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Investigating the role of calcium on coronavirus membrane fusion

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2024-06-02
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Abstract

Coronaviruses (CoVs) are a diverse family of enveloped viruses responsible for causing respiratory and/or enteric diseases across a wide range of species. The expansive animal host range of CoVs can be attributed to their ability to adapt to diverse cellular environments (i.e. pH, ions, proteases, receptors), and exploit different entry pathways to mediate viral-host cell membrane fusion and infect cells. Ions have arisen as an important factor in the viral membrane fusion mechanism. Within the CoV family, our team has found that calcium availability leads to increased virus infection of cells. Previously, we observed that calcium availability also promotes insertion of SARS FP into the host cell bilayer and subsequent membrane lipid ordering, pointing to the possible role of calcium in interacting directly with the FP during CoV membrane fusion activity. Due to the highly conserved nature of the FP within the CoV family, we chose to investigate the specific binding pockets of Ca2+ within SARS- and MERS-CoV. We used site-directed mutagenesis and infectivity assays to pinpoint specific residues that lead to changes in infectivity when calcium is present or not. We identified potential calcium-binding residues by substituting the charged residues (i.e. aspartic acid, glutamic acid) in the FP with non-charged amino residue, alanine. We compared the infectivity of mutant and wild-typed CoV pseudoparticles under calcium-rich or poor environments using available FDA-approved calcium blocking drugs. Our data suggests very similar residue coordination between SARS-CoV and SARS-CoV-2 as both FPs binds to two Ca2+. Overall, these results demonstrate that Ca2+ have specific interactions with the CoV FP and opens the possibility of utilizing FDA-approved calcium blocking drugs as a potential treatment against COVID-19.

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88 pages

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2022-05

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calcium; coronavirus; fusion peptide; host-pathogen interactions; membrane fusion; viral entry

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Union Local

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Committee Chair

Daniel, Susan

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Whittaker, Gary R.
Aguilar-Carreno, Hector

Degree Discipline

Chemical Engineering

Degree Name

M.S., Chemical Engineering

Degree Level

Master of Science

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Government Document

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Attribution 4.0 International

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dissertation or thesis

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