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Title: Cellular Changes Induced by Adenovirus Vaccine Vectors Expressing Foot-and-Mouth Disease Virus Structural and Nonstructural Proteins

item Moraes, Mauro
item Koster, Marla
item Zhu, James
item Grubman, Marvin

Submitted to: European Study Group on the Molecular Biology of Picornaviruses
Publication Type: Abstract Only
Publication Acceptance Date: 4/3/2008
Publication Date: 5/26/2008
Citation: Moraes, M., O'Donnell, V.K., Burrage, T.G., Pena, L., Diaz-San Segundo, F., Koster, M.J., Zhu, J., Grubman, M.J. 2008. Cellular Changes Induced by Adenovirus Vaccine Vectors Expressing Foot-and-Mouth Disease Virus Structural and Nonstructural Proteins. European Study Group on the Molecular Biology of Picornaviruses. P 203

Interpretive Summary:

Technical Abstract: Foot-and-mouth disease virus (FMDV) is the most contagious pathogen of cloven-hoofed animals including swine and bovines. The emergency control of outbreaks is dependent on rapid protection and prevention of virus spread. Adenovirus-based FMD subunit vaccines containing the coding region of viral capsid proteins (Ad5-FMD) induced early protection in susceptible animals. Recently, we demonstrated that addition of the coding region of nonstructural (NS) protein 2B improves the immune response and enhances protection of swine inoculated with an Ad5-FMD vaccine. We also observed by electron microscopy a dramatic increase in the number of small, single-membrane vesicles. In order to understand the molecular basis of the contribution of 2B, we constructed an additional Ad5 vector expressing 2B alone. By immunoelectron microscopy, we demonstrated that 2B localizes to the membranes of those vesicular structures, nuclear membrane, and endoplasmic reticulm. Using confocal microscopy, we observed a rearranged and more abundant endoplasmic reticulum marker, PDI, in transduced cells expressing 2B alone, but not in cells expressing the viral capsid proteins and 2B. Vesicular formation could be associated with an autophagy response of the transduced cells, because the expression of 2B also increased the presence of MAP1-LC-3 aggregates, a well known early autophagosome marker. To confirm this observation, we compared the production of FMDV capsid proteins in cells treated with an inhibitor (3-methyladenine) or inducer (rapamycin) of autophagy. The inhibition of autophagy reduced the expression of capsid proteins, but induction did not increase their expression without the presence of 2B. The expression of 2B with the capsid proteins induced an earlier production of damage-associated molecular patterns molecule, HSP72, compared with expression of 2B or capsid proteins alone. These results indicate that there are multiple cellular modifications that may contribute to the increased immune response to an Ad5-FMD subunit vaccine containing the 2B coding region.