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Research Project: Intervention Strategies to Control and Eradicate Foreign Animal Diseases of Swine

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Title: Classical swine fever virus structural glycoprotein E2 interacts with host protein ACADM during the virus infectious cycle

item VUONO, ELISABETH - Former ARS Employee
item Ramirez-Medina, Elizabeth
item Silva, Ediane
item BERGGREN, KEITH - Oak Ridge Institute For Science And Education (ORISE)
item RAI, AYUSHI - Oak Ridge Institute For Science And Education (ORISE)
item Espinoza, Nallely
item Gladue, Douglas
item Borca, Manuel

Submitted to: Viruses
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/13/2023
Publication Date: 4/23/2023
Citation: Vuono, E., Ramirez Medina, E., Silva, E.B., Berggren, K., Rai, A., Espinoza, N.N., Gladue, D.P., Borca, M.V. 2023. Classical swine fever virus structural glycoprotein E2 interacts with host protein ACADM during the virus infectious cycle. Viruses. 15(5).

Interpretive Summary: Classical swine fever virus (CSFV) causes a devastating disease in swine, called Classical Swine Fever (CSF), that is currently causing disease in Central and South America, Europe, and Asia and parts of Africa. Understanding the virus-host protein interactions is necessary to understand the pathogenesis of CSF and the differences in virulence between different CSFV strains. Understanding this information will advance the development of next generation vaccines and antivirals.

Technical Abstract: The E2 glycoprotein is one of the four structural proteins of the Classical Swine Fever Virus (CSFV) particle. E2 has been shown to be involved in many virus functions, including adsorption to host cells, virus virulence and interaction with several host proteins. Using a yeast two-hybrid screen, we have previously shown that the CSFV E2 specifically interacts with swine host protein medium-chain-specific acyl-Coenzyme A dehydrogenase (ACADM), an enzyme that catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Here, we show that interaction between ACADM and E2 also happens in swine cells infected with CSFV using two different procedures: coimmunoprecipitation and a proximity ligation assay (PLA). In addition, the amino acid residues in E2 critically mediating the interaction with ACADM, M49 and P130 were identified via a reverse yeast two-hybrid screen using an expression library composed of randomly mutated versions of E2. A recombinant CSFV, E2deltaACADMv, harboring substitutions at residues M49I and P130Q in E2, was developed via reverse genomics from the highly virulent Brescia isolate. E2deltaACADMv was shown to have the same kinetics growth in swine primary macrophages and SK6 cell cultures as the parental Brescia strain. Similarly, E2deltaACADMv demonstrated a similar level of virulence when inoculated to domestic pigs as the parental Brescia. Animals intranasally inoculated with 105 TCID50 developed a lethal form of clinical disease with virological and hematological kinetics changes indistinguishable from those produced by the parental strain. Therefore, interaction between CSFV E2 and host ACADM is not critically involved in the processes of virus replication and disease production.