic of the human respiratory tract, the primary site of infection. Using Calu-3 cells, I discovered that endogenous Transmembrane Protease Serine Subtype 2 is required for optimal SARS coronavirus entry. At physiological levels, this protease does not function redundantly with other known protease activators of SARS coronavirus, but rather multiple proteases may be necessary for virus entry. Additionally, this protease typically resides in a distinct cell surface microdomain from the host cellular receptor. However, viral binding triggers the relocalization of the protease to the same microdomain as the receptor, possibly allowing it to cleave the glycoprotein immediately after receptor binding.

While proteases are a key host cellular factor in coronavirus entry, there are other necessary factors. In this document, I briefly explore unknown host cellular factors that contribute to cellular cytotoxicity during another human coronavirus, Netherlands strain 63, infection. Finally, I look into how the host may protect itself from infection by stimulating a host immune response. In all, this expands our understanding of the various host factors that influence coronavirus entry.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Included in

Virology Commons

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